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Chen H, Lin Y, Chen J, Luo X, Kan Y, He Y, Zhu R, Jin J, Li D, Wang Y, Han Z. Targeting caspase-8: a new strategy for combating hepatocellular carcinoma. Front Immunol 2024; 15:1501659. [PMID: 39726605 PMCID: PMC11669555 DOI: 10.3389/fimmu.2024.1501659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/29/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents the most prevalent form of primary liver cancer and has a high mortality rate. Caspase-8 plays a pivotal role in an array of cellular signaling pathways and is essential for the governance of programmed cell death mechanisms, inflammatory responses, and the dynamics of the tumor microenvironment. Dysregulation of caspase-8 is intricately linked to the complex biological underpinnings of HCC. In this manuscript, we provide a comprehensive review of the regulatory roles of caspase-8 in apoptosis, necroptosis, pyroptosis, and PANoptosis, as well as its impact on inflammatory reactions and the intricate interplay with critical immune cells within the tumor microenvironment, such as tumor-associated macrophages, T cells, natural killer cells, and dendritic cells. Furthermore, we emphasize how caspase-8 plays pivotal roles in the development, progression, and drug resistance observed in HCC, and explore the potential of targeting caspase-8 as a promising strategy for HCC treatment.
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Affiliation(s)
- Haoran Chen
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Yumeng Lin
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jie Chen
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Xuemei Luo
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Yubo Kan
- Sichuan Provincial Woman’s and Children’s Hospital/The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, China
| | - Yuqi He
- Department of Blood Transfusion, Lu’an People’s Hospital, the Affiliated Hospital of Anhui Medical University, Lu’an, China
| | - Renhe Zhu
- Department of Blood Transfusion, Lu’an People’s Hospital, the Affiliated Hospital of Anhui Medical University, Lu’an, China
| | - Jiahui Jin
- Department of gastroenterology, Baoji Central Hospital, Baoji, China
| | - Dongxuan Li
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Yi Wang
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Zhongyu Han
- Department of General Surgery, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
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2
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Lecomte K, Toniolo A, Hoste E. Cell death as an architect of adult skin stem cell niches. Cell Death Differ 2024; 31:957-969. [PMID: 38649745 PMCID: PMC11303411 DOI: 10.1038/s41418-024-01297-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 04/09/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024] Open
Abstract
Our skin provides a physical and immunological barrier against dehydration and environmental insults ranging from microbial attacks, toxins and UV irradiation to wounding. Proper functioning of the skin barrier largely depends on the interplay between keratinocytes- the epithelial cells of the skin- and immune cells. Two spatially distinct populations of keratinocyte stem cells (SCs) maintain the epidermal barrier function and the hair follicle. These SCs are inherently long-lived, but cell death can occur within their niches and impacts their functionality. The default cell death programme in skin is apoptosis, an orderly and non-inflammatory suicide programme. However, recent findings are shedding light on the significance of various modes of regulated necrotic cell death, which are lytic and can provoke inflammation within the local skin environment. While the presence of dying cells was generally regarded as a mere consequence of inflammation, findings in various human dermatological conditions and experimental mouse models of aberrant cell death control demonstrated that cell death programmes in keratinocytes (KCs) can drive skin inflammation and even tumour initiation. When cells die, they need to be removed by phagocytosis and KCs can function as non-professional phagocytes of apoptotic cells with important implications for their SC capacities. It is becoming apparent that in conditions of heightened SC activity, distinct cell death modalities differentially impact the different skin SC populations in their local niches. Here, we describe how regulated cell death modalities functionally affect epidermal SC niches along with their relevance to injury repair, inflammatory skin disorders and cancer.
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Affiliation(s)
- Kim Lecomte
- VIB Center for Inflammation Research, 9052, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium
| | - Annagiada Toniolo
- VIB Center for Inflammation Research, 9052, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium
| | - Esther Hoste
- VIB Center for Inflammation Research, 9052, Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, 9052, Ghent, Belgium.
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3
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Oda H, Manthiram K, Chavan PP, Rieser E, Veli Ö, Kaya Ö, Rauch C, Nakabo S, Kuehn HS, Swart M, Wang Y, Çelik NI, Molitor A, Ziaee V, Movahedi N, Shahrooei M, Parvaneh N, Alipour-Olyei N, Carapito R, Xu Q, Preite S, Beck DB, Chae JJ, Nehrebecky M, Ombrello AK, Hoffmann P, Romeo T, Deuitch NT, Matthíasardóttir B, Mullikin J, Komarow H, Stoddard J, Niemela J, Dobbs K, Sweeney CL, Anderton H, Lawlor KE, Yoshitomi H, Yang D, Boehm M, Davis J, Mudd P, Randazzo D, Tsai WL, Gadina M, Kaplan MJ, Toguchida J, Mayer CT, Rosenzweig SD, Notarangelo LD, Iwai K, Silke J, Schwartzberg PL, Boisson B, Casanova JL, Bahram S, Rao AP, Peltzer N, Walczak H, Lalaoui N, Aksentijevich I, Kastner DL. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nat Immunol 2024; 25:764-777. [PMID: 38609546 PMCID: PMC11626442 DOI: 10.1038/s41590-024-01817-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 03/14/2024] [Indexed: 04/14/2024]
Abstract
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
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Affiliation(s)
- Hirotsugu Oda
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
- Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
| | - Kalpana Manthiram
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pallavi Pimpale Chavan
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Eva Rieser
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany
| | - Önay Veli
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Öykü Kaya
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Charles Rauch
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany
| | - Shuichiro Nakabo
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hye Sun Kuehn
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Mariël Swart
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Yanli Wang
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Nisa Ilgim Çelik
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Anne Molitor
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, CRBS, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
- Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Strasbourg, France
| | - Vahid Ziaee
- Division of Rheumatology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
- Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran
- Pediatric Rheumatology Society of Iran, Tehran, Iran
- Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran, Iran
| | - Nasim Movahedi
- Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran
- Pediatric Rheumatology Society of Iran, Tehran, Iran
- School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Shahrooei
- Clinical and Diagnostic Immunology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
- Dr. Shahrooei Lab, 22 Bahman St., Ashrafi Esfahani Blvd, Tehran, Iran
| | - Nima Parvaneh
- Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasrin Alipour-Olyei
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, CRBS, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
- Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Strasbourg, France
| | - Raphael Carapito
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, CRBS, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
- Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Strasbourg, France
- Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Qin Xu
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Silvia Preite
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David B Beck
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, NY, USA
- Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Jae Jin Chae
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michele Nehrebecky
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Amanda K Ombrello
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Patrycja Hoffmann
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tina Romeo
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Natalie T Deuitch
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - James Mullikin
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hirsh Komarow
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jennifer Stoddard
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Julie Niemela
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Kerry Dobbs
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Colin L Sweeney
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Holly Anderton
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Kate E Lawlor
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
| | - Hiroyuki Yoshitomi
- Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Dan Yang
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Manfred Boehm
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeremy Davis
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Pamela Mudd
- Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC, USA
| | - Davide Randazzo
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Wanxia Li Tsai
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Massimo Gadina
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mariana J Kaplan
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Junya Toguchida
- Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Christian T Mayer
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sergio D Rosenzweig
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Luigi D Notarangelo
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kazuhiro Iwai
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
| | - Pamela L Schwartzberg
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
- Laboratory of Human Genetics of Infectious Diseases, INSERM, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, Paris Cité University, Paris, France
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
- Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA
| | - Seiamak Bahram
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, CRBS, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
- Institut Thématique Interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Strasbourg, France
- Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | | | - Nieves Peltzer
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Department of Translational Genomics, University of Cologne, Cologne, Germany
| | - Henning Walczak
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer, and Inflammation, UCL Cancer Institute, University College, London, UK
| | - Najoua Lalaoui
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
| | - Ivona Aksentijevich
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Daniel L Kastner
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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4
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Nakano H. Necroptosis and Its Involvement in Various Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1444:129-143. [PMID: 38467977 DOI: 10.1007/978-981-99-9781-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Necroptosis is a regulated form of cell death involved in the development of various pathological conditions. In contrast to apoptosis, plasma membrane rupture (PMR) occurs in cells in the relatively early stage of necroptosis; therefore, necroptosis induces a strong inflammatory response. Stimuli, including tumor necrosis factor (TNF), interferon (IFN)α/β, lipopolysaccharide, polyI:C, and viral infection, induce the formation of necrosomes that lead to membrane rupture and the release of intracellular contents, termed danger-associated molecular patterns (DAMPs). DAMPs are the collective term for molecules that normally reside in the cytoplasm or nucleus in living cells without inducing inflammation but induce strong inflammatory responses when released outside cells. Recent studies have provided a better understanding of the mechanisms underlying PMR and the release of DAMPs. Moreover, necroptosis is involved in various pathological conditions, and mutations in necroptosis-related genes can cause hereditary autoinflammatory syndromes. Thus, manipulating necroptosis signaling pathways may be useful for treating diseases involving necroptosis.
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Affiliation(s)
- Hiroyasu Nakano
- Department of Biochemistry, Faculty of Medicine, Toho University School of Medicine, Tokyo, Japan.
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5
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Davidovich P, Higgins CA, Najda Z, Longley DB, Martin SJ. cFLIP L acts as a suppressor of TRAIL- and Fas-initiated inflammation by inhibiting assembly of caspase-8/FADD/RIPK1 NF-κB-activating complexes. Cell Rep 2023; 42:113476. [PMID: 37988267 DOI: 10.1016/j.celrep.2023.113476] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 08/16/2023] [Accepted: 11/03/2023] [Indexed: 11/23/2023] Open
Abstract
TRAIL and FasL are potent inducers of apoptosis but can also promote inflammation through assembly of cytoplasmic caspase-8/FADD/RIPK1 (FADDosome) complexes, wherein caspase-8 acts as a scaffold to drive FADD/RIPK1-mediated nuclear factor κB (NF-κB) activation. cFLIP is also recruited to FADDosomes and restricts caspase-8 activity and apoptosis, but whether cFLIP also regulates death receptor-initiated inflammation is unclear. Here, we show that silencing or deletion of cFLIP leads to robustly enhanced Fas-, TRAIL-, or TLR3-induced inflammatory cytokine production, which can be uncoupled from the effects of cFLIP on caspase-8 activation and apoptosis. Mechanistically, cFLIPL suppresses Fas- or TRAIL-initiated NF-κB activation through inhibiting the assembly of caspase-8/FADD/RIPK1 FADDosome complexes, due to the low affinity of cFLIPL for FADD. Consequently, increased cFLIPL occupancy of FADDosomes diminishes recruitment of FADD/RIPK1 to caspase-8, thereby suppressing NF-κB activation and inflammatory cytokine production downstream. Thus, cFLIP acts as a dual suppressor of apoptosis and inflammation via distinct modes of action.
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Affiliation(s)
- Pavel Davidovich
- Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Catherine A Higgins
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | - Zaneta Najda
- Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Daniel B Longley
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | - Seamus J Martin
- Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
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Xi L, Wang L, Zhang M, He C, Yang X, Pang Y, Chen H, Cheng F. TNF-R1 Cellular Nanovesicles Loaded on the Thermosensitive F-127 Hydrogel Enhance the Repair of Scalded Skin. ACS Biomater Sci Eng 2023; 9:5843-5854. [PMID: 37043416 PMCID: PMC10566511 DOI: 10.1021/acsbiomaterials.2c01257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 02/13/2023] [Indexed: 04/13/2023]
Abstract
Excessive inflammatory response after severe scalding is an important cause of delayed wound healing and is even life-threatening. Tumor necrosis factor α (TNF-α) is a key pro-inflammatory factor of skin trauma. Interacting with tumor necrosis factor receptor 1 (TNF-R1), TNF-α causes excessive inflammation and poor prognosis by activating NF-κB pathway. Antagonizing high levels of TNF-α is one of the therapeutic approaches for diseases associated with the overactivation of inflammatory responses. However, the available monoclonal antibodies are limited in their application due to their complex preparation process, high price, and the lack of cell targeting ability leading to systemic toxicity and side effects. In this study, by using a genetic bioengineering technique, we modified TNF-R1 on the cell membrane surface-derived nanovesicles (NVs). We confirmed that TNF-R1 NVs stably expressed TNF-R1 on the membrane surface and interacted with its ligand TNF-α. Furthermore, TNF-R1 NVs competitively antagonized the effect of TNF-α in the wound healing assay in vitro. In the scalded mouse model, TNF-R1 NVs were released continuously from the thermosensitive hydrogel Pluronic F-127, resulting in less inflammation and better wound healing. Our results revealed TNF-R1 NVs as promising cell-free therapeutic agents in alleviating TNF-α-mediated pro-inflammatory signaling and promoting wound repair.
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Affiliation(s)
- Lifang Xi
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
| | - Linglu Wang
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
| | - Manqi Zhang
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
| | - Chao He
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
| | - Xinrui Yang
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
| | - Yuxin Pang
- School
of Pharmacy, Guizhou University of Traditional
Chinese Medicine, Guiyang, Guizhou, 550025, China
| | - Hongbo Chen
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
| | - Fang Cheng
- School
of Pharmaceutical Sciences (Shenzhen), Shenzhen
Campus of Sun Yat-sen University, Shenzhen, China, 518107
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7
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Rayego-Mateos S, Marquez-Exposito L, Basantes P, Tejedor-Santamaria L, Sanz AB, Nguyen TQ, Goldschmeding R, Ortiz A, Ruiz-Ortega M. CCN2 Activates RIPK3, NLRP3 Inflammasome, and NRF2/Oxidative Pathways Linked to Kidney Inflammation. Antioxidants (Basel) 2023; 12:1541. [PMID: 37627536 PMCID: PMC10451214 DOI: 10.3390/antiox12081541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/27/2023] [Accepted: 07/30/2023] [Indexed: 08/27/2023] Open
Abstract
Inflammation is a key characteristic of both acute and chronic kidney diseases. Preclinical data suggest the involvement of the NLRP3/Inflammasome, receptor-interacting protein kinase-3 (RIPK3), and NRF2/oxidative pathways in the regulation of kidney inflammation. Cellular communication network factor 2 (CCN2, also called CTGF in the past) is an established fibrotic biomarker and a well-known mediator of kidney damage. CCN2 was shown to be involved in kidney damage through the regulation of proinflammatory and profibrotic responses. However, to date, the potential role of the NLRP3/RIPK3/NRF2 pathways in CCN2 actions has not been evaluated. In experimental acute kidney injury induced with folic acid in mice, CCN2 deficiency diminished renal inflammatory cell infiltration (monocytes/macrophages and T lymphocytes) as well as the upregulation of proinflammatory genes and the activation of NLRP3/Inflammasome-related components and specific cytokine products, such as IL-1β. Moreover, the NRF2/oxidative pathway was deregulated. Systemic administration of CCN2 to C57BL/6 mice induced kidney immune cell infiltration and activated the NLRP3 pathway. RIPK3 deficiency diminished the CCN2-induced renal upregulation of proinflammatory mediators and prevented NLRP3 modulation. These data suggest that CCN2 plays a fundamental role in sterile inflammation and acute kidney injury by modulating the RIKP3/NLRP3/NRF2 inflammatory pathways.
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Affiliation(s)
- Sandra Rayego-Mateos
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (S.R.-M.); (L.M.-E.); (P.B.); (L.T.-S.)
- Ricor2040, 28029 Madrid, Spain
| | - Laura Marquez-Exposito
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (S.R.-M.); (L.M.-E.); (P.B.); (L.T.-S.)
- Ricor2040, 28029 Madrid, Spain
| | - Pamela Basantes
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (S.R.-M.); (L.M.-E.); (P.B.); (L.T.-S.)
- Ricor2040, 28029 Madrid, Spain
| | - Lucia Tejedor-Santamaria
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (S.R.-M.); (L.M.-E.); (P.B.); (L.T.-S.)
- Ricor2040, 28029 Madrid, Spain
| | - Ana B. Sanz
- Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain; (A.B.S.); (A.O.)
| | - Tri Q. Nguyen
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 Utrecht, The Netherlands; (T.Q.N.); (R.G.)
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 Utrecht, The Netherlands; (T.Q.N.); (R.G.)
| | - Alberto Ortiz
- Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain; (A.B.S.); (A.O.)
| | - Marta Ruiz-Ortega
- Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain; (S.R.-M.); (L.M.-E.); (P.B.); (L.T.-S.)
- Ricor2040, 28029 Madrid, Spain
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8
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Martinez Lagunas K, Savcigil DP, Zrilic M, Carvajal Fraile C, Craxton A, Self E, Uranga-Murillo I, de Miguel D, Arias M, Willenborg S, Piekarek M, Albert MC, Nugraha K, Lisewski I, Janakova E, Igual N, Tonnus W, Hildebrandt X, Ibrahim M, Ballegeer M, Saelens X, Kueh A, Meier P, Linkermann A, Pardo J, Eming S, Walczak H, MacFarlane M, Peltzer N, Annibaldi A. Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair. SCIENCE ADVANCES 2023; 9:eadg2829. [PMID: 37494451 PMCID: PMC10371024 DOI: 10.1126/sciadv.adg2829] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/22/2023] [Indexed: 07/28/2023]
Abstract
Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, CflipD377A, exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)-induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs.
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Affiliation(s)
- Kristel Martinez Lagunas
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Deniz Pinar Savcigil
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Matea Zrilic
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Carlos Carvajal Fraile
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Andrew Craxton
- MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK
| | - Emily Self
- MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK
| | - Iratxe Uranga-Murillo
- Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain
| | - Diego de Miguel
- Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain
| | - Maykel Arias
- Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain
- Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Michael Piekarek
- Department of Dermatology, University of Cologne, 50937 Cologne, Germany
| | - Marie Christine Albert
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
- Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Kalvin Nugraha
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Ina Lisewski
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Erika Janakova
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Natalia Igual
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
| | - Wulf Tonnus
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Ximena Hildebrandt
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
- Department of Translational Genomics, University of Cologne, Weyertal 115b, 50931 Köln, Germany
| | - Mohammed Ibrahim
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
- Department of Translational Genomics, University of Cologne, Weyertal 115b, 50931 Köln, Germany
| | - Marlies Ballegeer
- VIB-UGent Center for Medical Biotechnology, VIB, B-9052 Ghent, Belgium
- Department of Biochemistry and Microbiology, Ghent University, B-9000 Ghent, Belgium
| | - Xavier Saelens
- VIB-UGent Center for Medical Biotechnology, VIB, B-9052 Ghent, Belgium
- Department of Biochemistry and Microbiology, Ghent University, B-9000 Ghent, Belgium
| | - Andrew Kueh
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
- Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Julian Pardo
- Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain
- Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain
- CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Sabine Eming
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
- Department of Dermatology, University of Cologne, 50937 Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
- Institute of Zoology, Developmental Biology Unit, University of Cologne, 50674 Cologne, Germany
| | - Henning Walczak
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
- Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany
- Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College, London WC1E 6BT, UK
| | - Marion MacFarlane
- MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK
| | - Nieves Peltzer
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
- Department of Translational Genomics, University of Cologne, Weyertal 115b, 50931 Köln, Germany
| | - Alessandro Annibaldi
- Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany
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9
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Huyghe J, Priem D, Bertrand MJM. Cell death checkpoints in the TNF pathway. Trends Immunol 2023:S1471-4906(23)00105-9. [PMID: 37357102 DOI: 10.1016/j.it.2023.05.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/19/2023] [Accepted: 05/19/2023] [Indexed: 06/27/2023]
Abstract
Tumor necrosis factor (TNF) plays a central role in orchestrating mammalian inflammatory responses. It promotes inflammation either directly by inducing inflammatory gene expression or indirectly by triggering cell death. TNF-mediated cell death-driven inflammation can be beneficial during infection by providing cell-extrinsic signals that help to mount proper immune responses. Uncontrolled cell death caused by TNF is instead highly detrimental and is believed to cause several human autoimmune diseases. Death is not the default response to TNF sensing. Molecular brakes, or cell death checkpoints, actively repress TNF cytotoxicity to protect the organism from its detrimental consequences. These checkpoints therefore constitute essential safeguards against inflammatory diseases. Recent advances in the field have revealed the existence of several new and unexpected brakes against TNF cytotoxicity and pathogenicity.
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Affiliation(s)
- Jon Huyghe
- Cell Death and Inflammation Unit, Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Dario Priem
- Cell Death and Inflammation Unit, Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Mathieu J M Bertrand
- Cell Death and Inflammation Unit, Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
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10
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Patankar JV, Bubeck M, Acera MG, Becker C. Breaking bad: necroptosis in the pathogenesis of gastrointestinal diseases. Front Immunol 2023; 14:1203903. [PMID: 37409125 PMCID: PMC10318896 DOI: 10.3389/fimmu.2023.1203903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/07/2023] [Indexed: 07/07/2023] Open
Abstract
A delicate balance between programmed cell death and proliferation of intestinal epithelial cells (IEC) exists in the gut to maintain homeostasis. Homeostatic cell death programs such as anoikis and apoptosis ensure the replacement of dead epithelia without overt immune activation. In infectious and chronic inflammatory diseases of the gut, this balance is invariably disturbed by increased levels of pathologic cell death. Pathological forms of cell death such as necroptosis trigger immune activation barrier dysfunction, and perpetuation of inflammation. A leaky and inflamed gut can thus become a cause of persistent low-grade inflammation and cell death in other organs of the gastrointestinal (GI) tract, such as the liver and the pancreas. In this review, we focus on the advances in the molecular and cellular understanding of programmed necrosis (necroptosis) in tissues of the GI tract. In this review, we will first introduce the reader to the basic molecular aspects of the necroptosis machinery and discuss the pathways leading to necroptosis in the GI system. We then highlight the clinical significance of the preclinical findings and finally evaluate the different therapeutic approaches that attempt to target necroptosis against various GI diseases. Finally, we review the recent advances in understanding the biological functions of the molecules involved in necroptosis and the potential side effects that may occur due to their systemic inhibition. This review is intended to introduce the reader to the core concepts of pathological necroptotic cell death, the signaling pathways involved, its immuno-pathological implications, and its relevance to GI diseases. Further advances in our ability to control the extent of pathological necroptosis will provide better therapeutic opportunities against currently intractable GI and other diseases.
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Affiliation(s)
- Jay V. Patankar
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Marvin Bubeck
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Miguel Gonzalez Acera
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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11
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Guo XX, Pu Q, Hu JJ, Chang XJ, Li AL, Li XY. The role of regulated necrosis in inflammation and ocular surface diseases. Exp Eye Res 2023:109537. [PMID: 37302745 DOI: 10.1016/j.exer.2023.109537] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/28/2023] [Accepted: 06/08/2023] [Indexed: 06/13/2023]
Abstract
In recent decades, numerous types of regulated cell death have been identified, including pyroptosis, ferroptosis and necroptosis. Regulated necrosis is characterized by a series of amplified inflammatory responses that result in cell death. Therefore, it has been suggested to play an essential role in the pathogenesis of ocular surface diseases. The cell morphological features and molecular mechanisms of regulated necrosis are discussed in this review. Furthermore, it summarizes the role of ocular surface diseases, such as dry eye, keratitis, and cornea alkali burn, as potential disease prevention and treatment targets.
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Affiliation(s)
- Xiao-Xiao Guo
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Qi Pu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Jing-Jie Hu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xue-Jiao Chang
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ao-Ling Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xin-Yu Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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12
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Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 2023; 30:1097-1154. [PMID: 37100955 PMCID: PMC10130819 DOI: 10.1038/s41418-023-01153-w] [Citation(s) in RCA: 150] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/28/2023] Open
Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
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Affiliation(s)
- Ilio Vitale
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Emma Guilbaud
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institut für Immunologie, Kiel University, Kiel, Germany
| | - Massimiliano Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patrizia Agostinis
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- BIOGEM, Avellino, Italy
| | - Ivano Amelio
- Division of Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - David W Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Rami I Aqeilan
- Hebrew University of Jerusalem, Lautenberg Center for Immunology & Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Jerusalem, Israel
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniele Bano
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Nickolai A Barlev
- Department of Biomedicine, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Jiri Bartek
- Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesca Bernassola
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Mathieu J M Bertrand
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Marco E Bianchi
- Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy and Ospedale San Raffaele IRCSS, Milan, Italy
| | | | - J Magarian Blander
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Carl D Bortner
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Pierluigi Bove
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patricia Boya
- Centro de Investigaciones Biologicas Margarita Salas, CSIC, Madrid, Spain
| | - Catherine Brenner
- Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques, Villejuif, France
| | - Petr Broz
- Department of Immunobiology, University of Lausanne, Epalinges, Vaud, Switzerland
| | - Thomas Brunner
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- UCL Consortium for Mitochondrial Research, London, UK
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Francesco Cecconi
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francis K-M Chan
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guo-Qiang Chen
- State Key Lab of Oncogene and its related gene, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quan Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Youhai H Chen
- Shenzhen Institute of Advanced Technology (SIAT), Shenzhen, Guangdong, China
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Aaron Ciechanover
- The Technion-Integrated Cancer Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Marcus Conrad
- Helmholtz Munich, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Mads Daugaard
- Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Ted M Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruggero De Maria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bart De Strooper
- VIB Centre for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
- The Francis Crick Institute, London, UK
- UK Dementia Research Institute at UCL, University College London, London, UK
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J Deberardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexei Degterev
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Giannino Del Sal
- Department of Life Sciences, University of Trieste, Trieste, Italy
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | | | - Marc Diederich
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - John W Elrod
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Kurt Engeland
- Molecular Oncology, University of Leipzig, Leipzig, Germany
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Carlo Ganini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
| | - Ana J Garcia-Saez
- CECAD, Institute of Genetics, University of Cologne, Cologne, Germany
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM, UMR, 1231, Dijon, France
- Faculty of Medicine, Université de Bourgogne Franche-Comté, Dijon, France
- Anti-cancer Center Georges-François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Motti Gerlic
- Department of Clinical Microbiology and Immunology, Sackler school of Medicine, Tel Aviv university, Tel Aviv, Israel
| | - Sourav Ghosh
- Department of Neurology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Hinrich Gronemeyer
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Departments of Molecular Microbiology and Immunology, Pharmacology, Oncology and Neurology, Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA
| | - Ygal Haupt
- VITTAIL Ltd, Melbourne, VIC, Australia
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Sudan He
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- National Cancer Center Research Institute, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ana Janic
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philipp J Jost
- Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Michael Karin
- Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA, USA
| | - Hamid Kashkar
- CECAD Research Center, Institute for Molecular Immunology, University of Cologne, Cologne, Germany
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Ruth Kluck
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Dagmar Kulms
- Department of Dermatology, Experimental Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, Dresden, Germany
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Sergio Lavandero
- Universidad de Chile, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
- Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Inna N Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - John J Lemasters
- Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Gianmaria Liccardi
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
| | - Richard A Lockshin
- Department of Biology, Queens College of the City University of New York, Flushing, NY, USA
- St. John's University, Jamaica, NY, USA
| | - Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Field of Excellence BioHealth - University of Graz, Graz, Austria
| | - Walter Malorni
- Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gwenola Manic
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - Jean-Christophe Marine
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Pier G Mastroberardino
- Department of Molecular Genetics, Rotterdam, the Netherlands
- IFOM-ETS The AIRC Institute for Molecular Oncology, Milan, Italy
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer, and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Ute M Moll
- Department of Pathology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Daniel J Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Dimitry Ofengeim
- Rare and Neuroscience Therapeutic Area, Sanofi, Cambridge, MA, USA
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine and Howard Hughes Medical Institute, New York, NY, USA
| | - Theocharis Panaretakis
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | | | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, YLL School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
- National University Cancer Institute, NUHS, Singapore, Singapore
- ISEP, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - Marcus E Peter
- Department of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Porta
- Center of Genomic Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | | | - Kodi S Ravichandran
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Cell Clearance, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Barak Rotblat
- Department of Life sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- The NIBN, Beer Sheva, Israel
| | - Carla V Rothlin
- Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Thomas Rudel
- Microbiology Biocentre, University of Würzburg, Würzburg, Germany
| | - Alessandro Rufini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- University of Leicester, Leicester Cancer Research Centre, Leicester, UK
| | - Kevin M Ryan
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA
- Department of Systems Biology, Lab of Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
- Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Akira Sawa
- Johns Hopkins Schizophrenia Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emre Sayan
- Faculty of Medicine, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, PR China
| | - Yufang Shi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Giuseppe S Sica
- Department of Surgical Science, University Tor Vergata, Rome, Italy
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Antonella Sistigu
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Brent R Stockwell
- Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
| | - Flavie Strapazzon
- IRCCS Fondazione Santa Lucia, Rome, Italy
- Univ Lyon, Univ Lyon 1, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyogène CNRS, INSERM, Lyon, France
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Liming Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Daolin Tang
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Carol M Troy
- Departments of Pathology & Cell Biology and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Boris Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicoletta Urbano
- Department of Oncohaematology, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Methusalem Program, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
- School of Forensic Medicine, China Medical University, Shenyang, China
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
- The Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences (OeAW), Vienna, Austria
- The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Daniela Vuri
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Achim Weber
- University of Zurich and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
- University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
| | - Will Wood
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Huang-Tian Yang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, Flushing, NY, USA
| | - Joanna E Zawacka-Pankau
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Biochemistry, Laboratory of Biophysics and p53 protein biology, Medical University of Warsaw, Warsaw, Poland
| | - Lin Zhang
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Wenzhao Zhou
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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Hoff J, Xiong L, Kammann T, Neugebauer S, Micheel JM, Gaßler N, Bauer M, Press AT. RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis. Cell Death Dis 2023; 14:275. [PMID: 37072399 PMCID: PMC10113265 DOI: 10.1038/s41419-023-05794-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/24/2023] [Accepted: 04/04/2023] [Indexed: 04/20/2023]
Abstract
Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a significant role in various liver diseases, albeit the cell-type-specific regulation of necroptosis in the liver and especially hepatocytes, has not yet been conceptualized. We demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis, the RIPK3 expression is induced in mice and humans in a cell-type-specific manner. Overexpression of RIPK3 in HepG2 cells leads to RIPK3 activation by phosphorylation and cell death, further modulated by different bile acids. Additionally, bile acids and RIPK3 activation further facilitate JNK phosphorylation, IL-8 expression, and its release. This suggests that hepatocytes suppress RIPK3 expression to protect themselves from necroptosis and cytokine release induced by bile acid and RIPK3. In chronic liver diseases associated with cholestasis, induction of RIPK3 expression may be an early event signaling danger and repair through releasing IL-8.
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Affiliation(s)
- Jessica Hoff
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Ling Xiong
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Tobias Kammann
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Sophie Neugebauer
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
- Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, 07747, Germany
| | - Julia M Micheel
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | | | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine, Nanophysiology Group, Jena University Hospital, Jena, 07747, Germany.
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07743, Germany.
- Faculty of Medicine, Friedrich Schiller University Jena, Jena, 07747, Germany.
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14
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Yan D, Wu Z, Qi X. Ferroptosis-Related Metabolic Mechanism and Nanoparticulate Anticancer Drug Delivery Systems Based on Ferroptosis. Saudi Pharm J 2023; 31:554-568. [PMID: 37063438 PMCID: PMC10102556 DOI: 10.1016/j.jsps.2023.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
Ferroptosis is a new type of cell death discovered in recent years that distinguishes from apoptosis and necrosis, mainly caused by the imbalance between the production and degradation of lipid reactive oxygen species in cells. Although the mechanism of ferroptosis is not yet clear, the phenomenon of ferroptosis has attracted widespread attention from researchers and has become a new hotspot in anti-tumor research. Studies have shown that ferroptosis is involved in the occurrence and development of a variety of diseases such as nervous system diseases, cardiovascular diseases and cancer. And inhibiting or inducing the occurrence of ferroptosis can effectively intervene in related diseases. At the same time, nanotechnology, by virtue of its distinct advantages, has been widely used in the development of nanodrug delivery systems. This review outlines current the advance on the intersection of ferroptosis and biomedical nanotechnology. In this review, the discovery and characteristics of ferroptosis, the mechanism of occurrence and the relationship with disease are summarized. More importantly, we summarized the strategies for inducing ferroptosis based on nanoparticulate drug delivery systems for cancer treatment.
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15
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Abstract
Tumour necrosis factor (TNF) is a central cytokine in inflammatory reactions, and biologics that neutralize TNF are among the most successful drugs for the treatment of chronic inflammatory and autoimmune pathologies. In recent years, it became clear that TNF drives inflammatory responses not only directly by inducing inflammatory gene expression but also indirectly by inducing cell death, instigating inflammatory immune reactions and disease development. Hence, inhibitors of cell death are being considered as a new therapy for TNF-dependent inflammatory diseases.
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16
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Rodriguez DA, Quarato G, Liedmann S, Tummers B, Zhang T, Guy C, Crawford JC, Palacios G, Pelletier S, Kalkavan H, Shaw JJP, Fitzgerald P, Chen MJ, Balachandran S, Green DR. Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis. Proc Natl Acad Sci U S A 2022; 119:e2207240119. [PMID: 36191211 PMCID: PMC9565532 DOI: 10.1073/pnas.2207240119] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
The absence of Caspase-8 or its adapter, Fas-associated death domain (FADD), results in activation of receptor interacting protein kinase-3 (RIPK3)- and mixed-lineage kinase-like (MLKL)-dependent necroptosis in vivo. Here, we show that spontaneous activation of RIPK3, phosphorylation of MLKL, and necroptosis in Caspase-8- or FADD-deficient cells was dependent on the nucleic acid sensor, Z-DNA binding protein-1 (ZBP1). We genetically engineered a mouse model by a single insertion of FLAG tag onto the N terminus of endogenous MLKL (MlklFLAG/FLAG), creating an inactive form of MLKL that permits monitoring of phosphorylated MLKL without activating necroptotic cell death. Casp8-/-MlklFLAG/FLAG mice were viable and displayed phosphorylated MLKL in a variety of tissues, together with dramatically increased expression of ZBP1 compared to Casp8+/+ mice. Studies in vitro revealed an increased expression of ZBP1 in cells lacking FADD or Caspase-8, which was suppressed by reconstitution of Caspase-8 or FADD. Ablation of ZBP1 in Casp8-/-MlklFLAG/FLAG mice suppressed spontaneous MLKL phosphorylation in vivo. ZBP1 expression and downstream activation of RIPK3 and MLKL in cells lacking Caspase-8 or FADD relied on a positive feedback mechanism requiring the nucleic acid sensors cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and TBK1 signaling pathways. Our study identifies a molecular mechanism whereby Caspase-8 and FADD suppress spontaneous necroptotic cell death.
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Affiliation(s)
- Diego A. Rodriguez
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Giovanni Quarato
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Swantje Liedmann
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Bart Tummers
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Ting Zhang
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, 19111
| | - Cliff Guy
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | | | - Gustavo Palacios
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Stephane Pelletier
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Halime Kalkavan
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Jeremy J. P. Shaw
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Patrick Fitzgerald
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Mark J. Chen
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, 19111
| | - Douglas R. Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105
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Long X, Zhu N, Qiu J, Yu X, Ruan X, Wang X, Tian L. Necroptosis in inflammatory bowel disease: A potential effective target. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:1289-1298. [PMID: 36411714 PMCID: PMC10930328 DOI: 10.11817/j.issn.1672-7347.2022.210501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Indexed: 06/16/2023]
Abstract
The morbidity of inflammatory bowel diseases (IBD) is rising rapidly but no curative therapies to prevent its recurrence. Cell death is crucial to maintaining homeostasis. Necroptosis is a newly identified programmed cell death and its roles played in IBD need to be explored. Necroptosis is mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), which resulted in cell swelling, plasma membrane rupture, intracellular content leaking, and eventually cell death as well as the promotion of inflammation. Studies have found that inhibiting necroptosis alleviated IBD in animal models and IBD patients with an increased level of necroptosis in inflammatory tissues, indicating that necroptosis is related to the pathogenesis of IBD. However, due to the complexity in regulation of necroptosis and the involvement of multiple functions of relevant signaling molecules, the specific mechanism remains elusive. Necroptosis may play a vital regulatory role in the pathogenesis of IBD, which provides a new idea and method for further exploring the therapeutic target of IBD.
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Affiliation(s)
- Xiuyan Long
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013.
| | - Ningxin Zhu
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Jianing Qiu
- Eight-Years Program of Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Xiaoyu Yu
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Xixian Ruan
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013
| | - Xiaoyan Wang
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013.
| | - Li Tian
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013.
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18
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Tisch N, Mogler C, Stojanovic A, Luck R, Korhonen EA, Ellerkmann A, Adler H, Singhal M, Schermann G, Erkert L, Patankar JV, Karakatsani A, Scherr AL, Fuchs Y, Cerwenka A, Wirtz S, Köhler BC, Augustin HG, Becker C, Schmidt T, Ruiz de Almodóvar C. Caspase-8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice. EMBO Mol Med 2022; 14:e14121. [PMID: 35491615 PMCID: PMC9174885 DOI: 10.15252/emmm.202114121] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 12/18/2022] Open
Abstract
The gut has a specific vascular barrier that controls trafficking of antigens and microbiota into the bloodstream. However, the molecular mechanisms regulating the maintenance of this vascular barrier remain elusive. Here, we identified Caspase-8 as a pro-survival factor in mature intestinal endothelial cells that is required to actively maintain vascular homeostasis in the small intestine in an organ-specific manner. In particular, we find that deletion of Caspase-8 in endothelial cells results in small intestinal hemorrhages and bowel inflammation, while all other organs remained unaffected. We also show that Caspase-8 seems to be particularly needed in lymphatic endothelial cells to maintain gut homeostasis. Our work demonstrates that endothelial cell dysfunction, leading to the breakdown of the gut-vascular barrier, is an active driver of chronic small intestinal inflammation, highlighting the role of the intestinal vasculature as a safeguard of organ function.
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Affiliation(s)
- Nathalie Tisch
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carolin Mogler
- Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Ana Stojanovic
- Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Robert Luck
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Emilia A Korhonen
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alexander Ellerkmann
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Heike Adler
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Mahak Singhal
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Géza Schermann
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Erkert
- Department of Medicine 1, Friedrich-Alexander-University, Erlangen, Germany
| | - Jay V Patankar
- Department of Medicine 1, Friedrich-Alexander-University, Erlangen, Germany
| | - Andromachi Karakatsani
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anna-Lena Scherr
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Yaron Fuchs
- Laboratory of Stem Cell Biology & Regenerative Medicine, Department of Biology, Technion -Israel Institute of Technology, Haifa, Israel
| | - Adelheid Cerwenka
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Stefan Wirtz
- Department of Medicine 1, Friedrich-Alexander-University, Erlangen, Germany
| | - Bruno Christian Köhler
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Hellmut G Augustin
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University, Erlangen, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.,Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine with University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Carmen Ruiz de Almodóvar
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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19
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Li Z, Fang J, Chen S, Liu H, Zhou J, Huang J, Liu S, Peng Y. A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs. Front Immunol 2022; 13:870264. [PMID: 35422802 PMCID: PMC9001936 DOI: 10.3389/fimmu.2022.870264] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 02/28/2022] [Indexed: 02/05/2023] Open
Abstract
Background Necroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients with hepatocellular carcinoma, and to find potentially effective drugs. Methods The three algorithms ssGSEA, EPIC, and ESTIMATE were used to quantify the immune cell infiltration of the samples, differentially expressed genes (DEGs) analysis, and weighted gene co-expression network analysis were used to screen necroptosis related genes. Variables were screened according to random survival forest analysis, and combinations with significant p-values and a low number of genes were defined as prognostic signatures by using log-rank test after gene combination. Based on the sensitivity data of PRISM and CTRP2.0 datasets, we predicted the potential therapeutic agents for high-NRS patients. Results Seven genes such as TOP2A were used to define necroptosis-related risk score (NRS). The prognostic value of risk score was further validated, where high NRS was identified as a poor prognostic factor and tended to have higher grades of histologic grade, pathologic stage, T stage, BCLC, CLIP, and higher AFP. Higher NRS was also negatively correlated with the abundance of DCs, Neutrophils, Th17 cells, Macrophages, Endothelial, and positively correlated with Th2 cells. Necroptosis is often accompanied by the release of multiple cytokines, and we found that some cytokines were significantly correlated with both NRS and immune cells, suggesting that necroptosis may affect the infiltration of immune cells through cytokines. In addition, we found that TP53 mutations were more common in samples with high NRS, and these mutations may be associated with changes in NRS. Patients with high NRS may be more sensitive to gemcitabine, and gemcitabine may be an effective drug to improve the prognosis of patients with high NRS, which may play a role by inhibiting the expression of TOP2A. Conclusions We constructed a necroptosis-related scoring model to predict OS in HCC patients, and NRS was associated with immune response, TP53 mutation, and poor clinical classification in HCC patients. In addition, gemcitabine may be an effective drug for high-NRS patients.
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Affiliation(s)
- Zedong Li
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.,Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jianyu Fang
- Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Sheng Chen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jun Zhou
- Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiangsheng Huang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Sushun Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yu Peng
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
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20
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Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia. Cell Death Differ 2022; 29:1500-1512. [PMID: 35064213 PMCID: PMC9345959 DOI: 10.1038/s41418-022-00938-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 11/08/2022] Open
Abstract
Caspase-8 is an initiator of death receptor-induced apoptosis and an inhibitor of RIPK3-MLKL-dependent necroptosis. In addition, caspase-8 has been implicated in diseases such as lymphoproliferation, immunodeficiency, and autoimmunity in humans. Although auto-cleavage is indispensable for caspase-8 activation, its physiological functions remain poorly understood. Here, we generated a caspase-8 mutant lacking E385 in auto-cleavage site knock-in mouse (Casp8ΔE385/ΔE385). Casp8ΔE385/ΔE385 cells were expectedly resistant to Fas-induced apoptosis, however, Casp8ΔE385/ΔE385 cells could switch TNF-α-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(ΔE385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably, Casp8ΔE385/ΔE385Ripk3-/- mice partially rescued the perinatal death of Ripk1-/- mice by blocking apoptosis and necroptosis. In contrast to the Casp8-/-Ripk3-/- and Casp8-/-Mlkl-/- mice appearing autoimmune lymphoproliferative syndrome (ALPS), both Casp8ΔE385/ΔE385Ripk3-/- and Casp8ΔE385/ΔE385Mlkl-/- mice developed transplantable lymphopenia that could be significantly reversed by RIPK1 heterozygosity, but not by RIPK1 kinase dead mutation. Collectively, these results demonstrate previously unappreciated roles for caspase-8 auto-cleavage in regulating necroptosis and maintaining lymphocytes homeostasis.
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21
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Standiford MM, Grund EM, Howe CL. Citrullinated myelin induces microglial TNFα and inhibits endogenous repair in the cuprizone model of demyelination. J Neuroinflammation 2021; 18:305. [PMID: 34961522 PMCID: PMC8711191 DOI: 10.1186/s12974-021-02360-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/15/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Microglia are the primary phagocytes of the central nervous system and are responsible for removing damaged myelin following demyelination. Previous investigations exploring the consequences of myelin phagocytosis on microglial activation overlooked the biochemical modifications present on myelin debris. Such modifications, including citrullination, are increased within the inflammatory environment of multiple sclerosis lesions. METHODS Mouse cortical myelin isolated by ultracentrifugation was citrullinated ex vivo by incubation with the calcium-dependent peptidyl arginine deiminase PAD2. Demyelination was induced by 6 weeks of cuprizone (0.3%) treatment and spontaneous repair was initiated by reversion to normal chow. Citrullinated or unmodified myelin was injected into the primary motor cortex above the cingulum bundle at the time of reversion to normal chow and the consequent impact on remyelination was assessed by measuring the surface area of myelin basic protein-positive fibers in the cortex 3 weeks later. Microglial responses to myelin were characterized by measuring cytokine release, assessing flow cytometric markers of microglial activation, and RNAseq profiling of transcriptional changes. RESULTS Citrullinated myelin induced a unique microglial response marked by increased tumor necrosis factor α (TNFα) production both in vitro and in vivo. This response was not induced by unmodified myelin. Injection of citrullinated myelin but not unmodified myelin into the cortex of cuprizone-demyelinated mice significantly inhibited spontaneous remyelination. Antibody-mediated neutralization of TNFα blocked this effect and restored remyelination to normal levels. CONCLUSIONS These findings highlight the role of post-translation modifications such as citrullination in the determination of microglial activation in response to myelin during demyelination. The inhibition of endogenous repair induced by citrullinated myelin and the reversal of this effect by neutralization of TNFα may have implications for therapeutic approaches to patients with inflammatory demyelinating disorders.
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Affiliation(s)
- Miranda M Standiford
- Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, 55905, USA.,Translational Neuroimmunology Lab, Mayo Clinic, Rochester, MN, 55905, USA.,Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, MA, 02142, USA
| | - Ethan M Grund
- Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, 55905, USA.,Translational Neuroimmunology Lab, Mayo Clinic, Rochester, MN, 55905, USA
| | - Charles L Howe
- Translational Neuroimmunology Lab, Mayo Clinic, Rochester, MN, 55905, USA. .,Division of Experimental Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA. .,Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
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22
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Abstract
[Figure: see text].
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Affiliation(s)
- Kim Newton
- Physiological Chemistry Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Vishva M Dixit
- Physiological Chemistry Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Nobuhiko Kayagaki
- Physiological Chemistry Department, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
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23
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Wang R, Li W, Zhang S, Song Y, Dai H, Tan T, Hu X, Xing Y. The effects of intrinsic apoptosis on cystogenesis in PKD1-deficient ADPKD pig model. Gene 2021; 798:145792. [PMID: 34175399 DOI: 10.1016/j.gene.2021.145792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Apoptosis is a form of cell death that plays a critical role in the maintenance of tissue homeostasis involving the development and elimination of unwanted cells. Dysregulation of apoptosis appears to be associated in the pathogenesis of many human diseases. Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease and is mainly caused by mutations in PKD1. Previous studies proved that increased cell death occurred in ADPKD patients and animal models. However, the role of apoptosis in kidney cystogenesis is not clear. METHODS In current study, due to the high similarities between human and pig, PKD1-deficient (PKD1+/-) pigs and PKD1-knockdown (PKD1KD) pig kidney epithelial cells were used to investigate the mechanisms of apoptosis in driving cystogenesis. RESULTS In PKD1+/- pigs, increased intrinsic and extrinsic apoptosis were found at ages of 1 month and 3 months, whereas the autophagy and pyroptosis were not altered. Meanwhile, the intrinsic apoptosis was activated along with untouched extrinsic apoptosis in PKD1KD pig kidney cells. Thus, the intrinsic apoptosis played important roles in cystogenesis. CONCLUSIONS This work provides detail analysis of the roles of different cell death types during cystogenesis in ADPKD pig model. The results suggested a potential new strategy for the diagnosis and treatment of ADPKD by targeting intrinsic apoptosis.
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Affiliation(s)
- Runming Wang
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China
| | - Wenya Li
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China
| | - Suhong Zhang
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China
| | - Ya Song
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China
| | - Haiting Dai
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China
| | - Tan Tan
- College of Animal Science and Technology, China Agricultural University, Beijing, PR China
| | - Xiaoxiang Hu
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China; National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, PR China
| | - Yiming Xing
- College of Biological Sciences, State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing, PR China.
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Liu D, Wu H, Li YZ, Yang J, Yang J, Ding JW, Zhou G, Zhang J, Wang X, Fan ZX. Cellular FADD-like IL-1β-converting enzyme-inhibitory protein attenuates myocardial ischemia/reperfusion injury via suppressing apoptosis and autophagy simultaneously. Nutr Metab Cardiovasc Dis 2021; 31:1916-1928. [PMID: 33895078 DOI: 10.1016/j.numecd.2021.02.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 02/14/2021] [Accepted: 02/22/2021] [Indexed: 01/25/2023]
Abstract
BACKGROUND AND AIMS Myocardial ischemia/reperfusion injury (MI/RI) is a result of coronary revascularization, and often increases cell apoptosis and autophagy. Downregulated cellular FADD-like-IL-1β-converting enzyme-inhibitory protein (cFLIP) was associated with development of several myocardial diseases, whether overexpression of cFLIP can attenuate MI/RI remains unclear. This study aimed to determine the effects of cFLIP on apoptosis and autophagy in MI/RI. METHODS AND RESULTS Ischemia/reperfusion (I/R) rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. Both I/R injury and H/R injury down-regulated expression of two cFLIP isoforms (cFLIPL and cFLIPS), and instigated apoptosis and autophagy simultaneously. Overexpression of cFLIPL and/or cFLIPS led to a significant increase in cardiomyocytes viability in vitro, and also reduced the myocardial infarct volume in vivo, these changes were associated with suppressed apoptosis and autophagy. Mechanistically, overexpression of cFLIP significantly downregulated pro-apoptotic molecules (Caspase-3, -8, -9), and pro-autophagic molecules (Beclin-1 and LC3-II). Moreover, cFLIP significantly suppressed activity of NF-κB pathway to upregulate the expression of Bcl-2, which is the molecular of interplay of apoptosis and autophagy. CONCLUSION Overexpression of cFLIP significantly attenuated MI/RI both in vivo and vitro via suppression of apoptosis and lethal autophagy. cFLIP can suppress activity of NF-κB pathway, and further upregulated expression of Bcl-2.
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Affiliation(s)
- Di Liu
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Hui Wu
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China.
| | - Yun Zhao Li
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Jun Yang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Jian Yang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
| | - Jia Wang Ding
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Gang Zhou
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Jing Zhang
- Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China; Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
| | - Xin'an Wang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China; Department of Cardiology, Yichang Central People's Hospital, Yichang, 443003, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Zhi Xing Fan
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
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Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate. Nat Commun 2021; 12:819. [PMID: 33547302 PMCID: PMC7864959 DOI: 10.1038/s41467-020-20806-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/18/2020] [Indexed: 11/17/2022] Open
Abstract
Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome. The core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP, coordinate cell fate. Here authors present the structure of full-length procaspase-8 in a complex with FADD and reveal how recruitment of c-FLIPS into this complex inhibits Caspase-8 activity.
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Zhou M, He J, Shi Y, Liu X, Luo S, Cheng C, Ge W, Qu C, Du P, Chen Y. ABIN3 Negatively Regulates Necroptosis-induced Intestinal Inflammation Through Recruiting A20 and Restricting the Ubiquitination of RIPK3 in Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:99-114. [PMID: 32599618 DOI: 10.1093/ecco-jcc/jjaa131] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS There is evidence for a disturbed necroptosis function in many inflammatory diseases, but its role in inflammatory bowel diseases [IBD] and the underlying mechanisms are unclear. Here, we studied the functional significance and molecular mechanisms of ABIN3, a ubiquitin-binding protein, in regulating the ubiquitination and activation of necroptosis in IBD. METHODS The expression of necroptosis hallmarks and ABIN3 were assessed in inflamed samples of IBD patients, dextran sodium sulphate [DSS]-induced colitis models, and azoxymethane [AOM]/DSS models in mice. ABIN3 was overexpressed and silenced to explore its function in regulating necroptosis, inflammation, and intestinal barrier function. Immuoprecipitiation [IP] and co-IP assays were performed to investigate the cross-talk between ABIN3 and deubiquitinating enzyme A20, and the mechanisms of coordinating ubiquitination modification to regulate necroptosis. RESULTS Excessive necroptosis is an important contributory factor towards the uncontrolled inflammation and intestinal barrier defects in IBD and experimental colitis. Blocking necroptosis by Nec-1s or GSK'872 significantly prevented cell death and alleviated DSS-induced colitis in vivo, whereas in the AOM/DSS model, necroptosis inhibitors aggravated the severity of colitis-associated colon carcinogenesis [CAC]. Mechanistically, ABIN3 is rapidly recruited to the TNF-RSC complex, which interacts and coordinates with deubiquitinating enzyme A20 to control the K63 deubiquitination modification and subsequent activation of the critical necroptosis kinase, RIPK3, to suppress necroptosis. CONCLUSIONS ABIN3 regulates inflammatory response and intestinal barrier function by interacting with A20 and coordinating the K63 deubiquitination modification of necroptosis in IBD.
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Affiliation(s)
- Mingxia Zhou
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jing He
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yingying Shi
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xiaoman Liu
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Shangjian Luo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Cheng Cheng
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wensong Ge
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunying Qu
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingwei Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
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Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inflammation. Mucosal Immunol 2021; 14:1160-1171. [PMID: 34045680 PMCID: PMC8379077 DOI: 10.1038/s41385-021-00415-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 05/02/2021] [Accepted: 05/06/2021] [Indexed: 02/04/2023]
Abstract
Regulation of epithelial cell death has emerged as a key mechanism controlling immune homeostasis in barrier surfaces. Necroptosis is a type of regulated necrotic cell death induced by receptor interacting protein kinase 3 (RIPK3) that has been shown to cause inflammatory pathologies in different tissues. The role of regulated cell death and particularly necroptosis in lung homeostasis and disease remains poorly understood. Here we show that mice with Airway Epithelial Cell (AEC)-specific deficiency of Fas-associated with death domain (FADD), an adapter essential for caspase-8 activation, developed exacerbated allergic airway inflammation in a mouse model of asthma induced by sensitization and challenge with house dust mite (HDM) extracts. Genetic inhibition of RIPK1 kinase activity by crossing to mice expressing kinase inactive RIPK1 as well as RIPK3 or MLKL deficiency prevented the development of exaggerated HDM-induced asthma pathology in FADDAEC-KO mice, suggesting that necroptosis of FADD-deficient AECs augmented the allergic immune response. These results reveal a role of AEC necroptosis in amplifying airway allergic inflammation and suggest that necroptosis could contribute to asthma exacerbations caused by respiratory virus infections inducing AEC death.
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28
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Zanetti LC, Weinlich R. Necroptosis, the Other Main Caspase-Independent Cell Death. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1301:123-138. [PMID: 34370290 DOI: 10.1007/978-3-030-62026-4_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The past decades witnessed the discovery of novel modes of cell death, such as ferroptosis, pyroptosis and necroptosis, all of them presenting common necrotic traits. In this chapter, we revisit the early discoveries that unveiled necroptosis as a distinct cell death mechanism. We describe necroptosis, its main regulators and their role in maintaining cellular homeostasis and in the disease state. We conclude by discussing its phenotypic similarities with ferroptosis and the possible crosstalk between these pathways.
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Affiliation(s)
- Larissa C Zanetti
- Hospital Israelita Albert Einstein. Av. Albert Einstein, São Paulo, SP, Brazil.
| | - Ricardo Weinlich
- Hospital Israelita Albert Einstein. Av. Albert Einstein, São Paulo, SP, Brazil
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29
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Feoktistova M, Makarov R, Leverkus M, Yazdi AS, Panayotova-Dimitrova D. TNF Is Partially Required for Cell-Death-Triggered Skin Inflammation upon Acute Loss of cFLIP. Int J Mol Sci 2020; 21:ijms21228859. [PMID: 33238518 PMCID: PMC7700656 DOI: 10.3390/ijms21228859] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 11/30/2022] Open
Abstract
cFLIP is required for epidermal integrity and skin inflammation silencing via protection from TNF-induced keratinocyte apoptosis. Here, we generated and analyzed cFLIP epidermal KO mice with additional TNF deficiency. Intriguingly, the ablation of TNF rescued the pathological phenotype of epidermal cFLIP KO from characteristic weight loss and increased mortality. Moreover, the lack of TNF in these animals strongly reduced and delayed the epidermal hyperkeratosis and the increased apoptosis in keratinocytes. Our data demonstrate that TNF signaling in cFLIP-deficient keratinocytes is the critical factor for the regulation of skin inflammation via modulated cytokine and chemokine expression and, thus, the attraction of immune cells. Our data suggest that autocrine TNF loop activation upon cFLIP deletion is dispensable for T cells, but is critical for neutrophil attraction. Our findings provide evidence for a negative regulatory role of cFLIP for TNF-dependent apoptosis and partially for epidermal inflammation. However, alternative signaling pathways may contribute to the development of the dramatic skin disease upon cFLIP deletion. Our data warrant future studies of the regulatory mechanism controlling the development of skin disease upon cFLIP deficiency and the role of cFLIP/TNF in a number of inflammatory skin diseases, including toxic epidermal necrolysis (TEN).
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30
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Weir A, Hughes S, Rashidi M, Hildebrand JM, Vince JE. Necroptotic movers and shakers: cell types, inflammatory drivers and diseases. Curr Opin Immunol 2020; 68:83-97. [PMID: 33160107 DOI: 10.1016/j.coi.2020.09.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
The necroptotic cell death pathway has received significant attention for its ability to trigger inflammatory responses and its potential involvement in related conditions. Recent insights into the essential membrane damaging necroptotic pseudokinase effector, Mixed lineage kinase domain like (MLKL), have revealed a number of diverse MLKL functions that contribute to the inflammatory nature of necroptosis. Here we review distinct MLKL signalling roles and document the immunogenic molecules released by necroptosis. We discuss specific in vivo MLKL-driven responses, the activation of inflammasome complexes and innate lymphoid cells, which have been documented to drive disease. Finally, we list necroptotic competent cell types and their involvement in MLKL-driven cell death-associated and inflammatory-associated conditions.
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Affiliation(s)
- Ashley Weir
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Sebastian Hughes
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Maryam Rashidi
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Joanne M Hildebrand
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
| | - James E Vince
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
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31
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Schwarzer R, Jiao H, Wachsmuth L, Tresch A, Pasparakis M. FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells. Immunity 2020; 52:978-993.e6. [PMID: 32362323 DOI: 10.1016/j.immuni.2020.04.002] [Citation(s) in RCA: 185] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/29/2020] [Accepted: 04/08/2020] [Indexed: 12/24/2022]
Abstract
Pathways controlling intestinal epithelial cell (IEC) death regulate gut immune homeostasis and contribute to the pathogenesis of inflammatory bowel diseases. Here, we show that caspase-8 and its adapter FADD act in IECs to regulate intestinal inflammation downstream of Z-DNA binding protein 1 (ZBP1)- and tumor necrosis factor receptor-1 (TNFR1)-mediated receptor interacting protein kinase 1 (RIPK1) and RIPK3 signaling. Mice with IEC-specific FADD or caspase-8 deficiency developed colitis dependent on mixed lineage kinase-like (MLKL)-mediated epithelial cell necroptosis. However, MLKL deficiency fully prevented ileitis caused by epithelial caspase-8 ablation, but only partially ameliorated ileitis in mice lacking FADD in IECs. Our genetic studies revealed that caspase-8 and gasdermin-D (GSDMD) were both required for the development of MLKL-independent ileitis in mice with epithelial FADD deficiency. Therefore, FADD prevents intestinal inflammation downstream of ZBP1 and TNFR1 by inhibiting both MLKL-induced necroptosis and caspase-8-GSDMD-dependent pyroptosis-like death of epithelial cells.
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Affiliation(s)
- Robin Schwarzer
- Institute for Genetics, University of Cologne, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany
| | - Huipeng Jiao
- Institute for Genetics, University of Cologne, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany
| | - Laurens Wachsmuth
- Institute for Genetics, University of Cologne, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany
| | - Achim Tresch
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany; Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Bachemer Str. 86, Cologne 50931, Germany; Center for Data and Simulation Science (CDS), University of Cologne, Cologne, Germany
| | - Manolis Pasparakis
- Institute for Genetics, University of Cologne, Cologne 50674, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne 50931, Germany.
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32
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Ishii S, Yamada M, Koibuchi N. Chicken ovalbumin upstream promoter-transcription factor II protects against cisplatin-induced acute kidney injury. Endocr J 2020; 67:283-293. [PMID: 31801919 DOI: 10.1507/endocrj.ej19-0459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays essential roles in organogenesis of embryos. Recently COUP-TFII is also implicated in several diseases in adults. Here we focus on the role of COUP-TFII in cisplatin-induced acute kidney injury (AKI). COUP-TFII was the most abundantly expressed in the kidney among organs. Male tamoxifen-inducible COUP-TFII-knockout mice or control mice were intraperitoneally treated with 30 mg/kg body weight of cisplatin at 12 weeks old to induce AKI. The kidney samples were subject to morphological studies, terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling (TUNEL) assay, immunohistochemistry and RT-qPCR. Serum levels of creatinine, blood urea nitrogen (BUN) and tumor necrosis factor alpha (TNF-α) were measured. Administration of cisplatin induced a more severe AKI in adult COUP-TFII-knockout mice. An increase in dead cells in both the proximal tubules and thick ascending limb of Henle's loop (TAL) was observed in the knockout mouse kidney. The expression levels of COUP-TFII decreased in the TAL by cisplatin administration. There was no difference in the expression levels of transporter mRNAs responsible for cellular cisplatin uptake between control and knockout mouse kidney. COUP-TFII-knockout mice and COUP-TFII-depleted cells exhibited an elevation in TNF-α levels, suggesting the involvement of the TNF-α pathway. Chromatin immunoprecipitation showed that COUP-TFII was enriched in the potential binding site, suggesting that COUP-TFII might directly suppress the TNF-α gene at transcriptional level. These results indicate the involvement of COUP-TFII in the pathophysiology of AKI and COUP-TFII may be a potential therapeutic target for AKI.
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Affiliation(s)
- Sumiyasu Ishii
- Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Masanobu Yamada
- Department of Internal Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Noriyuki Koibuchi
- Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
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Heib M, Rose-John S, Adam D. Necroptosis, ADAM proteases and intestinal (dys)function. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 353:83-152. [PMID: 32381179 DOI: 10.1016/bs.ircmb.2020.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Recently, an unexpected connection between necroptosis and members of the a disintegrin and metalloproteinase (ADAM) protease family has been reported. Necroptosis represents an important cell death routine which helps to protect from viral, bacterial, fungal and parasitic infections, maintains adult T cell homeostasis and contributes to the elimination of potentially defective organisms before parturition. Equally important for organismal homeostasis, ADAM proteases control cellular processes such as development and differentiation, immune responses or tissue regeneration. Notably, necroptosis as well as ADAM proteases have been implicated in the control of inflammatory responses in the intestine. In this review, we therefore provide an overview of the physiology and pathophysiology of necroptosis, ADAM proteases and intestinal (dys)function, discuss the contribution of necroptosis and ADAMs to intestinal (dys)function, and review the current knowledge on the role of ADAMs in necroptotic signaling.
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Affiliation(s)
- Michelle Heib
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Dieter Adam
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
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Miller DR, Cramer SD, Thorburn A. The interplay of autophagy and non-apoptotic cell death pathways. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 352:159-187. [PMID: 32334815 DOI: 10.1016/bs.ircmb.2019.12.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autophagy, the process of macromolecular degradation through the lysosome, has been extensively studied for the past decade or two. Autophagy can regulate cell death, especially apoptosis, through selective degradation of both positive and negative apoptosis regulators. However, multiple other programmed cell death pathways exist. As knowledge of these other types of cell death expand, it has been suggested that they also interact with autophagy. In this review, we discuss the molecular mechanisms that comprise three non-apoptotic forms of cell death (necroptosis, pyroptosis and ferroptosis) focusing on how the autophagy machinery regulates these different cell death mechanisms through (i) its degradative functions, i.e., true autophagy, and (ii) other non-degradative functions of the autophagy machinery such as serving as a signaling scaffold or by participating in other autophagy-independent cellular processes.
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Affiliation(s)
- Dannah R Miller
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Scott D Cramer
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Andrew Thorburn
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
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35
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Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 2019; 20:19-33. [PMID: 30467385 DOI: 10.1038/s41583-018-0093-1] [Citation(s) in RCA: 612] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
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Affiliation(s)
- Junying Yuan
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
| | - Palak Amin
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
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Tabrez S, Jabir NR, Khan MI, Khan MS, Shakil S, Siddiqui AN, Zaidi SK, Ahmed BA, Kamal MA. Association of autoimmunity and cancer: An emphasis on proteolytic enzymes. Semin Cancer Biol 2019; 64:19-28. [PMID: 31100322 DOI: 10.1016/j.semcancer.2019.05.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 12/24/2022]
Abstract
Cancer and autoimmune diseases are the two devastating conditions that together constitute a leading health problem worldwide. The rising burden of these disorders in the developing world demands a multifaceted approach to address the challenges it poses. Understanding the root causes and specific molecular mechanisms by which the progression of the diseases takes place is need of the hour. A strong inflammatory background and common developmental pathways, such as activation of immune cells, proliferation, increased cell survival and migration which are controlled by growth factors and inflammatory cytokines have been considered as the critical culprits in the progression and complications of these disorders. Enzymes are the potential immune modulators which regulate various inflammatory events and can break the circulating immune complexes via macrophages production. In the current manuscript, we have uncovered the possible role of proteolytic enzymes in the pathogenesis and progression of cancer and autoimmune diseases. In the light of the available scientific literature, we advocate in-depth comprehensive studies which will shed light towards the role of proteolytic enzymes in the modulation of inflammatory responses in cancer and autoimmune diseases together.
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Affiliation(s)
- Shams Tabrez
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Nasimudeen R Jabir
- Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, India
| | - Mohammad Imran Khan
- Protein Research Chair, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohd Shahnawaz Khan
- Protein Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Shazi Shakil
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | | | - Syed Kashif Zaidi
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Bakrudeen Ali Ahmed
- Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, India
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
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D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43:582-592. [PMID: 30958602 DOI: 10.1002/cbin.11137] [Citation(s) in RCA: 1387] [Impact Index Per Article: 231.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 03/11/2019] [Accepted: 03/23/2019] [Indexed: 12/16/2022]
Abstract
Cell death was once believed to be the result of one of two distinct processes, apoptosis (also known as programmed cell death) or necrosis (uncontrolled cell death); in recent years, however, several other forms of cell death have been discovered highlighting that a cell can die via a number of differing pathways. Apoptosis is characterised by a number of characteristic morphological changes in the structure of the cell, together with a number of enzyme-dependent biochemical processes. The result being the clearance of cells from the body, with minimal damage to surrounding tissues. Necrosis, however, is generally characterised to be the uncontrolled death of the cell, usually following a severe insult, resulting in spillage of the contents of the cell into surrounding tissues and subsequent damage thereof. Failure of apoptosis and the resultant accumulation of damaged cells in the body can result in various forms of cancer. An understanding of the pathways is therefore important in developing efficient chemotherapeutics. It has recently become clear that there exists a number of subtypes of apoptosis and that there is an overlap between apoptosis, necrosis and autophagy. The goal of this review is to provide a general overview of the current knowledge relating to the various forms of cell death, including apoptosis, necrosis, oncosis, pyroptosis and autophagy. This will provide researchers with a summary of the major forms of cell death and allow them to compare and contrast between them.
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Affiliation(s)
- Mark S D'Arcy
- Hertfordshire International College (HIC), Collage Lane, Hatfield, AL10 9AB, UK
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Ghanekar Y, Sadasivam S. In silico analysis reveals a shared immune signature in CASP8-mutated carcinomas with varying correlations to prognosis. PeerJ 2019; 7:e6402. [PMID: 30775178 PMCID: PMC6375258 DOI: 10.7717/peerj.6402] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/07/2019] [Indexed: 12/25/2022] Open
Abstract
Background Sequencing studies across multiple cancers continue to reveal mutations and genes involved in the pathobiology of these cancers. Exome sequencing of oral cancers, a subset of Head and Neck Squamous cell Carcinomas (HNSCs) common among tobacco-chewing populations, revealed that ∼34% of the affected patients harbor mutations in the CASP8 gene. Uterine Corpus Endometrial Carcinoma (UCEC) is another cancer where ∼10% cases harbor CASP8 mutations. Caspase-8, the protease encoded by CASP8 gene, plays a dual role in programmed cell death, which in turn has an important role in tumor cell death and drug resistance. CASP8 is a protease required for the extrinsic pathway of apoptosis and is also a negative regulator of necroptosis. Using multiple tools such as differential gene expression, gene set enrichment, gene ontology, in silico immune cell estimates, and survival analyses to mine data in The Cancer Genome Atlas, we compared the molecular features and survival of these carcinomas with and without CASP8 mutations. Results Differential gene expression followed by gene set enrichment analysis showed that HNSCs with CASP8 mutations displayed a prominent signature of genes involved in immune response and inflammation. Analysis of abundance estimates of immune cells in these tumors further revealed that mutant-CASP8 HNSCs were rich in immune cell infiltrates. However, in contrast to Human Papilloma Virus-positive HNSCs that also exhibit high immune cell infiltration, which in turn is correlated with better overall survival, HNSC patients with mutant-CASP8 tumors did not display any survival advantage. Similar analyses of UCECs revealed that while UCECs with CASP8 mutations also displayed an immune signature, they had better overall survival, in contrast to the HNSC scenario. There was also a significant up-regulation of neutrophils (p-value = 0.0001638) as well as high levels of IL33 mRNA (p-value = 7.63747E-08) in mutant-CASP8 HNSCs, which were not observed in mutant-CASP8 UCECs. Conclusions These results suggested that carcinomas with mutant CASP8 have broadly similar immune signatures albeit with different effects on survival. We hypothesize that subtle tissue-dependent differences could influence survival by modifying the micro-environment of mutant-CASP8 carcinomas. High neutrophil numbers, a well-known negative prognosticator in HNSCs, and/or high IL33 levels may be some of the factors affecting survival of mutant-CASP8 cases.
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Affiliation(s)
| | - Subhashini Sadasivam
- DeepSeeq Bioinformatics, Bangalore, Karnataka, India.,Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, India
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Zhang J, Qin D, Yang YJ, Hu GQ, Qin XX, Du CT, Chen W. MLKL deficiency inhibits DSS-induced colitis independent of intestinal microbiota. Mol Immunol 2019; 107:132-141. [PMID: 30738250 DOI: 10.1016/j.molimm.2019.01.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/28/2019] [Accepted: 01/28/2019] [Indexed: 12/11/2022]
Abstract
The maintenance of intestinal tissue homeostasis is vital for the resistance against inflammatory bowel diseases (IBDs). Necroptosis is identified as an alternative mode of regulated cell death, which plays a pivotal role in tissue homeostasis. Thus, the roles of RIP3-mediated necroptosis in intestinal inflammation have been extensively studied. However, the biological implications of the mixed lineage kinase-like protein (MLKL), a molecule downstream of RIP3 in gut remain unclear. In this study, the role of MLKL in DSS-induced colitis was examined, and the contribution of gut microbiota was also determined. Compared with non-littermate WT mice, the survival rate, clinical score, intestinal damage and intestinal mucosal barrier integrity of non-littermate MLKL-deficient mice are significantly improved. MLKL deficiency prevents inflammatory cytokines production and MAPK signaling activation. Hence, MLKL deficiency inhibits DSS-induced colitis. Moreover, we proved that DSS susceptibility difference between two genotypes is not driven by intestinal microbiota based on the co-housing of two non-littermate genotypes and qPCR detection of fecal dominant bacterial taxa.
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Affiliation(s)
- Jie Zhang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Di Qin
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yong-Jun Yang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Gui-Qiu Hu
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xiao-Xia Qin
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Chong-Tao Du
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wei Chen
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
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Li S, Ning LG, Lou XH, Xu GQ. Necroptosis in inflammatory bowel disease and other intestinal diseases. World J Clin Cases 2018; 6:745-752. [PMID: 30510938 PMCID: PMC6265005 DOI: 10.12998/wjcc.v6.i14.745] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 10/18/2018] [Accepted: 10/31/2018] [Indexed: 02/05/2023] Open
Abstract
For a long time, it was believed that apoptosis and necrosis were the main pathways for cell death, but a growing body of research has shown that there are other pathways. Among these, necroptosis, a regulatory caspase-independent, programmed cell death pathway, is supposed to be of importance in the pathogenesis of many diseases. The mechanism of regulating, inducing and blocking necroptosis is a complex process that involves expression and regulation of a series of molecules including receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase like protein. By blocking or downregulating expression of key molecules in the necroptotic pathway, intestinal inflammation can be affected to some extent. In this paper, we introduce the concept of necroptosis, its main pathway, and its impact on the pathogenesis of inflammatory bowel disease (IBD) and other intestinal diseases, to explore new drug targets for intestinal diseases, including IBD.
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Affiliation(s)
- Sha Li
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Long-Gui Ning
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xin-He Lou
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Guo-Qiang Xu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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Tang Y, Joo D, Liu G, Tu H, You J, Jin J, Zhao X, Hung MC, Lin X. Linear ubiquitination of cFLIP induced by LUBAC contributes to TNFα-induced apoptosis. J Biol Chem 2018; 293:20062-20072. [PMID: 30361438 DOI: 10.1074/jbc.ra118.005449] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/14/2018] [Indexed: 12/17/2022] Open
Abstract
The linear ubiquitin chain assembly complex (LUBAC) regulates NF-κB activation by modifying proteins with linear (M1-linked) ubiquitination chains. Although LUBAC also regulates the apoptosis pathway, the precise mechanism by which LUBAC regulates apoptosis remains not fully defined. Here, we report that LUBAC-mediated M1-linked ubiquitination of cellular FLICE-like inhibitory protein (cFLIP), an anti-apoptotic molecule, contributes to tumor necrosis factor (TNF) α-induced apoptosis. We found that deficiency of RNF31, the catalytic subunit of the LUBAC complex, promoted cFLIP degradation in a proteasome-dependent manner. Moreover, we observed RNF31 directly interact with cFLIP, and LUBAC further conjugated M1-linked ubiquitination chains at Lys-351 and Lys-353 of cFLIP to stabilize cFLIP, thereby protecting cells from TNFα-induced apoptosis. Together, our study identifies a new substrate of LUBAC and reveals a new molecular mechanism through which LUBAC regulates TNFα-induced apoptosis via M1-linked ubiquitination.
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Affiliation(s)
- Yong Tang
- From the Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China
| | - Donghyun Joo
- the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, and
| | - Guangna Liu
- From the Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China
| | - Hailin Tu
- From the Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China
| | - Jeffrey You
- the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, and
| | - Jianping Jin
- the Life Science Institute, Zhejiang University, Hangzhou 310058, China
| | - Xueqiang Zhao
- From the Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China
| | - Mien-Chie Hung
- the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, and
| | - Xin Lin
- From the Institute for Immunology, Tsinghua University School of Medicine, Beijing 100084, China,.
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Janke LJ, Ward JM, Vogel P. Classification, Scoring, and Quantification of Cell Death in Tissue Sections. Vet Pathol 2018; 56:33-38. [DOI: 10.1177/0300985818800026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The analysis and description of the appearance of cell death in tissue sections can add valuable information to research studies. The scoring/grading and quantification of cell death can be used either as part of a larger scoring scheme or as the final end point of a study. The degree of precision needed is study dependent and will be determined by the question being addressed and the complexity of the model. The methods one uses to quantify cell death are often guided by the tissue of interest. For example, in the brain, it is sometimes necessary to examine death of specific neuronal populations, whereas in more homogeneous tissue such as a tumor xenograft, quantification can be done on a whole-slide basis. In addition to examination of hematoxylin and eosin (HE)–stained sections, immunohistochemistry can be employed to highlight areas of cell death or to identify specific types of cell death, for example, when differentiating apoptosis from necrosis. Automated quantification can be useful in generating statistically comparable data from HE-stained or immunolabeled samples. The rapidly expanding classification of cell death requires the use of multiple techniques to identify them in vivo. This article will provide examples of how different methods of examining and quantifying cell death are used in a variety of research areas, ranging from semiquantitative evaluation in HE-stained intestine to automated quantification of immunohistochemistry-immunolabeled brain and tumor xenografts. The recently described process of necroptosis will be discussed briefly, with the description and example of the methods used to differentiate this from apoptosis.
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Affiliation(s)
- Laura J. Janke
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | | | - Peter Vogel
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
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43
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LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L. Nat Commun 2018; 9:3910. [PMID: 30254289 PMCID: PMC6156229 DOI: 10.1038/s41467-018-06155-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 08/17/2018] [Indexed: 12/13/2022] Open
Abstract
The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in HoipE-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone. TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.
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44
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RIP kinases as modulators of inflammation and immunity. Nat Immunol 2018; 19:912-922. [DOI: 10.1038/s41590-018-0188-x] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/24/2018] [Indexed: 12/13/2022]
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45
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Humphreys L, Espona-Fiedler M, Longley DB. FLIP as a therapeutic target in cancer. FEBS J 2018; 285:4104-4123. [PMID: 29806737 DOI: 10.1111/febs.14523] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/11/2018] [Accepted: 05/24/2018] [Indexed: 12/13/2022]
Abstract
One of the classic hallmarks of cancer is disruption of cell death signalling. Inhibition of cell death promotes tumour growth and metastasis, causes resistance to chemo- and radiotherapies as well as targeted agents, and is frequently due to overexpression of antiapoptotic proteins rather than loss of pro-apoptotic effectors. FLIP is a major apoptosis-regulatory protein frequently overexpressed in solid and haematological cancers, in which its high expression is often correlated with poor prognosis. FLIP, which is expressed as long (FLIP(L)) and short (FLIP(S)) splice forms, achieves its cell death regulatory functions by binding to FADD, a critical adaptor protein which links FLIP to the apical caspase in the extrinsic apoptotic pathway, caspase-8, in a number of cell death regulating complexes, such as the death-inducing signalling complexes (DISCs) formed by death receptors. FLIP also plays a key role (together with caspase-8) in regulating another form of cell death termed programmed necrosis or 'necroptosis', as well as in other key cellular processes that impact cell survival, including autophagy. In addition, FLIP impacts activation of the intrinsic mitochondrial-mediated apoptotic pathway by regulating caspase-8-mediated activation of the pro-apoptotic Bcl-2 family member Bid. It has been demonstrated that FLIP can not only inhibit death receptor-mediated apoptosis, but also cell death induced by a range of clinically relevant chemotherapeutic and targeted agents as well as ionizing radiation. More recently, key roles for FLIP in promoting the survival of immunosuppressive tumour-promoting immune cells have been discovered. Thus, FLIP is of significant interest as an anticancer therapeutic target. In this article, we review FLIP's biology and potential ways of targeting this important tumour and immune cell death regulator.
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Affiliation(s)
- Luke Humphreys
- Drug Resistance Group, Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, UK
| | - Margarita Espona-Fiedler
- Drug Resistance Group, Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, UK
| | - Daniel B Longley
- Drug Resistance Group, Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, UK
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Abstract
The intestinal tract is a site of intense immune cell activity that is poised to mount an effective response against a pathogen and yet maintain tolerance toward commensal bacteria and innocuous dietary antigens. The role of cell death in gut pathologies is particularly important as the intestinal epithelium undergoes self-renewal every 4-7 days through a continuous process of cell death and cell division. Cell death is also required for removal of infected, damaged, and cancerous cells. Certain forms of cell death trigger inflammation through release of damage-associated molecular patterns. Further, molecules involved in cell death decisions also moonlight as critical nodes in immune signaling. The manner of cell death is, therefore, highly instructive of the immunological consequences that ensue. Perturbations in cell death pathways can impact the regulation of the immune system with deleterious consequences. In this review, we discuss the various forms of cell death with a special emphasis on lytic cell death pathways of pyroptosis and necroptosis and their implications in inflammation and cancer in the gut. Understanding the implications of distinct cell death pathways will help in the development of therapeutic interventions in intestinal pathologies.
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Affiliation(s)
- Deepika Sharma
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
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Tang Y, Tu H, Liu G, Zheng G, Wang M, Li L, Zhao X, Lin X. RNF31 Regulates Skin Homeostasis by Protecting Epidermal Keratinocytes from Cell Death. THE JOURNAL OF IMMUNOLOGY 2018; 200:4117-4124. [DOI: 10.4049/jimmunol.1800172] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 04/13/2018] [Indexed: 11/19/2022]
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Li X, Ling Y, Cao Z, Shen J, Chen S, Liu W, Yuan B, Wen S. Targeting intestinal epithelial cell-programmed necrosis alleviates tissue injury after intestinal ischemia/reperfusion in rats. J Surg Res 2018; 225:108-117. [PMID: 29605020 DOI: 10.1016/j.jss.2018.01.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 11/19/2017] [Accepted: 01/04/2018] [Indexed: 11/21/2022]
Abstract
BACKGROUND Intestinal dysfunction, especially acute pathologies linked to intestinal ischemia/reperfusion (I/R) injury, is profoundly affected by inflammation and improper execution of cell death. Few studies have examined the efficacy of combined strategies in regulated intestinal epithelial necrosis after intestinal I/R. Here, we evaluated the functional interaction between poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1)-induced parthanatos and receptor-interacting protein 1/3 (RIP1/3) kinase-induced necroptosis in the pathophysiological course of acute ischemic intestinal injury. METHODS Anesthetized adult male Sprague-Dawley rats were subjected to superior mesenteric artery occlusion consisting of 1.5 h of ischemia and 6 h of reperfusion. The PARP-1-specific inhibitor PJ34 (10 mg/kg) and the RIP1-specific inhibitor Necrostatin-1 (1 mg/kg) were intraperitoneally administered 30 min before the induction of ischemia. RESULTS Intestinal I/R was found to result in PARP-1 activation and RIP1/3-mediated necrosome formation. PJ34 or Necrostatin-1 treatment significantly improved the mucosal injury, while the combined inhibition of PARP-1 and RIP1/3 conferred optimal protection of the intestine. Meanwhile, results from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay showed a decrease in intestinal epithelial cell death. Interestingly, we further showed that PARP-1 might act as a downstream signaling molecule of RIP1 in the process of I/R-induced intestinal injury and that the RIP1/PARP-1-dependent cell death signaling pathway functioned independently of caspase 3 inhibition. CONCLUSIONS The results of our study provide a molecular basis for combination therapy that targets both pathways of regulated necrosis (parthanatos and necroptosis), to treat acute intestinal I/R-induced intestinal epithelial barrier disruption.
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Affiliation(s)
- Xiang Li
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yihong Ling
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhongming Cao
- Department of Anesthesiology, Guangdong Cardiovascular Institute and Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiantong Shen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shaoqian Chen
- Department of Medical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weifeng Liu
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baolong Yuan
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Shihong Wen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Piao X, Miura R, Miyake S, Komazawa-Sakon S, Koike M, Shindo R, Takeda J, Hasegawa A, Abe R, Nishiyama C, Mikami T, Yagita H, Uchiyama Y, Nakano H. Blockade of TNF receptor superfamily 1 (TNFR1)-dependent and TNFR1-independent cell death is crucial for normal epidermal differentiation. J Allergy Clin Immunol 2018; 143:213-228.e10. [PMID: 29596938 DOI: 10.1016/j.jaci.2018.02.043] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 02/13/2018] [Accepted: 02/26/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND A delicate balance between cell death and keratinocyte proliferation is crucial for normal skin development. Previous studies have reported that cellular FLICE (FADD-like ICE)-inhibitory protein plays a crucial role in prevention of keratinocytes from TNF-α-dependent apoptosis and blocking of dermatitis. However, a role for cellular FLICE-inhibitory protein in TNF-α-independent cell death remains unclear. OBJECTIVE We investigated contribution of TNF-α-dependent and TNF-α-independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (CflarE-KO) mice. METHODS We examined the histology and expression of epidermal differentiation markers and inflammatory cytokines in the skin of CflarE-KO;Tnfrsf1a+/- and CflarE-KO;Tnfrsf1a-/- mice. Mice were treated with neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand to block TNF-α-independent cell death of CflarE-KO;Tnfrsf1a-/- mice. RESULTS CflarE-KO;Tnfrsf1a-/- mice were born but experienced severe dermatitis and succumbed soon after birth. CflarE-KO;Tnfrsf1a+/- mice exhibited embryonic lethality caused by massive keratinocyte apoptosis. Although keratinocytes from CflarE-KO;Tnfrsf1a-/- mice still died of apoptosis, neutralizing antibodies against Fas ligand and TNF-related apoptosis-inducing ligand substantially prolonged survival of CflarE-KO;Tnfrsf1a-/- mice. Expression of inflammatory cytokines, such as Il6 and Il17a was increased; conversely, expression of epidermal differentiation markers was severely downregulated in the skin of CflarE-KO;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6 and, to a lesser extent, IL-17A suppressed expression of epidermal differentiation markers. CONCLUSION TNF receptor superfamily 1 (TNFR1)-dependent or TNFR1-independent apoptosis of keratinocytes promotes inflammatory cytokine production, which subsequently blocks epidermal differentiation. Thus blockade of both TNFR1-dependent and TNFR1-independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNF-α antibody alone is not sufficient.
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Affiliation(s)
- Xuehua Piao
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan
| | - Ryosuke Miura
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan; Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Sanae Miyake
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan
| | | | - Masato Koike
- Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryodai Shindo
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan
| | - Junji Takeda
- Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Akito Hasegawa
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Riichiro Abe
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Chiharu Nishiyama
- Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Tetsuo Mikami
- Department of Pathology, Toho University School of Medicine, Tokyo, Japan
| | - Hideo Yagita
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuo Uchiyama
- Department of Cellular Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyasu Nakano
- Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan; Host Defense Research Center, Toho University School of Medicine, Tokyo, Japan.
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Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, DeBerardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, García-Sáez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, Jäättelä M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine JC, Martin SJ, Martinou JC, Medema JP, Mehlen P, Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, Muñoz-Pinedo C, Nagata S, Nuñez G, Oberst A, Oren M, Overholtzer M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon HU, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018; 25:486-541. [PMID: 29362479 PMCID: PMC5864239 DOI: 10.1038/s41418-017-0012-4] [Citation(s) in RCA: 4282] [Impact Index Per Article: 611.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 10/13/2017] [Indexed: 02/06/2023] Open
Abstract
Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
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Affiliation(s)
- Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Paris Descartes/Paris V University, Paris, France.
| | - Ilio Vitale
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
- Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institute of Immunology, Kiel University, Kiel, Germany
| | - Patrizia Agostinis
- Cell Death Research & Therapy (CDRT) Lab, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Ivano Amelio
- Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, UK
| | - David W Andrews
- Biological Sciences, Sunnybrook Research Institute, Toronto, Canada
- Department of Biochemistry, University of Toronto, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | | | - Alexey V Antonov
- Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, UK
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Nickolai A Barlev
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, New Orleans, LA, USA
| | - Francesca Bernassola
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Mathieu J M Bertrand
- VIB Center for Inflammation Research (IRC), Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Katiuscia Bianchi
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Albert Ludwigs University, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany
| | - Patricia Boya
- Department of Cellular and Molecular Biology, Center for Biological Investigation (CIB), Spanish National Research Council (CSIC), Madrid, Spain
| | - Catherine Brenner
- INSERM U1180, Châtenay Malabry, France
- University of Paris Sud/Paris Saclay, Orsay, France
| | - Michelangelo Campanella
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
- Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- University College London Consortium for Mitochondrial Research, London, UK
| | - Eleonora Candi
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | | | - Francesco Cecconi
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
- Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Francis K-M Chan
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Navdeep S Chandel
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
| | - Aaron Ciechanover
- Technion Integrated Cancer Center (TICC), The Ruth and Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel
| | - Gerald M Cohen
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Marcus Conrad
- Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Munich, Germany
| | - Juan R Cubillos-Ruiz
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Vincenzo D'Angiolella
- Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Vincenzo De Laurenzi
- Department of Medical, Oral and Biotechnological Sciences, CeSI-MetUniversity of Chieti-Pescara "G. d'Annunzio", Chieti, Italy
| | - Ruggero De Maria
- Institute of General Pathology, Catholic University "Sacro Cuore", Rome, Italy
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J DeBerardinis
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA
| | - Nicola Di Daniele
- Hypertension and Nephrology Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Vishva M Dixit
- Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Colin S Duckett
- Baylor Scott & White Research Institute, Baylor College of Medicine, Dallas, TX, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University School of Medicine, New York, NY, USA
- Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - John W Elrod
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University School of Medicine, Philadelphia, PA, USA
| | - Gian Maria Fimia
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy
| | - Simone Fulda
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ana J García-Sáez
- Interfaculty Institute of Biochemistry, Tübingen University, Tübingen, Germany
| | - Abhishek D Garg
- Cell Death Research & Therapy (CDRT) Lab, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM U1231 "Lipides Nutrition Cancer", Dijon, France
- Faculty of Medicine, University of Burgundy France Comté, Dijon, France
- Cancer Centre Georges François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Pierre Golstein
- Immunology Center of Marseille-Luminy, Aix Marseille University, Marseille, France
| | - Eyal Gottlieb
- Technion Integrated Cancer Center (TICC), The Ruth and Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Hinrich Gronemeyer
- Team labeled "Ligue Contre le Cancer", Department of Functional Genomics and Cancer, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France
- CNRS UMR 7104, Illkirch, France
- INSERM U964, Illkirch, France
- University of Strasbourg, Illkirch, France
| | - Atan Gross
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Gyorgy Hajnoczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Isaac S Harris
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Cellular and Molecular Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Bertrand Joseph
- Toxicology Unit, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Philipp J Jost
- III Medical Department for Hematology and Oncology, Technical University Munich, Munich, Germany
| | - Philippe P Juin
- Team 8 "Stress adaptation and tumor escape", CRCINA-INSERM U1232, Nantes, France
- University of Nantes, Nantes, France
- University of Angers, Angers, France
- Institute of Cancer Research in Western France, Saint-Herblain, France
| | - William J Kaiser
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center, San Antonio, TX, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, University of California San Diego, La Jolla, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Oliver Kepp
- Paris Descartes/Paris V University, Paris, France
- Faculty of Medicine, Paris Sud/Paris XI University, Kremlin-Bicêtre, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Campus, Villejuif, France
- Team 11 labeled "Ligue Nationale contre le Cancer", Cordeliers Research Center, Paris, France
- INSERM U1138, Paris, France
- Pierre et Marie Curie/Paris VI University, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Daniel J Klionsky
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
| | - Richard A Knight
- Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, UK
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Sam W Lee
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - John J Lemasters
- Center for Cell Death, Injury and Regeneration, Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
- Center for Cell Death, Injury and Regeneration, Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Beth Levine
- Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Andreas Linkermann
- Division of Nephrology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Stuart A Lipton
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA
- Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA, USA
| | - Richard A Lockshin
- Department of Biology, St. John's University, Queens, NY, USA
- Queens College of the City University of New York, Queens, NY, USA
| | - Carlos López-Otín
- Departament of Biochemistry and Molecular Biology, Faculty of Medicine, University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain
| | - Scott W Lowe
- Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tom Luedde
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany
| | - Enrico Lugli
- Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Marion MacFarlane
- Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, UK
| | - Frank Madeo
- Department Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Michal Malewicz
- Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, UK
| | - Walter Malorni
- National Centre for Gender Medicine, Italian National Institute of Health (ISS), Rome, Italy
| | - Gwenola Manic
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
- Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, Leuven, Belgium
- Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Seamus J Martin
- Departments of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland
| | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
- Cancer Genomics Center, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer and Development laboratory, CRCL, Lyon, France
- Team labeled "La Ligue contre le Cancer", Lyon, France
- LabEx DEVweCAN, Lyon, France
- INSERM U1052, Lyon, France
- CNRS UMR5286, Lyon, France
- Department of Translational Research and Innovation, Léon Bérard Cancer Center, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, London, UK
| | - Sonia Melino
- Department of Chemical Sciences and Technologies, University of Rome, Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Jeffery D Molkentin
- Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ute M Moll
- Department of Pathology, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Cell Death Regulation Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
| | - Shigekazu Nagata
- Laboratory of Biochemistry and Immunology, World Premier International (WPI) Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Gabriel Nuñez
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
- Center for Innate Immunity and Immune Disease, Seattle, WA, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, Weizmann Institute, Rehovot, Israel
| | - Michael Overholtzer
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michele Pagano
- Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
- Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA
| | - Theocharis Panaretakis
- Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Manolis Pasparakis
- Institute for Genetics, Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Campus Vienna BioCentre, Vienna, Austria
| | - David M Pereira
- REQUIMTE/LAQV, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
- National University Cancer Institute, National University Health System (NUHS), Singapore, Singapore
| | - Marcus E Peter
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Mauro Piacentini
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Paolo Pinton
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
- LTTA center, University of Ferrara, Ferrara, Italy
- Maria Cecilia Hospital, GVM Care & Research, Health Science Foundation, Cotignola, Italy
| | - Jochen H M Prehn
- Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry, La Trobe University, Victoria, Australia
| | - Gabriel A Rabinovich
- Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina
- Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
- Stuttgart Research Center Systems Biology, Stuttgart, Germany
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
| | - Thomas Rudel
- Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
| | - Kevin M Ryan
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Emre Sayan
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Venetian Institute of Molecular Medicine, Padua, Italy
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, China
| | - Yufang Shi
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, China
- Jiangsu Key Laboratory of Stem Cells and Medicinal Biomaterials, Institutes for Translational Medicine, Soochow University, Suzhou, China
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - John Silke
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
- Division of Inflammation, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Antonella Sistigu
- Institute of General Pathology, Catholic University "Sacro Cuore", Rome, Italy
- Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy
| | - Brent R Stockwell
- Department of Biological Sciences, Columbia University, New York, NY, USA
- Department of Chemistry, Columbia University, New York, NY, USA
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, University College London Consortium for Mitochondrial Research, London, UK
- Francis Crick Institute, London, UK
| | | | - Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- Center for DAMP Biology, Guangzhou Medical University, Guangzhou, Guangdong, China
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou Medical University, Guangzhou, Guangdong, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, Guangdong, China
- Key Laboratory for Protein Modification and Degradation of Guangdong Province, Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas Medical School, University of Crete, Heraklion, Greece
| | - Andrew Thorburn
- Department of Pharmacology, University of Colorado, Aurora, CO, USA
| | | | - Boris Turk
- Department Biochemistry and Molecular Biology, "Jozef Stefan" Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Tom Vanden Berghe
- VIB Center for Inflammation Research (IRC), Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Peter Vandenabeele
- VIB Center for Inflammation Research (IRC), Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Andreas Villunger
- Division of Developmental Immunology, Innsbruck Medical University, Innsbruck, Austria
| | - Herbert W Virgin
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Erwin F Wagner
- Genes, Development and Disease Group, Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Henning Walczak
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Ying Wang
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - James A Wells
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
| | - Will Wood
- School of Cellular and Molecular Medicine, Faculty of Biomedical Sciences, University of Bristol, Bristol, UK
| | - Junying Yuan
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Department of Biology, Queens College of the City University of New York, Queens, NY, USA
| | - Boris Zhivotovsky
- Toxicology Unit, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Laurence Zitvogel
- Faculty of Medicine, Paris Sud/Paris XI University, Kremlin-Bicêtre, France
- Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
- INSERM U1015, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France
| | - Gerry Melino
- Medical Research Council (MRC) Toxicology Unit, Leicester University, Leicester, UK
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Guido Kroemer
- Paris Descartes/Paris V University, Paris, France.
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Campus, Villejuif, France.
- Team 11 labeled "Ligue Nationale contre le Cancer", Cordeliers Research Center, Paris, France.
- INSERM U1138, Paris, France.
- Pierre et Marie Curie/Paris VI University, Paris, France.
- Biology Pole, European Hospital George Pompidou, AP-HP, Paris, France.
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