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1
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Alirzayeva H, Loureiro R, Koyuncu S, Hommen F, Nabawi Y, Zhang WH, Dao TTP, Wehrmann M, Lee HJ, Vilchez D. ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes. Cell Rep 2024; 43:114626. [PMID: 39167487 DOI: 10.1016/j.celrep.2024.114626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 05/13/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024] Open
Abstract
The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUSP525L variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUSP525L with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUSP525L aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.
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Affiliation(s)
- Hafiza Alirzayeva
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Rute Loureiro
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Seda Koyuncu
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Franziska Hommen
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Yara Nabawi
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - William Hongyu Zhang
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Thien T P Dao
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Markus Wehrmann
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Hyun Ju Lee
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - David Vilchez
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
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2
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Hipp MS, Hartl FU. Interplay of Proteostasis Capacity and Protein Aggregation: Implications for Cellular Function and Disease. J Mol Biol 2024; 436:168615. [PMID: 38759929 DOI: 10.1016/j.jmb.2024.168615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/13/2024] [Accepted: 05/13/2024] [Indexed: 05/19/2024]
Abstract
Eukaryotic cells are equipped with an intricate proteostasis network (PN), comprising nearly 3,000 components dedicated to preserving proteome integrity and sustaining protein homeostasis. This protective system is particularly important under conditions of external and intrinsic cell stress, where inherently dynamic proteins may unfold and lose functionality. A decline in proteostasis capacity is associated with the aging process, resulting in a reduced folding efficiency of newly synthesized proteins and a deficit in the cellular capacity to degrade misfolded proteins. A critical consequence of PN insufficiency is the accumulation of cytotoxic protein aggregates that underlie various age-related neurodegenerative conditions and other pathologies. By interfering with specific proteostasis components, toxic aggregates place an excessive burden on the PN's ability to maintain proteome integrity. This initiates a feed-forward loop, wherein the generation of misfolded and aggregated proteins ultimately leads to proteostasis collapse and cellular demise.
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Affiliation(s)
- Mark S Hipp
- Department of Biomedical Sciences, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan, 1, 9713 AV Groningen, the Netherlands; Research School of Behavioural and Cognitive Neurosciences, University of Groningen, Groningen, the Netherlands; School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.
| | - F Ulrich Hartl
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
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3
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Lottes EN, Ciger F, Bhattacharjee S, Timmins EA, Tete B, Tran T, Matta J, Patel AA, Cox DN. CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease. Cells 2024; 13:1029. [PMID: 38920658 PMCID: PMC11201622 DOI: 10.3390/cells13121029] [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: 01/27/2024] [Revised: 06/03/2024] [Accepted: 06/09/2024] [Indexed: 06/27/2024] Open
Abstract
The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multi-dendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1) in vitro. Through targeted genetic manipulations, we confirm that an LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases the dendritic complexity in CIV neurons. Furthermore, both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus, we examine CIV dendritic development in disease conditions as well. The expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through the regulation of TORC1 in both health and disease.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Daniel N. Cox
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA
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4
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Zeng C, Han S, Pan Y, Huang Z, Zhang B, Zhang B. Revisiting the chaperonin T-complex protein-1 ring complex in human health and disease: A proteostasis modulator and beyond. Clin Transl Med 2024; 14:e1592. [PMID: 38363102 PMCID: PMC10870801 DOI: 10.1002/ctm2.1592] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/28/2024] [Accepted: 02/05/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Disrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T-complex protein-1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes. MAIN BODY In this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC-associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment. CONCLUSION This review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.
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Affiliation(s)
- Chenglong Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhanChina
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Shenqi Han
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhanChina
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Yonglong Pan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhanChina
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Zhao Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhanChina
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Binhao Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhanChina
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Clinical Medical Research Center of Hepatic Surgery at Hubei ProvinceWuhanChina
- Hubei Key Laboratory of Hepato‐Pancreatic‐Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ Transplantation, Ministry of EducationWuhanChina
- Key Laboratory of Organ Transplantation, National Health CommissionWuhanChina
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical SciencesWuhanChina
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5
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Llamas E, Koyuncu S, Lee HJ, Wehrmann M, Gutierrez-Garcia R, Dunken N, Charura N, Torres-Montilla S, Schlimgen E, Mandel AM, Theile EB, Grossbach J, Wagle P, Lackmann JW, Schermer B, Benzing T, Beyer A, Pulido P, Rodriguez-Concepcion M, Zuccaro A, Vilchez D. In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation. NATURE AGING 2023; 3:1345-1357. [PMID: 37783816 PMCID: PMC10645592 DOI: 10.1038/s43587-023-00502-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 09/01/2023] [Indexed: 10/04/2023]
Abstract
In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington's disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. To investigate this phenomenon, we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants. In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis. Inhibition of chloroplast proteostasis diminishes the capacity of plants to prevent cytosolic Q69 aggregation. Moreover, endogenous polyQ-containing proteins also aggregate on chloroplast dysfunction. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Synthetic Arabidopsis SPP prevents polyQ-expanded HTT aggregation in human cells. Likewise, ectopic SPP expression in Caenorhabditis elegans reduces neuronal Q67 aggregation and subsequent neurotoxicity. Our findings suggest that synthetic plant proteins, such as SPP, hold therapeutic potential for polyQ disorders and other age-related diseases involving protein aggregation.
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Affiliation(s)
- Ernesto Llamas
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Cluster of Excellence on Plant Sciences, Institute for Plant Sciences, University of Cologne, Cologne, Germany
| | - Seda Koyuncu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Hyun Ju Lee
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Markus Wehrmann
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Ricardo Gutierrez-Garcia
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Nick Dunken
- Cluster of Excellence on Plant Sciences, Institute for Plant Sciences, University of Cologne, Cologne, Germany
| | - Nyasha Charura
- Cluster of Excellence on Plant Sciences, Institute for Plant Sciences, University of Cologne, Cologne, Germany
| | | | - Elena Schlimgen
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
| | - Amrei M Mandel
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Department II of Internal Medicine, University Hospital Cologne, Cologne, Germany
| | - Erik Boelen Theile
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Genetics, University of Cologne, Cologne, Germany
| | - Jan Grossbach
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Genetics, University of Cologne, Cologne, Germany
| | - Prerana Wagle
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Jan-Wilm Lackmann
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
| | - Bernhard Schermer
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Department II of Internal Medicine, University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Thomas Benzing
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Department II of Internal Medicine, University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Andreas Beyer
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
- Institute for Genetics, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Pablo Pulido
- Department of Plant Molecular Genetics, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | | | - Alga Zuccaro
- Cluster of Excellence on Plant Sciences, Institute for Plant Sciences, University of Cologne, Cologne, Germany
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany.
- Institute for Genetics, University of Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
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6
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Betancourt Moreira K, Collier MP, Leitner A, Li KH, Lachapel ILS, McCarthy F, Opoku-Nsiah KA, Morales-Polanco F, Barbosa N, Gestaut D, Samant RS, Roh SH, Frydman J. A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT. Mol Cell 2023; 83:3123-3139.e8. [PMID: 37625406 PMCID: PMC11209756 DOI: 10.1016/j.molcel.2023.07.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 05/07/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023]
Abstract
How the essential eukaryotic chaperonin TRiC/CCT assembles from eight distinct subunits into a unique double-ring architecture remains undefined. We show TRiC assembly involves a hierarchical pathway that segregates subunits with distinct functional properties until holocomplex (HC) completion. A stable, likely early intermediate arises from small oligomers containing CCT2, CCT4, CCT5, and CCT7, contiguous subunits that constitute the negatively charged hemisphere of the TRiC chamber, which has weak affinity for unfolded actin. The remaining subunits CCT8, CCT1, CCT3, and CCT6, which comprise the positively charged chamber hemisphere that binds unfolded actin more strongly, join the ring individually. Unincorporated late-assembling subunits are highly labile in cells, which prevents their accumulation and premature substrate binding. Recapitulation of assembly in a recombinant system demonstrates that the subunits in each hemisphere readily form stable, noncanonical TRiC-like HCs with aberrant functional properties. Thus, regulation of TRiC assembly along a biochemical axis disfavors the formation of stable alternative chaperonin complexes.
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Affiliation(s)
| | | | - Alexander Leitner
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Kathy H Li
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
| | | | | | | | | | - Natália Barbosa
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Daniel Gestaut
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Rahul S Samant
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Soung-Hun Roh
- School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea
| | - Judith Frydman
- Department of Biology, Stanford University, Stanford, CA, USA.
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7
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Lottes EN, Ciger FH, Bhattacharjee S, Timmins-Wilde EA, Tete B, Tran T, Matta J, Patel AA, Cox DN. CCT and Cullin1 regulate the TORC1 pathway to promote dendritic arborization in health and disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.31.551324. [PMID: 37577581 PMCID: PMC10418059 DOI: 10.1101/2023.07.31.551324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in homeostatic dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multidendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1), in vitro. Through targeted genetic manipulations, we have confirmed that LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases dendritic complexity in CIV neurons. Both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus we examined CIV dendritic development in disease conditions as well. Expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by TORC1 disinhibition via Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through regulation of TORC1 in both health and disease.
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Affiliation(s)
- Erin N. Lottes
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
| | - Feyza H. Ciger
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
| | | | | | - Benoit Tete
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
| | - Tommy Tran
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
| | - Jais Matta
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
| | - Atit A. Patel
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
| | - Daniel N. Cox
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, United States
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8
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Lee HJ, Alirzayeva H, Koyuncu S, Rueber A, Noormohammadi A, Vilchez D. Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes. NATURE AGING 2023; 3:546-566. [PMID: 37118550 DOI: 10.1038/s43587-023-00383-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 02/17/2023] [Indexed: 04/30/2023]
Abstract
Aging is a primary risk factor for neurodegenerative disorders that involve protein aggregation. Because lowering body temperature is one of the most effective mechanisms to extend longevity in both poikilotherms and homeotherms, a better understanding of cold-induced changes can lead to converging modifiers of pathological protein aggregation. Here, we find that cold temperature (15 °C) selectively induces the trypsin-like activity of the proteasome in Caenorhabditis elegans through PSME-3, the worm orthologue of human PA28γ/PSME3. This proteasome activator is required for cold-induced longevity and ameliorates age-related deficits in protein degradation. Moreover, cold-induced PA28γ/PSME-3 diminishes protein aggregation in C. elegans models of age-related diseases such as Huntington's and amyotrophic lateral sclerosis. Notably, exposure of human cells to moderate cold temperature (36 °C) also activates trypsin-like activity through PA28γ/PSME3, reducing disease-related protein aggregation and neurodegeneration. Together, our findings reveal a beneficial role of cold temperature that crosses evolutionary boundaries with potential implications for multi-disease prevention.
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Affiliation(s)
- Hyun Ju Lee
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Hafiza Alirzayeva
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Seda Koyuncu
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Amirabbas Rueber
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Alireza Noormohammadi
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - David Vilchez
- Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany.
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
- Institute for Genetics, University of Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
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9
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Aging Hallmarks and the Role of Oxidative Stress. Antioxidants (Basel) 2023; 12:antiox12030651. [PMID: 36978899 PMCID: PMC10044767 DOI: 10.3390/antiox12030651] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/26/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production.
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10
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Ma X, Feng Y, Quan X, Geng B, Li G, Fu X, Zeng L. Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimer's disease. Front Genet 2023; 13:967730. [PMID: 36704351 PMCID: PMC9871314 DOI: 10.3389/fgene.2022.967730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 12/07/2022] [Indexed: 01/12/2023] Open
Abstract
Chaperonin containing TCP1 subunit 2 (CCT2) is essential in various neurodegenerative diseases, albeit its role in the pathogenesis of Alzheimer's disease (AD) remains elusive. This study aimed to evaluate the role of CCT2 in Alzheimer's disease. First, bioinformatics database analysis revealed that CCT2 was significantly downregulated in patients with Alzheimer's disease and associated with autophagic clearance of β-amyloid. The 789 differentially expressed genes overlapped in AD-group and CCT2-low/high group, and the CCT2-high-associated genes screened by Pearson coefficients were enriched in protein folding, autophagy, and messenger RNA stability regulation pathways. These results suggest that CCT2 is significantly and positively associated with multiple pathways linked to autophagy and negatively associated with neuronal death. The logistic prediction model with 13 key genes, such as CCT2, screened in this study better predicts Alzheimer's disease occurrence (AUC = 0.9671) and is a favorable candidate for predicting potential biological targets of Alzheimer's disease. Additionally, this study predicts reciprocal micro RNAs and small molecule drugs for hub genes. Our findings suggest that low CCT2 expression may be responsible for the autophagy suppression in Alzheimer's disease, providing an accurate explanation for its pathogenesis and new targets and small molecule inhibitors for its treatment.
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Affiliation(s)
- Xueting Ma
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Yuxin Feng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Xiangyu Quan
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Bingyu Geng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Guodong Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Xueqi Fu
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Linlin Zeng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China,*Correspondence: Linlin Zeng,
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11
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Sap KA, Geijtenbeek KW, Schipper-Krom S, Guler AT, Reits EA. Ubiquitin-modifying enzymes in Huntington's disease. Front Mol Biosci 2023; 10:1107323. [PMID: 36926679 PMCID: PMC10013475 DOI: 10.3389/fmolb.2023.1107323] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/16/2023] [Indexed: 02/10/2023] Open
Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the N-terminus of the HTT gene. The CAG repeat expansion translates into a polyglutamine expansion in the mutant HTT (mHTT) protein, resulting in intracellular aggregation and neurotoxicity. Lowering the mHTT protein by reducing synthesis or improving degradation would delay or prevent the onset of HD, and the ubiquitin-proteasome system (UPS) could be an important pathway to clear the mHTT proteins prior to aggregation. The UPS is not impaired in HD, and proteasomes can degrade mHTT entirely when HTT is targeted for degradation. However, the mHTT protein is differently ubiquitinated when compared to wild-type HTT (wtHTT), suggesting that the polyQ expansion affects interaction with (de) ubiquitinating enzymes and subsequent targeting for degradation. The soluble mHTT protein is associated with several ubiquitin-modifying enzymes, and various ubiquitin-modifying enzymes have been identified that are linked to Huntington's disease, either by improving mHTT turnover or affecting overall homeostasis. Here we describe their potential mechanism of action toward improved mHTT targeting towards the proteostasis machinery.
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Affiliation(s)
- Karen A Sap
- Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Karlijne W Geijtenbeek
- Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Sabine Schipper-Krom
- Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Arzu Tugce Guler
- Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Eric A Reits
- Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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12
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Loose JA, Amrit FRG, Patil T, Yanowitz JL, Ghazi A. Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans. Aging Cell 2022; 21:e13716. [PMID: 36176234 PMCID: PMC9649607 DOI: 10.1111/acel.13716] [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: 03/13/2022] [Revised: 08/07/2022] [Accepted: 08/31/2022] [Indexed: 01/25/2023] Open
Abstract
An expanding body of evidence, from studies in model organisms to human clinical data, reveals that reproductive health influences organismal aging. However, the impact of germline integrity on somatic aging is poorly understood. Moreover, assessing the causal relationship of such an impact is challenging to address in human and vertebrate models. Here, we demonstrate that disruption of meiosis, a germline restricted process, shortened lifespan, impaired individual aspects of healthspan, and accelerated somatic aging in Caenorhabditis elegans. Young meiotic mutants exhibited transcriptional profiles that showed remarkable overlap with the transcriptomes of old worms and shared similarities with transcriptomes of aging human tissues as well. We found that meiosis dysfunction caused increased expression of functionally relevant longevity determinants whose inactivation enhanced the lifespan of normal animals. Further, meiotic mutants manifested destabilized protein homeostasis and enhanced proteasomal activity partially rescued the associated lifespan defects. Our study demonstrates a role for meiotic integrity in controlling somatic aging and reveals proteostasis control as a potential mechanism through which germline status impacts overall organismal health.
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Affiliation(s)
- Julia A. Loose
- Department of Pediatrics, John G. Rangos Sr. Research CenterUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Francis R. G. Amrit
- Department of Pediatrics, John G. Rangos Sr. Research CenterUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Thayjas Patil
- Department of Pediatrics, John G. Rangos Sr. Research CenterUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Judith L. Yanowitz
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee‐Womens Research InstituteUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Arjumand Ghazi
- Department of Pediatrics, John G. Rangos Sr. Research CenterUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA,Department of Developmental Biology, John G. Rangos Sr. Research CenterUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA,Department of Cell Biology & PhysiologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
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13
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Söderhäll I, Fasterius E, Ekblom C, Söderhäll K. Characterization of hemocytes and hematopoietic cells of a freshwater crayfish based on single-cell transcriptome analysis. iScience 2022; 25:104850. [PMID: 35996577 PMCID: PMC9391574 DOI: 10.1016/j.isci.2022.104850] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/30/2022] [Accepted: 07/22/2022] [Indexed: 11/29/2022] Open
Abstract
Crustaceans constitute a species-rich and ecologically important animal group, and their circulating blood cells (hemocytes) are of critical importance in immunity as key players in pathogen recognition, phagocytosis, melanization, and antimicrobial defense. To gain a better understanding of the immune responses to different pathogens, it is crucial that we identify different hemocyte subpopulations with different functions and gain a better understanding of how these cells are formed. Here, we performed single-cell RNA sequencing of isolated hematopoietic tissue (HPT) cells and hemocytes from the crayfish Pacifastacus leniusculus to identify hitherto undescribed hemocyte types in the circulation and show that the circulating cells are more diversified than previously recognized. In addition, we discovered cell populations in the HPT with clear precursor characteristics as well as cells involved in iron homeostasis, representing a previously undiscovered cell type. These findings may improve our understanding of hematopoietic stem cell regulation in crustaceans and other animals.
Single-cell RNA sequencing of hematopoietic cell types reveals new cell types One cell type contains iron homeostasis-associated transcripts Hemocytes and hematopoietic cells differ in their transcript profiles Prophenoloxidase is only expressed in hemocytes
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Affiliation(s)
- Irene Söderhäll
- Department of Organismal Biology, Uppsala University, Norbyvägen 18 A, SE752 36 Uppsala, Sweden
- Corresponding author
| | - Erik Fasterius
- National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Tomtebodavägen 23, SE171 65 Solna, Sweden
| | - Charlotta Ekblom
- Department of Organismal Biology, Uppsala University, Norbyvägen 18 A, SE752 36 Uppsala, Sweden
| | - Kenneth Söderhäll
- Department of Organismal Biology, Uppsala University, Norbyvägen 18 A, SE752 36 Uppsala, Sweden
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14
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Katyal G, Ebanks B, Dowle A, Shephard F, Papetti C, Lucassen M, Chakrabarti L. Quantitative Proteomics and Network Analysis of Differentially Expressed Proteins in Proteomes of Icefish Muscle Mitochondria Compared with Closely Related Red-Blooded Species. BIOLOGY 2022; 11:biology11081118. [PMID: 35892974 PMCID: PMC9330239 DOI: 10.3390/biology11081118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022]
Abstract
Simple Summary Antarctic icefish are unusual in that they are the only vertebrates that survive without the protein haemoglobin. One way to try and understand the biological processes that support this anomaly is to record how proteins are regulated in these animals and to compare what we find to closely related Antarctic fish that do still retain haemoglobin. The part of the cell that most clearly utilises oxygen, which is normally transported by haemoglobin, is the mitochondrion. Therefore, we chose to catalogue all the proteins and their relative quantities in the mitochondria (pl.) from two different muscle types in two species of icefish and two species of red-blooded notothenioids. We used an approach called mass spectrometry to reveal relative amounts of the proteins from the muscles of each fish. We present analysis that shows how the connections and relative quantities of proteins differ between these species. Abstract Antarctic icefish are extraordinary in their ability to thrive without haemoglobin. We wanted to understand how the mitochondrial proteome has adapted to the loss of this protein. Metabolic pathways that utilise oxygen are most likely to be rearranged in these species. Here, we have defined the mitochondrial proteomes of both the red and white muscle of two different icefish species (Champsocephalus gunnari and Chionodraco rastrospinosus) and compared these with two related red-blooded Notothenioids (Notothenia rossii, Trematomus bernacchii). Liquid Chromatography-Mass spectrometry (LC-MS/MS) was used to generate and examine the proteomic profiles of the two groups. We recorded a total of 91 differentially expressed proteins in the icefish red muscle mitochondria and 89 in the white muscle mitochondria when compared with the red-blooded related species. The icefish have a relatively higher abundance of proteins involved with Complex V of oxidative phosphorylation, RNA metabolism, and homeostasis, and fewer proteins for striated muscle contraction, haem, iron, creatine, and carbohydrate metabolism. Enrichment analyses showed that many important pathways were different in both red muscle and white muscle, including the citric acid cycle, ribosome machinery and fatty acid degradation. Life in the Antarctic waters poses extra challenges to the organisms that reside within them. Icefish have successfully inhabited this environment and we surmise that species without haemoglobin uniquely maintain their physiology. Our study highlights the mitochondrial protein pathway differences between similar fish species according to their specific tissue oxygenation idiosyncrasies.
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Affiliation(s)
- Gunjan Katyal
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington LE12 5RD, UK; (G.K.); (B.E.); (F.S.)
| | - Brad Ebanks
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington LE12 5RD, UK; (G.K.); (B.E.); (F.S.)
| | - Adam Dowle
- Department of Biology, Bioscience Technology Facility, University of York, York YO10 5DD, UK;
| | - Freya Shephard
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington LE12 5RD, UK; (G.K.); (B.E.); (F.S.)
| | - Chiara Papetti
- Biology Department, University of Padova, Via U. Bassi, 58/b, 35121 Padova, Italy;
| | | | - Lisa Chakrabarti
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington LE12 5RD, UK; (G.K.); (B.E.); (F.S.)
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Liverpool L7 8TX, UK
- Correspondence:
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15
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Ghozlan H, Cox A, Nierenberg D, King S, Khaled AR. The TRiCky Business of Protein Folding in Health and Disease. Front Cell Dev Biol 2022; 10:906530. [PMID: 35602608 PMCID: PMC9117761 DOI: 10.3389/fcell.2022.906530] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/20/2022] [Indexed: 01/03/2023] Open
Abstract
Maintenance of the cellular proteome or proteostasis is an essential process that when deregulated leads to diseases like neurological disorders and cancer. Central to proteostasis are the molecular chaperones that fold proteins into functional 3-dimensional (3D) shapes and prevent protein aggregation. Chaperonins, a family of chaperones found in all lineages of organisms, are efficient machines that fold proteins within central cavities. The eukaryotic Chaperonin Containing TCP1 (CCT), also known as Tailless complex polypeptide 1 (TCP-1) Ring Complex (TRiC), is a multi-subunit molecular complex that folds the obligate substrates, actin, and tubulin. But more than folding cytoskeletal proteins, CCT differs from most chaperones in its ability to fold proteins larger than its central folding chamber and in a sequential manner that enables it to tackle proteins with complex topologies or very large proteins and complexes. Unique features of CCT include an asymmetry of charges and ATP affinities across the eight subunits that form the hetero-oligomeric complex. Variable substrate binding capacities endow CCT with a plasticity that developed as the chaperonin evolved with eukaryotes and acquired functional capacity in the densely packed intracellular environment. Given the decades of discovery on the structure and function of CCT, much remains unknown such as the scope of its interactome. New findings on the role of CCT in disease, and potential for diagnostic and therapeutic uses, heighten the need to better understand the function of this essential molecular chaperone. Clues as to how CCT causes cancer or neurological disorders lie in the early studies of the chaperonin that form a foundational knowledgebase. In this review, we span the decades of CCT discoveries to provide critical context to the continued research on the diverse capacities in health and disease of this essential protein-folding complex.
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Affiliation(s)
- Heba Ghozlan
- Division of Cancer Research, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
- Department of Physiology and Biochemistry, Jordan University of Science and Technology, Irbid, Jordan
| | - Amanda Cox
- Division of Cancer Research, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Daniel Nierenberg
- Division of Cancer Research, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Stephen King
- Division of Neuroscience, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Annette R. Khaled
- Division of Cancer Research, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States
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16
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Ma X, Lu C, Chen Y, Li S, Ma N, Tao X, Li Y, Wang J, Zhou M, Yan YB, Li P, Heydari K, Deng H, Zhang M, Yi C, Ge L. CCT2 is an aggrephagy receptor for clearance of solid protein aggregates. Cell 2022; 185:1325-1345.e22. [PMID: 35366418 DOI: 10.1016/j.cell.2022.03.005] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/13/2021] [Accepted: 03/01/2022] [Indexed: 12/12/2022]
Abstract
Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.
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Affiliation(s)
- Xinyu Ma
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Caijing Lu
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yuting Chen
- Department of Biochemistry, and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shulin Li
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ningjia Ma
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xuan Tao
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ying Li
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jing Wang
- State Key Laboratory of Membrane Biology, Beijing, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Min Zhou
- Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Beijing 100084, China
| | - Yong-Bin Yan
- State Key Laboratory of Membrane Biology, Beijing, China; School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Pilong Li
- Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Beijing 100084, China
| | - Kartoosh Heydari
- Cancer Research Laboratory FACS Core Facility, University of California, Berkeley, CA 94720, USA
| | - Haiteng Deng
- School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Beijing 100084, China; MOE Key Laboratory of Bioinformatics, Beijing, China
| | - Min Zhang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
| | - Cong Yi
- Department of Biochemistry, and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Liang Ge
- State Key Laboratory of Membrane Biology, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
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17
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Zhang WH, Koyuncu S, Vilchez D. Insights Into the Links Between Proteostasis and Aging From C. elegans. FRONTIERS IN AGING 2022; 3:854157. [PMID: 35821832 PMCID: PMC9261386 DOI: 10.3389/fragi.2022.854157] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/22/2022] [Indexed: 04/20/2023]
Abstract
Protein homeostasis (proteostasis) is maintained by a tightly regulated and interconnected network of biological pathways, preventing the accumulation and aggregation of damaged or misfolded proteins. Thus, the proteostasis network is essential to ensure organism longevity and health, while proteostasis failure contributes to the development of aging and age-related diseases that involve protein aggregation. The model organism Caenorhabditis elegans has proved invaluable for the study of proteostasis in the context of aging, longevity and disease, with a number of pivotal discoveries attributable to the use of this organism. In this review, we discuss prominent findings from C. elegans across the many key aspects of the proteostasis network, within the context of aging and disease. These studies collectively highlight numerous promising therapeutic targets, which may 1 day facilitate the development of interventions to delay aging and prevent age-associated diseases.
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Affiliation(s)
- William Hongyu Zhang
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Seda Koyuncu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Faculty of Medicine, University Hospital Cologne, Cologne, Germany
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18
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Chen C, Zhang X, Wang Y, Chen X, Chen W, Dan S, She S, Hu W, Dai J, Hu J, Cao Q, Liu Q, Huang Y, Qin B, Kang B, Wang YJ. Translational and post-translational control of human naïve versus primed pluripotency. iScience 2022; 25:103645. [PMID: 35005567 PMCID: PMC8718978 DOI: 10.1016/j.isci.2021.103645] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 10/22/2021] [Accepted: 12/10/2021] [Indexed: 01/05/2023] Open
Abstract
Deciphering the regulatory network for human naive and primed pluripotency is of fundamental theoretical and applicable significance. Here, by combining quantitative proteomics, phosphoproteomics, and acetylproteomics analyses, we revealed RNA processing and translation as the most differentially regulated processes between naive and primed human embryonic stem cells (hESCs). Although glycolytic primed hESCs rely predominantly on the eukaryotic initiation factor 4E (eIF4E)-mediated cap-dependent pathway for protein translation, naive hESCs with reduced mammalian target of rapamycin complex (mTORC1) activity are more tolerant to eIF4E inhibition, and their bivalent metabolism allows for translating selective mRNAs via both eIF4E-dependent and eIF4E-independent/eIF4A2-dependent pathways to form a more compact naive proteome. Globally up-regulated proteostasis and down-regulated post-translational modifications help to further refine the naive proteome that is compatible with the more rapid cycling of naive hESCs, where CDK1 plays an indispensable coordinative role. These findings may assist in better understanding the unrestricted lineage potential of naive hESCs and in further optimizing conditions for future clinical applications
RNA processing and translation are most different between naive and primed hESCs Glycolytic primed hESCs mainly rely on eIF4E-dependent translation Bivalent metabolism in naive hESCs promotes eIF4E-independent translation CDK1 is required for naive pluripotency partially by activating E-cadherin signaling
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Affiliation(s)
- Cheng Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.,Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, China
| | - Xiaobing Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Yisha Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Xinyu Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Wenjie Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Songsong Dan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Shiqi She
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.,Zhejiang Museum of Natural History, Hangzhou, Zhejiang 310014, China
| | - Weiwei Hu
- Shanghai Bioprofile Technology Co., Ltd., Shanghai 200241, China
| | - Jie Dai
- Shanghai Bioprofile Technology Co., Ltd., Shanghai 200241, China
| | - Jianwen Hu
- Shanghai Bioprofile Technology Co., Ltd., Shanghai 200241, China
| | - Qingyi Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Qianyu Liu
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yinghua Huang
- Laboratory of Metabolism and Cell Fate, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Baoming Qin
- Laboratory of Metabolism and Cell Fate, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Bo Kang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Ying-Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.,Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China
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19
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Jain S, Hu C, Kluza J, Ke W, Tian G, Giurgiu M, Bleilevens A, Campos AR, Charbono A, Stickeler E, Maurer J, Holinski-Feder E, Vaisburg A, Bureik M, Luo G, Marchetti P, Cheng Y, Wolf DA. Metabolic targeting of cancer by a ubiquinone uncompetitive inhibitor of mitochondrial complex I. Cell Chem Biol 2021; 29:436-450.e15. [PMID: 34852219 DOI: 10.1016/j.chembiol.2021.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/12/2021] [Accepted: 11/03/2021] [Indexed: 12/18/2022]
Abstract
SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through an as-yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, complex I [CI]). Instead of affecting the quinone-binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple-negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer.
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Affiliation(s)
- Shashi Jain
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92024, USA
| | - Cheng Hu
- State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'An South Road, Xiamen, China
| | - Jerome Kluza
- Université de Lille, CNRS, Inserm, CHU Lille, Institut pour la Recherche sur le Cancer de Lille, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France
| | - Wei Ke
- State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'An South Road, Xiamen, China
| | - Guiyou Tian
- State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'An South Road, Xiamen, China
| | | | - Andreas Bleilevens
- Department of Obstetrics and Gynecology, University of Aachen, Aachen, Germany
| | | | - Adriana Charbono
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92024, USA
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, University of Aachen, Aachen, Germany
| | - Jochen Maurer
- Department of Obstetrics and Gynecology, University of Aachen, Aachen, Germany
| | - Elke Holinski-Feder
- MGZ Medical Genetics Center Munich, 80335 Munich, Germany; Department of Medicine IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany
| | - Arkadii Vaisburg
- Crocus Laboratories Inc., Montreal, QC, Canada; NuChem Sciences Inc., Montreal, QC, Canada
| | - Matthias Bureik
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Guangcheng Luo
- Department of Urology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Philippe Marchetti
- Université de Lille, CNRS, Inserm, CHU Lille, Institut pour la Recherche sur le Cancer de Lille, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France; Centre de Bio-Pathologie, Banque de Tissus, CHU of Lille, Lille, France
| | - Yabin Cheng
- State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'An South Road, Xiamen, China.
| | - Dieter A Wolf
- State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'An South Road, Xiamen, China; MGZ Medical Genetics Center Munich, 80335 Munich, Germany; Department of Internal Medicine II, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
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20
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Analysis of Homozygous-by-Descent (HBD) Segments for Purebred and Crossbred Pigs in Russia. Life (Basel) 2021; 11:life11080861. [PMID: 34440604 PMCID: PMC8400874 DOI: 10.3390/life11080861] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 12/30/2022] Open
Abstract
Intensive selection raises the efficiency of pig farming considerably, but it also promotes the accumulation of homozygosity, which can lead to an increase in inbreeding and the accumulation of deleterious variation. The analysis of segments homozygous-by-descent (HBD) and non-HBD segments in purebred and crossbred pigs is of great interest. Research was carried out on 657 pigs, of which there were Large White (LW, n = 280), Landrace (LR, n = 218) and F1 female (♂LR × ♀LW) (F1, n = 159). Genotyping was performed using the GeneSeek® GGP Porcine HD Genomic Profiler v1 (Illumina Inc., USA). To identify HBD segments and estimate autozygosity (inbreeding coefficient), we used the multiple HBD classes model. LW pigs exhibited 50,420 HBD segments, an average of 180 per animal; LR pigs exhibited 33,586 HBD segments, an average of 154 per animal; F1 pigs exhibited 21,068 HBD segments, an average of 132 per animal. The longest HBD segments in LW were presented in SSC1, SSC13 and SSC15; in LR, in SSC1; and in F1, in SSC15. In these segments, 3898 SNPs localized in 1252 genes were identified. These areas overlap with 441 QTLs (SSC1—238 QTLs; SSC13—101 QTLs; and SSC15—102 QTLs), including 174 QTLs for meat and carcass traits (84 QTLs—fatness), 127 QTLs for reproduction traits (100 QTLs—litter traits), 101 for production traits (69 QTLs—growth and 30 QTLs—feed intake), 21 QTLs for exterior traits (9 QTLs—conformation) and 18 QTLs for health traits (13 QTLs—blood parameters). Thirty SNPs were missense variants. Whilst estimating the potential for deleterious variation, six SNPs localized in the NEDD4, SEC11C, DCP1A, CCT8, PKP4 and TENM3 genes were identified, which may show deleterious variation. A high frequency of potential deleterious variation was noted for LR in DCP1A, and for LW in TENM3 and PKP4. In all cases, the genotype frequencies in F1 were intermediate between LR and LW. The findings presented in our work show the promise of genome scanning for HBD as a strategy for studying population history, identifying genomic regions and genes associated with important economic traits, as well as deleterious variation.
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21
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Koyuncu S, Loureiro R, Lee HJ, Wagle P, Krueger M, Vilchez D. Rewiring of the ubiquitinated proteome determines ageing in C. elegans. Nature 2021; 596:285-290. [PMID: 34321666 PMCID: PMC8357631 DOI: 10.1038/s41586-021-03781-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/29/2021] [Indexed: 12/20/2022]
Abstract
Ageing is driven by a loss of cellular integrity1. Given the major role of ubiquitin modifications in cell function2, here we assess the link between ubiquitination and ageing by quantifying whole-proteome ubiquitin signatures in Caenorhabditis elegans. We find a remodelling of the ubiquitinated proteome during ageing, which is ameliorated by longevity paradigms such as dietary restriction and reduced insulin signalling. Notably, ageing causes a global loss of ubiquitination that is triggered by increased deubiquitinase activity. Because ubiquitination can tag proteins for recognition by the proteasome3, a fundamental question is whether deficits in targeted degradation influence longevity. By integrating data from worms with a defective proteasome, we identify proteasomal targets that accumulate with age owing to decreased ubiquitination and subsequent degradation. Lowering the levels of age-dysregulated proteasome targets prolongs longevity, whereas preventing their degradation shortens lifespan. Among the proteasomal targets, we find the IFB-2 intermediate filament4 and the EPS-8 modulator of RAC signalling5. While increased levels of IFB-2 promote the loss of intestinal integrity and bacterial colonization, upregulation of EPS-8 hyperactivates RAC in muscle and neurons, and leads to alterations in the actin cytoskeleton and protein kinase JNK. In summary, age-related changes in targeted degradation of structural and regulatory proteins across tissues determine longevity.
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Affiliation(s)
- Seda Koyuncu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Rute Loureiro
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Hyun Ju Lee
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Prerana Wagle
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Marcus Krueger
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
- Faculty of Medicine, University Hospital Cologne, Cologne, Germany.
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22
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Llamas E, Torres‐Montilla S, Lee HJ, Barja MV, Schlimgen E, Dunken N, Wagle P, Werr W, Zuccaro A, Rodríguez‐Concepción M, Vilchez D. The intrinsic chaperone network of Arabidopsis stem cells confers protection against proteotoxic stress. Aging Cell 2021; 20:e13446. [PMID: 34327811 PMCID: PMC8373342 DOI: 10.1111/acel.13446] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/25/2021] [Accepted: 07/08/2021] [Indexed: 01/21/2023] Open
Abstract
The biological purpose of plant stem cells is to maintain themselves while providing new pools of differentiated cells that form organs and rejuvenate or replace damaged tissues. Protein homeostasis or proteostasis is required for cell function and viability. However, the link between proteostasis and plant stem cell identity remains unknown. In contrast to their differentiated counterparts, we find that root stem cells can prevent the accumulation of aggregated proteins even under proteotoxic stress conditions such as heat stress or proteasome inhibition. Notably, root stem cells exhibit enhanced expression of distinct chaperones that maintain proteome integrity. Particularly, intrinsic high levels of the T-complex protein-1 ring complex/chaperonin containing TCP1 (TRiC/CCT) complex determine stem cell maintenance and their remarkable ability to suppress protein aggregation. Overexpression of CCT8, a key activator of TRiC/CCT assembly, is sufficient to ameliorate protein aggregation in differentiated cells and confer resistance to proteotoxic stress in plants. Taken together, our results indicate that enhanced proteostasis mechanisms in stem cells could be an important requirement for plants to persist under extreme environmental conditions and reach extreme long ages. Thus, proteostasis of stem cells can provide insights to design and breed plants tolerant to environmental challenges caused by the climate change.
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Affiliation(s)
- Ernesto Llamas
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - Salvador Torres‐Montilla
- Centre for Research in Agricultural Genomics (CRAG) CSIC‐IRTA‐UAB‐UBCampus UAB Bellaterra Barcelona Spain
| | - Hyun Ju Lee
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - María Victoria Barja
- Centre for Research in Agricultural Genomics (CRAG) CSIC‐IRTA‐UAB‐UBCampus UAB Bellaterra Barcelona Spain
| | - Elena Schlimgen
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - Nick Dunken
- Cluster of Excellence on Plant Sciences (CEPLAS) Institute for Plant Sciences University of Cologne Cologne Germany
| | - Prerana Wagle
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - Wolfgang Werr
- Developmental Biology Biocenter University of Cologne Cologne Germany
| | - Alga Zuccaro
- Cluster of Excellence on Plant Sciences (CEPLAS) Institute for Plant Sciences University of Cologne Cologne Germany
| | - Manuel Rodríguez‐Concepción
- Centre for Research in Agricultural Genomics (CRAG) CSIC‐IRTA‐UAB‐UBCampus UAB Bellaterra Barcelona Spain
- Institute for Plant Molecular and Cell Biology (IBMCP) CSIC‐UPV Valencia Spain
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
- Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany
- Faculty of Medicine University Hospital Cologne Cologne Germany
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23
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Gutiérrez-Gutiérrez Ó, Felix DA, Salvetti A, Amro EM, Thems A, Pietsch S, Koeberle A, Rudolph KL, González-Estévez C. Regeneration in starved planarians depends on TRiC/CCT subunits modulating the unfolded protein response. EMBO Rep 2021; 22:e52905. [PMID: 34190393 PMCID: PMC8344900 DOI: 10.15252/embr.202152905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
Planarians are able to stand long periods of starvation by maintaining adult stem cell pools and regenerative capacity. The molecular pathways that are needed for the maintenance of regeneration during starvation are not known. Here, we show that down‐regulation of chaperonin TRiC/CCT subunits abrogates the regeneration capacity of planarians during starvation, but TRiC/CCT subunits are dispensable for regeneration in fed planarians. Under starvation, they are required to maintain mitotic fidelity and for blastema formation. We show that TRiC subunits modulate the unfolded protein response (UPR) and are required to maintain ATP levels in starved planarians. Regenerative defects in starved CCT‐depleted planarians can be rescued by either chemical induction of mild endoplasmic reticulum stress, which leads to induction of the UPR, or by the supplementation of fatty acids. Together, these results indicate that CCT‐dependent UPR induction promotes regeneration of planarians under food restriction.
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Affiliation(s)
| | - Daniel A Felix
- Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
| | - Alessandra Salvetti
- Department of Clinical and Experimental Medicine, Unit of Experimental Biology and Genetics, University of Pisa, Pisa, Italy
| | - Elias M Amro
- Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
| | - Anne Thems
- Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
| | - Stefan Pietsch
- Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
| | - Andreas Koeberle
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany.,Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
| | - K Lenhard Rudolph
- Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
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24
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Banfi F, Rubio A, Zaghi M, Massimino L, Fagnocchi G, Bellini E, Luoni M, Cancellieri C, Bagliani A, Di Resta C, Maffezzini C, Ianielli A, Ferrari M, Piazza R, Mologni L, Broccoli V, Sessa A. SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome. Nat Commun 2021; 12:4050. [PMID: 34193871 PMCID: PMC8245514 DOI: 10.1038/s41467-021-24391-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
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MESH Headings
- Abnormalities, Multiple/genetics
- Abnormalities, Multiple/metabolism
- Abnormalities, Multiple/pathology
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Cells, Cultured
- Craniofacial Abnormalities/genetics
- Craniofacial Abnormalities/metabolism
- Craniofacial Abnormalities/pathology
- DNA Damage
- Hand Deformities, Congenital/genetics
- Hand Deformities, Congenital/metabolism
- Hand Deformities, Congenital/pathology
- Heredodegenerative Disorders, Nervous System/genetics
- Heredodegenerative Disorders, Nervous System/metabolism
- Heredodegenerative Disorders, Nervous System/pathology
- Humans
- Intellectual Disability/genetics
- Intellectual Disability/metabolism
- Intellectual Disability/pathology
- Mutation
- Nails, Malformed/genetics
- Nails, Malformed/metabolism
- Nails, Malformed/pathology
- Neural Stem Cells/metabolism
- Neural Stem Cells/pathology
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Organoids
- Tumor Suppressor Protein p53/antagonists & inhibitors
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Affiliation(s)
- Federica Banfi
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- CNR Institute of Neuroscience, Milan, Italy
| | - Alicia Rubio
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- CNR Institute of Neuroscience, Milan, Italy
| | - Mattia Zaghi
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca Massimino
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Fagnocchi
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Edoardo Bellini
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mirko Luoni
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Cinzia Cancellieri
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Human Induced Pluripotent Stem Cells service, Istituto Italiano di Oncologia Molecolare (IFOM), Milan, Italy
| | - Anna Bagliani
- Medical Oncology Unit, ASST Ovest Milanese, Legnano Hospital, Legnano, Italy
| | - Chiara Di Resta
- Vita-Salute San Raffaele University, Milan, Italy
- Unit of Genomics for human disease diagnosis, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Camilla Maffezzini
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Ianielli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- CNR Institute of Neuroscience, Milan, Italy
| | | | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Luca Mologni
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Vania Broccoli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- CNR Institute of Neuroscience, Milan, Italy
| | - Alessandro Sessa
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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25
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Oftedal BE, Maio S, Handel AE, White MPJ, Howie D, Davis S, Prevot N, Rota IA, Deadman ME, Kessler BM, Fischer R, Trede NS, Sezgin E, Maizels RM, Holländer GA. The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function. Commun Biol 2021; 4:681. [PMID: 34083746 PMCID: PMC8175432 DOI: 10.1038/s42003-021-02203-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.
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Affiliation(s)
- Bergithe E Oftedal
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
- Department of Clinical Science, University of Bergen, Bergen, Norway, K.G. Jebsen Center for Autoimmune Disorders, Bergen, Norway
| | - Stefano Maio
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Adam E Handel
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Madeleine P J White
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK
| | - Duncan Howie
- Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK
| | - Simon Davis
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Nicolas Prevot
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Ioanna A Rota
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Mary E Deadman
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Benedikt M Kessler
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Roman Fischer
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
| | - Nikolaus S Trede
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Erdinc Sezgin
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA, UK
| | - Georg A Holländer
- Developmental Immunology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
- Paediatric Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
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26
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Calculli G, Lee HJ, Shen K, Pham U, Herholz M, Trifunovic A, Dillin A, Vilchez D. Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans. SCIENCE ADVANCES 2021; 7:7/26/eabg3012. [PMID: 34172445 PMCID: PMC8232903 DOI: 10.1126/sciadv.abg3012] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/12/2021] [Indexed: 05/15/2023]
Abstract
Protein aggregation causes intracellular changes in neurons, which elicit signals to modulate proteostasis in the periphery. Beyond the nervous system, a fundamental question is whether other organs also communicate their proteostasis status to distal tissues. Here, we examine whether proteostasis of the germ line influences somatic tissues. To this end, we induce aggregation of germline-specific PGL-1 protein in germline stem cells of Caenorhabditis elegans Besides altering the intracellular mitochondrial network of germline cells, PGL-1 aggregation also reduces the mitochondrial content of somatic tissues through long-range Wnt signaling pathway. This process induces the unfolded protein response of the mitochondria in the soma, promoting somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington's and amyotrophic lateral sclerosis. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.
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Affiliation(s)
- Giuseppe Calculli
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Hyun Ju Lee
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Koning Shen
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Uyen Pham
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Marija Herholz
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Aleksandra Trifunovic
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andrew Dillin
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Faculty of Medicine, University Hospital Cologne, Cologne, Germany
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27
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Johnson KR, Mallon BS, Fann YC, Chen KG. Multivariate meta-analysis reveals global transcriptomic signatures underlying distinct human naive-like pluripotent states. PLoS One 2021; 16:e0251461. [PMID: 33984026 PMCID: PMC8118304 DOI: 10.1371/journal.pone.0251461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/27/2021] [Indexed: 11/19/2022] Open
Abstract
The ground or naive pluripotent state of human pluripotent stem cells (hPSCs), which was initially established in mouse embryonic stem cells (mESCs), is an emerging and tentative concept. To verify this vital concept in hPSCs, we performed a multivariate meta-analysis of major hPSC datasets via the combined analytic powers of percentile normalization, principal component analysis (PCA), t-distributed stochastic neighbor embedding (t-SNE), and SC3 consensus clustering. This robust bioinformatics approach has significantly improved the predictive values of our meta-analysis. Accordingly, we revealed various similarities or dissimilarities between some naive-like hPSCs (NLPs) generated from different laboratories. Our analysis confirms some previous studies and provides new evidence concerning the existence of three distinct naive-like pluripotent states. Moreover, our study offers global transcriptomic markers that define diverse pluripotent states under various hPSC growth protocols.
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Affiliation(s)
- Kory R. Johnson
- Intramural IT and Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail: (KRJ); (KGC)
| | - Barbara S. Mallon
- NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Yang C. Fann
- Intramural IT and Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Kevin G. Chen
- NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail: (KRJ); (KGC)
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Ilyinsky NS, Nesterov SV, Shestoperova EI, Fonin AV, Uversky VN, Gordeliy VI. On the Role of Normal Aging Processes in the Onset and Pathogenesis of Diseases Associated with the Abnormal Accumulation of Protein Aggregates. BIOCHEMISTRY (MOSCOW) 2021; 86:275-289. [PMID: 33838629 DOI: 10.1134/s0006297921030056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Aging is a prime systemic cause of various age-related diseases, in particular, proteinopathies. In fact, most diseases associated with protein misfolding are sporadic, and their incidence increases with aging. This review examines the process of protein aggregate formation, the toxicity of such aggregates, the organization of cellular systems involved in proteostasis, and the impact of protein aggregates on important cellular processes leading to proteinopathies. We also analyze how manifestations of aging (mitochondrial dysfunction, dysfunction of signaling systems, changes in the genome and epigenome) facilitate pathogenesis of various proteinopathies either directly, by increasing the propensity of key proteins for aggregation, or indirectly, through dysregulation of stress responses. Such analysis might help in outlining approaches for treating proteinopathies and extending healthy longevity.
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Affiliation(s)
- Nikolay S Ilyinsky
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.
| | - Semen V Nesterov
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Institute of Cytochemistry and Molecular Pharmacology, Moscow, 115404, Russia
| | - Elizaveta I Shestoperova
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia
| | - Alexander V Fonin
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, 194064, Russia
| | - Vladimir N Uversky
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Valentin I Gordeliy
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.,Forschungszentrum Juelich, Juelich, 52428, Germany.,Institut de Biologie Structurale, Grenoble, 38000, France
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Garibay-Cerdenares OL, Sánchez-Meza LV, Encarnación-Guevara S, Hernández-Ortíz M, Martínez-Batallar G, Torres-Rojas FI, Mendoza-Catalán MÁ, Moral-Hernández OD, Leyva-Vázquez MA, Illades-Aguiar B. Effect of HPV 16 E6 Oncoprotein Variants on the Alterations of the Proteome of C33A Cells. Cancer Genomics Proteomics 2021; 18:273-283. [PMID: 33893080 PMCID: PMC8126335 DOI: 10.21873/cgp.20258] [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: 01/09/2021] [Revised: 02/19/2021] [Accepted: 02/23/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND/AIM The E6 genotypic variants of HPV 16 identified in lesions of women with cervical cancer (CC) in Southern of Mexico include the E-G350, AAa, AAc, E-C188/G350, and E-A176/G350, transcriptomic analysis cells transfected with those variants showed to induce differential expression of the host genes involved in the development of CC, the aim of this work was to understand how the over-expression of the E6 oncoprotein and its variants can induce molecular mechanisms that lead to more aggressive HPV 16 phenotypes in cervical cancer and which proteins could be associated with the process. MATERIALS AND METHODS Total extracts from C33A, C33A mock, C33A AAa, C33A E-C188/G350, C33A E-A176/G350, and C33A E-prototype cells were analyzed using 2D electrophoresis, PDQuest software and mass spectrometry, validation of results was performed through qPCR. RESULTS Statistically significant differential expression of 122 spots was detected, 12 of the identified proteins were associated with metabolism and metabolic programming. Out of these CCT8, ENO and ALDH1A were further validated. CONCLUSION CCT8 and ALDH1A were found to be over-expressed in C33A AAa and C33A E-A176/G350, compared to the E prototype. Both proteins could be associated with a most aggressive phenotype due to their relationship with metabolism, protein folding and stemness, mechanisms associated to E6 that could be useful in the design of new therapies.
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Affiliation(s)
- Olga Lilia Garibay-Cerdenares
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
- CONACyT- Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Luz Victoria Sánchez-Meza
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | | | | | | | - Francisco Israel Torres-Rojas
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Miguel Ángel Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Oscar Del Moral-Hernández
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México;
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30
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Pras A, Nollen EAA. Regulation of Age-Related Protein Toxicity. Front Cell Dev Biol 2021; 9:637084. [PMID: 33748125 PMCID: PMC7973223 DOI: 10.3389/fcell.2021.637084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/10/2021] [Indexed: 12/23/2022] Open
Abstract
Proteome damage plays a major role in aging and age-related neurodegenerative diseases. Under healthy conditions, molecular quality control mechanisms prevent toxic protein misfolding and aggregation. These mechanisms include molecular chaperones for protein folding, spatial compartmentalization for sequestration, and degradation pathways for the removal of harmful proteins. These mechanisms decline with age, resulting in the accumulation of aggregation-prone proteins that are harmful to cells. In the past decades, a variety of fast- and slow-aging model organisms have been used to investigate the biological mechanisms that accelerate or prevent such protein toxicity. In this review, we describe the most important mechanisms that are required for maintaining a healthy proteome. We describe how these mechanisms decline during aging and lead to toxic protein misassembly, aggregation, and amyloid formation. In addition, we discuss how optimized protein homeostasis mechanisms in long-living animals contribute to prolonging their lifespan. This knowledge might help us to develop interventions in the protein homeostasis network that delay aging and age-related pathologies.
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Affiliation(s)
| | - Ellen A. A. Nollen
- Laboratory of Molecular Neurobiology of Ageing, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
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31
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Qian L, TCW J. Human iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery. Int J Mol Sci 2021; 22:1203. [PMID: 33530458 PMCID: PMC7865494 DOI: 10.3390/ijms22031203] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.
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Affiliation(s)
- Lu Qian
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Ronald Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Julia TCW
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Ronald Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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32
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Response of Pluripotent Stem Cells to Environmental Stress and Its Application for Directed Differentiation. BIOLOGY 2021; 10:biology10020084. [PMID: 33498611 PMCID: PMC7912122 DOI: 10.3390/biology10020084] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/14/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022]
Abstract
Simple Summary Environmental changes in oxygen concentration, temperature, and mechanical stimulation lead to the activation of specific transcriptional factors and induce the expression of each downstream gene. In general, these responses are protective machinery against such environmental stresses, while these transcriptional factors also regulate cell proliferation, differentiation, and organ development in mammals. In the case of pluripotent stem cells, similar response mechanisms normally work and sometimes stimulate the differentiation cues. Up to now, differentiation protocols utilizing such environmental stresses have been reported to obtain various types of somatic cells from pluripotent stem cells. Basically, environmental stresses as hypoxia (low oxygen), hyperoxia, (high oxygen) and mechanical stress from cell culture plates are relatively safer than chemicals and gene transfers, which affect the genome irreversibly. Therefore, protocols designed with such environments in mind could be useful for the technology development of cell therapy and regenerative medicine. In this manuscript, we summarize recent findings of environmental stress-induced differentiation protocols and discuss their mechanisms. Abstract Pluripotent stem cells have unique characteristics compared to somatic cells. In this review, we summarize the response to environmental stresses (hypoxic, oxidative, thermal, and mechanical stresses) in embryonic stem cells (ESCs) and their applications in the differentiation methods directed to specific lineages. Those stresses lead to activation of each specific transcription factor followed by the induction of downstream genes, and one of them regulates lineage specification. In short, hypoxic stress promotes the differentiation of ESCs to mesodermal lineages via HIF-1α activation. Concerning mechanical stress, high stiffness tends to promote mesodermal differentiation, while low stiffness promotes ectodermal differentiation via the modulation of YAP1. Furthermore, each step in the same lineage differentiation favors each appropriate stiffness of culture plate; for example, definitive endoderm favors high stiffness, while pancreatic progenitor favors low stiffness during pancreatic differentiation of human ESCs. Overall, treatments utilizing those stresses have no genotoxic or carcinogenic effects except oxidative stress; therefore, the differentiated cells are safe and could be useful for cell replacement therapy. In particular, the effect of mechanical stress on differentiation is becoming attractive for the field of regenerative medicine. Therefore, the development of a stress-mediated differentiation protocol is an important matter for the future.
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33
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Yan P, Ren J, Zhang W, Qu J, Liu GH. Protein quality control of cell stemness. CELL REGENERATION (LONDON, ENGLAND) 2020; 9:22. [PMID: 33179756 PMCID: PMC7658286 DOI: 10.1186/s13619-020-00064-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023]
Abstract
Protein quality control (PQC) systems play essential roles in the recognition, refolding and clearance of aberrant proteins, thus ensuring cellular protein homeostasis, or proteostasis. Especially, continued proliferation and differentiation of stem cells require a high rate of translation; therefore, accurate PQC systems are essential to maintain stem cell function. Growing evidence suggested crucial roles of PQC systems in regulating the stemness and differentiation of stem cells. This review focuses on current knowledge regarding the components of the proteostasis network in stem cells, and the importance of proteostasis in maintaining stem cell identity and regenerative functions. A complete understanding of this process might uncover potential applications in aging intervention and aging-related diseases.
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Affiliation(s)
- Pengze Yan
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jie Ren
- University of Chinese Academy of Sciences, Beijing, 100049, China
- China National Center for Bioinformation, Beijing, 100101, China
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China
- Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Weiqi Zhang
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- China National Center for Bioinformation, Beijing, 100101, China.
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
- Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jing Qu
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
- Beijing Institute for Brain Disorders, Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, 100053, China.
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34
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The intrinsic proteostasis network of stem cells. Curr Opin Cell Biol 2020; 67:46-55. [PMID: 32890906 DOI: 10.1016/j.ceb.2020.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 01/03/2023]
Abstract
The proteostasis network adjusts protein composition and maintains protein integrity, which are essential processes for cell function and viability. Current efforts, given their intrinsic characteristics, regenerative potential and fundamental biological functions, have been directed to define proteostasis of stem cells. These insights demonstrate that embryonic stem cells and induced pluripotent stem cells exhibit an endogenous proteostasis network that not only modulates their pluripotency and differentiation but also provides a striking ability to suppress aggregation of disease-related proteins. Moreover, recent findings establish a central role of enhanced proteostasis to prevent the aging of somatic stem cells in adult organisms. Notably, proteostasis is also required for the biological purpose of adult germline stem cells, that is to be passed from one generation to the next. Beyond these links between proteostasis and stem cell function, we also discuss the implications of these findings for disease, aging, and reproduction.
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35
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Ribosomes: An Exciting Avenue in Stem Cell Research. Stem Cells Int 2020; 2020:8863539. [PMID: 32695182 PMCID: PMC7362291 DOI: 10.1155/2020/8863539] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023] Open
Abstract
Stem cell research has focused on genomic studies. However, recent evidence has indicated the involvement of epigenetic regulation in determining the fate of stem cells. Ribosomes play a crucial role in epigenetic regulation, and thus, we focused on the role of ribosomes in stem cells. Majority of living organisms possess ribosomes that are involved in the translation of mRNA into proteins and promote cellular proliferation and differentiation. Ribosomes are stable molecular machines that play a role with changes in the levels of RNA during translation. Recent research suggests that specific ribosomes actively regulate gene expression in multiple cell types, such as stem cells. Stem cells have the potential for self-renewal and differentiation into multiple lineages and, thus, require high efficiency of translation. Ribosomes induce cellular transdifferentiation and reprogramming, and disrupted ribosome synthesis affects translation efficiency, thereby hindering stem cell function leading to cell death and differentiation. Stem cell function is regulated by ribosome-mediated control of stem cell-specific gene expression. In this review, we have presented a detailed discourse on the characteristics of ribosomes in stem cells. Understanding ribosome biology in stem cells will provide insights into the regulation of stem cell function and cellular reprogramming.
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36
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The ubiquitin-conjugating enzyme UBE2K determines neurogenic potential through histone H3 in human embryonic stem cells. Commun Biol 2020; 3:262. [PMID: 32451438 PMCID: PMC7248108 DOI: 10.1038/s42003-020-0984-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 05/01/2020] [Indexed: 01/05/2023] Open
Abstract
Histones modulate gene expression by chromatin compaction, regulating numerous processes such as differentiation. However, the mechanisms underlying histone degradation remain elusive. Human embryonic stem cells (hESCs) have a unique chromatin architecture characterized by low levels of trimethylated histone H3 at lysine 9 (H3K9me3), a heterochromatin-associated modification. Here we assess the link between the intrinsic epigenetic landscape and ubiquitin-proteasome system of hESCs. We find that hESCs exhibit high expression of the ubiquitin-conjugating enzyme UBE2K. Loss of UBE2K upregulates the trimethyltransferase SETDB1, resulting in H3K9 trimethylation and repression of neurogenic genes during differentiation. Besides H3K9 trimethylation, UBE2K binds histone H3 to induce its polyubiquitination and degradation by the proteasome. Notably, ubc-20, the worm orthologue of UBE2K, also regulates histone H3 levels and H3K9 trimethylation in Caenorhabditis elegans germ cells. Thus, our results indicate that UBE2K crosses evolutionary boundaries to promote histone H3 degradation and reduce H3K9me3 repressive marks in immortal cells. Azra Fatima et al. show that ubiquitin-conjugating enzyme UBE2K regulates neurogenic potential through its target histone H3 in human embryonic stem cells. This study suggests that UBE2K promotes histone H3 degradation, reducing the H3K9me3 repressive marks in immortal cells of both worms and humans.
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37
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Sadler E, Ryals MM, May LA, Martin D, Welsh N, Boger ET, Morell RJ, Hertzano R, Cunningham LL. Cell-Specific Transcriptional Responses to Heat Shock in the Mouse Utricle Epithelium. Front Cell Neurosci 2020; 14:123. [PMID: 32528249 PMCID: PMC7247426 DOI: 10.3389/fncel.2020.00123] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/15/2020] [Indexed: 12/21/2022] Open
Abstract
Sensory epithelia of the inner ear contain mechanosensory hair cells (HCs) and glia-like supporting cells (SCs), both of which are required for hearing and balance functions. Each of these cell types has unique responses to ototoxic and cytoprotective stimuli. Non-lethal heat stress in the mammalian utricle induces heat shock proteins (HSPs) and protects against ototoxic drug-induced hair cell death. Induction of HSPs in the utricle demonstrates cell-type specificity at the protein level, with HSP70 induction occurring primarily in SCs, while HSP32 (also known as heme oxygenase 1, HMOX1) is induced primarily in resident macrophages. Neither of these HSPs are robustly induced in HCs, suggesting that HCs may have little capacity for induction of stress-induced protective responses. To determine the transcriptional responses to heat shock of these different cell types, we performed cell-type-specific transcriptional profiling using the RiboTag method, which allows for immunoprecipitation (IP) of actively translating mRNAs from specific cell types. RNA-Seq differential gene expression analyses demonstrated that the RiboTag method identified known cell type-specific markers as well as new markers for HCs and SCs. Gene expression differences suggest that HCs and SCs exhibit differential transcriptional heat shock responses. The chaperonin family member Cct8 was significantly enriched only in heat-shocked HCs, while Hspa1l (HSP70 family), and Hspb1 and Cryab (HSP27 and HSP20 families, respectively) were enriched only in SCs. Together our data indicate that HCs exhibit a limited but unique heat shock response, and SCs exhibit a broader and more robust transcriptional response to protective heat stress.
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Affiliation(s)
- Erica Sadler
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States
| | - Matthew M Ryals
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States.,Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Lindsey A May
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States
| | - Daniel Martin
- Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States.,Genomics and Computational Biology Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
| | - Nora Welsh
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States
| | - Erich T Boger
- Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States
| | - Robert J Morell
- Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States
| | - Ronna Hertzano
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, United States.,Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States.,Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Lisa L Cunningham
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, United States
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38
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Thiruvalluvan A, de Mattos EP, Brunsting JF, Bakels R, Serlidaki D, Barazzuol L, Conforti P, Fatima A, Koyuncu S, Cattaneo E, Vilchez D, Bergink S, Boddeke EHWG, Copray S, Kampinga HH. DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis. Mol Cell 2020; 78:346-358.e9. [PMID: 32268123 DOI: 10.1016/j.molcel.2020.02.022] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 12/31/2019] [Accepted: 02/25/2020] [Indexed: 01/09/2023]
Abstract
CAG-repeat expansions in at least eight different genes cause neurodegeneration. The length of the extended polyglutamine stretches in the corresponding proteins is proportionally related to their aggregation propensity. Although these proteins are ubiquitously expressed, they predominantly cause toxicity to neurons. To understand this neuronal hypersensitivity, we generated induced pluripotent stem cell (iPSC) lines of spinocerebellar ataxia type 3 and Huntington's disease patients. iPSC generation and neuronal differentiation are unaffected by polyglutamine proteins and show no spontaneous aggregate formation. However, upon glutamate treatment, aggregates form in neurons but not in patient-derived neural progenitors. During differentiation, the chaperone network is drastically rewired, including loss of expression of the anti-amyloidogenic chaperone DNAJB6. Upregulation of DNAJB6 in neurons antagonizes glutamate-induced aggregation, while knockdown of DNAJB6 in progenitors results in spontaneous polyglutamine aggregation. Loss of DNAJB6 expression upon differentiation is confirmed in vivo, explaining why stem cells are intrinsically protected against amyloidogenesis and protein aggregates are dominantly present in neurons.
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Affiliation(s)
- Arun Thiruvalluvan
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Eduardo P de Mattos
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jeanette F Brunsting
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Rob Bakels
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Despina Serlidaki
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Lara Barazzuol
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Paola Conforti
- Department of Biosciences, University of Milan, Milan, Italy; Istituto Nazionale di Genetica Molecolare, Romeo ed Enrica Invernizzi, Milan, Italy
| | - Azra Fatima
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Seda Koyuncu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Elena Cattaneo
- Department of Biosciences, University of Milan, Milan, Italy; Istituto Nazionale di Genetica Molecolare, Romeo ed Enrica Invernizzi, Milan, Italy
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Steven Bergink
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Erik H W G Boddeke
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Sjef Copray
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Harm H Kampinga
- Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Abstract
Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.
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40
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Zhang FQ, Jiang JL, Zhang JT, Niu H, Fu XQ, Zeng LL. Current status and future prospects of stem cell therapy in Alzheimer's disease. Neural Regen Res 2020; 15:242-250. [PMID: 31552889 PMCID: PMC6905342 DOI: 10.4103/1673-5374.265544] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/18/2019] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer's disease, and the current state of stem cell transplantation in the treatment of Alzheimer's disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer's disease.
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Affiliation(s)
- Fu-Qiang Zhang
- Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Jin-Lan Jiang
- Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Jing-Tian Zhang
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Han Niu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Xue-Qi Fu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Lin-Lin Zeng
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
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41
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Jayaraj GG, Hipp MS, Hartl FU. Functional Modules of the Proteostasis Network. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a033951. [PMID: 30833457 DOI: 10.1101/cshperspect.a033951] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cells invest in an extensive network of factors to maintain protein homeostasis (proteostasis) and prevent the accumulation of potentially toxic protein aggregates. This proteostasis network (PN) comprises the machineries for the biogenesis, folding, conformational maintenance, and degradation of proteins with molecular chaperones as central coordinators. Here, we review recent progress in understanding the modular architecture of the PN in mammalian cells and how it is modified during cell differentiation. We discuss the capacity and limitations of the PN in maintaining proteome integrity in the face of proteotoxic stresses, such as aggregate formation in neurodegenerative diseases. Finally, we outline various pharmacological interventions to ameliorate proteostasis imbalance.
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Affiliation(s)
- Gopal G Jayaraj
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
| | - Mark S Hipp
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
| | - F Ulrich Hartl
- Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
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42
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Matthews H, Noulin F. Unexpected encounter of the parasitic kind. World J Stem Cells 2019; 11:904-919. [PMID: 31768219 PMCID: PMC6851008 DOI: 10.4252/wjsc.v11.i11.904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/10/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Both parasitology and stem cell research are important disciplines in their own right. Parasites are a real threat to human health causing a broad spectrum of diseases and significant annual rates morbidity and mortality globally. Stem cell research, on the other hand, focuses on the potential for regenerative medicine for a range of diseases including cancer and regenerative therapies. Though these two topics might appear distant, there are some “unexpected encounters”. In this review, we summarise the various links between parasites and stem cells. First, we discuss how parasites’ own stem cells represent interesting models of regeneration that can be translated to human stem cell regeneration. Second, we explore the interactions between parasites and host stem cells during the course of infection. Third, we investigate from a clinical perspective, how stem cell regeneration can be exploited to help circumvent the damage induced by parasitic infection and its potential to serve as treatment options for parasitic diseases in the future. Finally, we discuss the importance of screening for pathogens during organ transplantation by presenting some clinical cases of parasitic infection following stem cell therapy.
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Affiliation(s)
- Holly Matthews
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
| | - Florian Noulin
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
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43
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Ramos J, Han L, Li Y, Hagelskamp F, Kellner SM, Alkuraya FS, Phizicky EM, Fu D. Formation of tRNA Wobble Inosine in Humans Is Disrupted by a Millennia-Old Mutation Causing Intellectual Disability. Mol Cell Biol 2019; 39:e00203-19. [PMID: 31263000 PMCID: PMC6751630 DOI: 10.1128/mcb.00203-19] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/11/2019] [Accepted: 06/27/2019] [Indexed: 12/20/2022] Open
Abstract
The formation of inosine at the wobble position of eukaryotic tRNAs is an essential modification catalyzed by the ADAT2/ADAT3 complex. In humans, a valine-to-methionine mutation (V144M) in ADAT3 that originated ∼1,600 years ago is the most common cause of autosomal recessive intellectual disability (ID) in Arabia. While the mutation is predicted to affect protein structure, the molecular and cellular effects of the V144M mutation are unknown. Here, we show that cell lines derived from ID-affected individuals expressing only ADAT3-V144M exhibit decreased wobble inosine in certain tRNAs. Moreover, extracts from the same cell lines of ID-affected individuals display a severe reduction in tRNA deaminase activity. While ADAT3-V144M maintains interactions with ADAT2, the purified ADAT2/3-V144M complexes exhibit defects in activity. Notably, ADAT3-V144M exhibits an increased propensity to form aggregates associated with cytoplasmic chaperonins that can be suppressed by ADAT2 overexpression. These results identify a key role for ADAT2-dependent folding of ADAT3 in wobble inosine modification and indicate that proper formation of an active ADAT2/3 complex is crucial for proper neurodevelopment.
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Affiliation(s)
- Jillian Ramos
- Department of Biology, University of Rochester, Rochester, New York, USA
- Center for RNA Biology, University of Rochester and University of Rochester Medical Center, Rochester, New York, USA
| | - Lu Han
- Center for RNA Biology, University of Rochester and University of Rochester Medical Center, Rochester, New York, USA
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA
| | - Yan Li
- Department of Biology, University of Rochester, Rochester, New York, USA
- Center for RNA Biology, University of Rochester and University of Rochester Medical Center, Rochester, New York, USA
| | - Felix Hagelskamp
- Department of Chemistry, Ludwig Maximilians Universität München, Munich, Germany
| | - Stefanie M Kellner
- Department of Chemistry, Ludwig Maximilians Universität München, Munich, Germany
| | - Fowzan S Alkuraya
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Eric M Phizicky
- Center for RNA Biology, University of Rochester and University of Rochester Medical Center, Rochester, New York, USA
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA
| | - Dragony Fu
- Department of Biology, University of Rochester, Rochester, New York, USA
- Center for RNA Biology, University of Rochester and University of Rochester Medical Center, Rochester, New York, USA
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44
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An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity. Proc Natl Acad Sci U S A 2019; 116:19513-19522. [PMID: 31492816 PMCID: PMC6765261 DOI: 10.1073/pnas.1903976116] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The ATP-fueled TRiC/CCT acts in the folding of 10% cytosolic proteins. TRiC consists of 8 paralogous subunits, each of which plays special roles in TRiC assembly, allosteric cooperativity, and substrate folding. However, due to lack of a thorough picture of TRiC conformational landscape and atomic-resolution details, the underlying structural mechanisms of TRiC subunit specificity in nucleotide usage and substrate binding, and the allosteric transition during ring closure remain unclear. Here, through cryo-electron microscopy (cryo-EM) analysis, we captured a thorough picture of TRiC conformational landscape from open to closed states and its gradually enhanced allosteric coordination, including the N termini, in unprecedented structural detail. Our study also offers insights into the TRiC subunit specificities in nucleotide usage and ring closure. TRiC/CCT assists the folding of ∼10% of cytosolic proteins through an ATP-driven conformational cycle and is essential in maintaining protein homeostasis. Here, we determined an ensemble of cryo-electron microscopy (cryo-EM) structures of yeast TRiC at various nucleotide concentrations, with 4 open-state maps resolved at near-atomic resolutions, and a closed-state map at atomic resolution, revealing an extra layer of an unforeseen N-terminal allosteric network. We found that, during TRiC ring closure, the CCT7 subunit moves first, responding to nucleotide binding; CCT4 is the last to bind ATP, serving as an ATP sensor; and CCT8 remains ADP-bound and is hardly involved in the ATPase-cycle in our experimental conditions; overall, yeast TRiC consumes nucleotide in a 2-ring positively coordinated manner. Our results depict a thorough picture of the TRiC conformational landscape and its allosteric transitions from the open to closed states in more structural detail and offer insights into TRiC subunit specificity in ATP consumption and ring closure, and potentially in substrate processing.
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45
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Ermolaeva M, Neri F, Ori A, Rudolph KL. Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol 2019; 19:594-610. [PMID: 29858605 DOI: 10.1038/s41580-018-0020-3] [Citation(s) in RCA: 164] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adult tissue stem cells have a pivotal role in tissue maintenance and regeneration throughout the lifespan of multicellular organisms. Loss of tissue homeostasis during post-reproductive lifespan is caused, at least in part, by a decline in stem cell function and is associated with an increased incidence of diseases. Hallmarks of ageing include the accumulation of molecular damage, failure of quality control systems, metabolic changes and alterations in epigenome stability. In this Review, we discuss recent evidence in support of a novel concept whereby cell-intrinsic damage that accumulates during ageing and cell-extrinsic changes in ageing stem cell niches and the blood result in modifications of the stem cell epigenome. These cumulative epigenetic alterations in stem cells might be the cause of the deregulation of developmental pathways seen during ageing. In turn, they could confer a selective advantage to mutant and epigenetically drifted stem cells with altered self-renewal and functions, which contribute to the development of ageing-associated organ dysfunction and disease.
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Affiliation(s)
- Maria Ermolaeva
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
| | - Francesco Neri
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
| | - Alessandro Ori
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
| | - K Lenhard Rudolph
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany. .,Medical Faculty Jena, University Hospital Jena (UKJ), Jena, Germany.
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46
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Lee HJ, Noormohammadi A, Koyuncu S, Calculli G, Simic MS, Herholz M, Trifunovic A, Vilchez D. Prostaglandin signals from adult germ stem cells delay somatic aging of Caenorhabditis elegans. Nat Metab 2019; 1:790-810. [PMID: 31485561 PMCID: PMC6726479 DOI: 10.1038/s42255-019-0097-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
A moderate reduction of body temperature can induce a remarkable lifespan extension. Here we examine the link between cold temperature, germ line fitness and organismal longevity. We show that low temperature reduces age-associated exhaustion of germ stem cells (GSCs) in Caenorhabditis elegans, a process modulated by thermosensory neurons. Notably, robust self-renewal of adult GSCs delays reproductive aging and is required for extended lifespan at cold temperatures. These cells release prostaglandin E2 (PGE2) to induce cbs-1 expression in the intestine, increasing somatic production of hydrogen sulfide (H2S), a gaseous signaling molecule that prolongs lifespan. Whereas loss of adult GSCs reduces intestinal cbs-1 expression and cold-induced longevity, application of exogenous PGE2 rescues these phenotypes. Importantly, tissue-specific intestinal overexpression of cbs-1 mimics cold-temperature conditions and extends longevity even at warm temperatures. Thus, our results indicate that GSCs communicate with somatic tissues to coordinate extended reproductive capacity with longevity.
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Affiliation(s)
- Hyun Ju Lee
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Alireza Noormohammadi
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Seda Koyuncu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Giuseppe Calculli
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Milos S Simic
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Marija Herholz
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Aleksandra Trifunovic
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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47
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The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells. Stem Cells Int 2019; 2019:1608787. [PMID: 31191665 PMCID: PMC6525796 DOI: 10.1155/2019/1608787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 03/05/2019] [Indexed: 12/19/2022] Open
Abstract
Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.
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48
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Irmak D, Fatima A, Gutiérrez-Garcia R, Rinschen MM, Wagle P, Altmüller J, Arrigoni L, Hummel B, Klein C, Frese CK, Sawarkar R, Rada-Iglesias A, Vilchez D. Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations. Hum Mol Genet 2019; 27:4117-4134. [PMID: 30452683 DOI: 10.1093/hmg/ddy304] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023] Open
Abstract
Pluripotent stem cells are invaluable resources to study development and disease, holding a great promise for regenerative medicine. Here we use human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) from patients with Huntington's disease (HD-iPSCs) to shed light into the normal function of huntingtin (HTT) and its demise in disease. We find that HTT binds ATF7IP, a regulator of the histone H3 methyltransferase SETDB1. HTT inhibits the interaction of the ATF7IP-SETDB1 complex with other heterochromatin regulators and transcriptional repressors, maintaining low levels of H3K9 trimethylation (H3K9me3) in hESCs. Loss of HTT promotes global increased H3K9me3 levels and enrichment of H3K9me3 marks at distinct genes, including transcriptional regulators of neuronal differentiation. Although these genes are normally expressed at low amounts in hESCs, HTT knockdown (KD) reduces their induction during neural differentiation. Notably, mutant expanded polyglutamine repeats in HTT diminish its interaction with ATF7IP-SETDB1 complex and trigger H3K9me3 in HD-iPSCs. Conversely, KD of ATF7IP in HD-iPSCs reduces H3K9me3 alterations and ameliorates gene expression changes in their neural counterparts. Taken together, our results indicate ATF7IP as a potential target to correct aberrant H3K9me3 levels induced by mutant HTT.
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Affiliation(s)
- Dilber Irmak
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Azra Fatima
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Ricardo Gutiérrez-Garcia
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Markus M Rinschen
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Prerana Wagle
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Janine Altmüller
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, Cologne, Germany.,Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Laura Arrigoni
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Barbara Hummel
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Corinna Klein
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Christian K Frese
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
| | - Ritwick Sawarkar
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Alvaro Rada-Iglesias
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, Cologne, Germany
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne, Germany
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49
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Kim AR, Choi KW. TRiC/CCT chaperonins are essential for organ growth by interacting with insulin/TOR signaling in Drosophila. Oncogene 2019; 38:4739-4754. [PMID: 30792539 PMCID: PMC6756063 DOI: 10.1038/s41388-019-0754-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 12/28/2018] [Accepted: 02/08/2019] [Indexed: 12/12/2022]
Abstract
Organ size is regulated by intercellular signaling for cell growth and proliferation. The TOR pathway mediates a key signaling mechanism for controlling cell size and number in organ growth. Chaperonin containing TCP-1 (CCT) is a complex that assists protein folding and function, but its role in animal development is largely unknown. Here we show that the CCT complex is required for organ growth by interacting with the TOR pathway in Drosophila. Reduction of CCT4 results in growth defects by affecting both cell size and proliferation. Loss of CCT4 causes preferential cell death anterior to the morphogenetic furrow in the eye disc and within wing pouch in the wing disc. Depletion of any CCT subunit in the eye disc results in headless phenotype. Overgrowth by active TOR signaling is suppressed by CCT RNAi. The CCT complex physically interacts with TOR signaling components including TOR, Rheb, and S6K. Loss of CCT leads to decreased phosphorylation of S6K and S6 while increasing phosphorylation of Akt. Insulin/TOR signaling is also necessary and sufficient for promoting CCT complex transcription. Our data provide evidence that the CCT complex regulates organ growth by directly interacting with the TOR signaling pathway.
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Affiliation(s)
- Ah-Ram Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Republic of Korea.,Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA
| | - Kwang-Wook Choi
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Republic of Korea.
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50
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Wu Y, Zhang J, Fang L, Lee HC, Zhao YJ. A cytosolic chaperone complex controls folding and degradation of type III CD38. J Biol Chem 2019; 294:4247-4258. [PMID: 30670591 DOI: 10.1074/jbc.ra118.005844] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 01/11/2019] [Indexed: 11/06/2022] Open
Abstract
Cluster of differentiation 38 (CD38) is the best-studied enzyme catalyzing the synthesis of the Ca2+ messenger cyclic ADP-ribose. It is a single-pass transmembrane protein, but possesses dual orientations. We have documented the natural existence of type III CD38 in cells and shown that it is regulated by a cytosolic activator, calcium- and integrin-binding 1 (CIB1). However, how type III CD38 can be folded correctly in the reductive cytosol has not been addressed. Using the yeast two-hybrid technique with CD38's catalytic domain (sCD38) as bait, here we identified a chaperone, Hsp70-interacting protein (Hip), that specifically interacts with both the type III CD38 and sCD38. Immunoprecipitation coupled with MS identified a chaperone complex associated specifically with sCD38. Pharmacological and siRNA-mediated knockdown of Hsp90 chaperones decreased the expression levels of both sCD38 and type III CD38, suggesting that these chaperones facilitate their folding. Moreover, knockdown of Hsc70 or DNAJA2 increased the levels of both CD38 types, consistent with the roles of these proteins in mediating CD38 degradation. Notably, Hip knockdown decreased type III CD38 substantially, but only marginally affected sCD38, indicating that Hip was selective for the former. More remarkably, DNAJA1 knockdown decreased sCD38 but increased type III CD38 levels. Mechanistically, we show that Hsc70 mediates lysosomal degradation of type III CD38, requiring the lysosomal receptor Lamp2A and the C19-motif in the C terminus of CD38. Our results indicate that folding and degradation of type III CD38 is effectively controlled in cells, providing further strong support of its physiological relevance.
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Affiliation(s)
- Yang Wu
- From the State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China, 518055 and
| | - Jingzi Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, China, 210093
| | - Lei Fang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, China, 210093
| | - Hon Cheung Lee
- From the State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China, 518055 and
| | - Yong Juan Zhao
- From the State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China, 518055 and
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