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1
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Fremlén H, Burmann BM. Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases. Chembiochem 2025:e202500048. [PMID: 40056010 DOI: 10.1002/cbic.202500048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 03/07/2025] [Indexed: 03/19/2025]
Abstract
Cells in all kingdoms of life employ dedicated protein quality control machineries for both their cytosolic and membrane proteome ensuring cellular functionality. These crucial systems consist besides a large variety of molecular chaperones, ensuring a proper fold and consequently function of the client's proteome, of several proteases to clean out damaged, unfunctional and potentially toxic proteins. One of the key features underlying the functional cycle of these quality control systems is the inherent flexibility of their bound clients which for a long time impaired detailed structural characterization, with advanced high-resolution NMR spectroscopy in the last decade playing a key role contributing to the present understanding of their functional properties. Although these studies laid the foundation of the present knowledge of the mechanistic details of the maintenance of cytosolic proteins, the understanding of related systems employed for membrane associated as well as integral membrane proteins remains rather sparse to date. Herein, we review the crucial contributions of structural and dynamical biology approaches, possessing the power to resolve both structure and dynamics of such systems as well as enabling the elucidation of the functional repertoire of multimeric proteases involved in maintaining a functional membrane proteome.
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Affiliation(s)
- Hannah Fremlén
- Department of Chemistry and Molecular Biology, Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 405 30, Göteborg, Sweden
| | - Björn M Burmann
- Department of Chemistry and Molecular Biology, Wallenberg Centre for Molecular and Translational Medicine, Science for Life Laboratory, Swedish NMR Centre, University of Gothenburg, 405 30, Göteborg, Sweden
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2
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Sun Z, He W, Meng H, Li P, Qu J. Endoplasmic reticulum stress in acute lung injury and pulmonary fibrosis. FASEB J 2024; 38:e70232. [PMID: 39651914 DOI: 10.1096/fj.202401849rr] [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: 08/10/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive and irreversible lung disease that leads to diminished lung function, respiratory failure, and ultimately death and typically has a poor prognosis, with an average survival time of 2 to 5 years. Related articles suggested that endoplasmic reticulum (ER) stress played a critical role in the occurrence and progression of PF. The ER is responsible for maintaining protein homeostasis. However, factors such as aging, hypoxia, oxidative stress, or inflammation can disrupt this balance, promoting the accumulation of misfolded proteins in the ER and triggering ER stress. To cope with this situation, cells activate the unfolded protein response (UPR). Since acute lung injury (ALI) is one of the key onset events of PF, in this review, we will discuss the role of ER stress in ALI and PF by activating multiple signaling pathways and molecular mechanisms that affect the function and behavior of different cell types, with a focus on epithelial cells, fibroblasts, and macrophages. Linking ER stress to these cell types may broaden our understanding of the mechanisms underlying lung fibrosis and help us target these cells through these mechanisms. The relationship between ER stress and PF is still evolving, and future research will explore new strategies to regulate UPR pathways, providing novel therapeutic targets.
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Affiliation(s)
- Zhiheng Sun
- College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
- State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China
| | - Wanyu He
- College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
- State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China
| | - Huiwen Meng
- College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
- State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China
| | - Peizhi Li
- Department of Anesthesiology, Xinxiang First People's Hospital, The Affiliated People's Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Junxing Qu
- Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Xinxiang, Henan, China
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3
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Dan W, Fan Y, Wang Y, Hou T, Wei Y, Liu B, Li M, Chen J, Fang Q, Que T, Lei Y, Guo C, Wang C, Gao Y, Zeng J, Li L. The Tumor Suppressor TPD52-Governed Endoplasmic Reticulum Stress is Modulated by APC Cdc20. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405441. [PMID: 39401430 PMCID: PMC11615746 DOI: 10.1002/advs.202405441] [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: 05/20/2024] [Revised: 09/25/2024] [Indexed: 12/06/2024]
Abstract
Aberrant regulation of unfolded protein response (UPR)/endoplasmic reticulum (ER) stress pathway is associated with cancer development, metastasis, and relapse, and the UPR signal transducer ATF6 has been proposed as a diagnostic and prognostic marker for many cancers. However, a causal molecular link between ATF6 activation and carcinogenesis is not established. Here, it is found that tumor protein D52 (TPD52) integrates ER stress and UPR signaling with the chaperone machinery by promoting S2P-mediated cleavage of ATF6. Although TPD52 has been generally considered as an oncogene, TPD52 is identified as a novel tumor suppressor in bladder cancer. Significantly, attenuation of the ER stress via depletion of TPD52 facilitated tumorigenesis in a subset of human carcinomas. Furthermore, the APCCdc20 E3 ligase is validated as the upstream regulator marking TPD52 for polyubiquitination-mediated proteolysis. In addition, inactivation of Cdc20 sensitized cancer cells to treatment with the ER stress inducer in a TPD52-dependent manner. Thus, the study suggests that TPD52 is a novel Cdc20 substrate that may modulate ER stress to prevent tumorigenesis.
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4
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Capolupo I, Miranda MR, Musella S, Di Sarno V, Manfra M, Ostacolo C, Bertamino A, Campiglia P, Ciaglia T. Exploring Endocannabinoid System: Unveiling New Roles in Modulating ER Stress. Antioxidants (Basel) 2024; 13:1284. [PMID: 39594426 PMCID: PMC11591047 DOI: 10.3390/antiox13111284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
The endoplasmic reticulum (ER) is the organelle mainly involved in maintaining cellular homeostasis and driving correct protein folding. ER-dependent defects or dysfunctions are associated with the genesis/progression of several pathological conditions, including cancer, inflammation, and neurodegenerative disorders, that are directly or indirectly correlated to a wide set of events collectively named under the term "ER stress". Despite the recent increase in interest concerning ER activity, further research studies are needed to highlight all the mechanisms responsible for ER failure. In this field, recent discoveries paved the way for the comprehension of the strong interaction between ER stress development and the endocannabinoid system. The activity of the endocannabinoid system is mediated by the activation of cannabinoid receptors (CB), G protein-coupled receptors that induce a decrease in cAMP levels, with downstream anti-inflammatory effects. CB activation drives, in most cases, the recovery of ER homeostasis through the regulation of ER stress hallmarks PERK, ATF6, and IRE1. In this review, we focus on the CB role in modulating ER stress, with particular attention to the cellular processes leading to UPR activation and oxidative stress response extinguishment, and to the mechanisms underlying natural cannabinoids' modulation of this complex cellular machine.
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Affiliation(s)
- Ilaria Capolupo
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
- PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, 84084 Salerno, Italy
| | - Maria Rosaria Miranda
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
- PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, 84084 Salerno, Italy
- NBFC—National Biodiversity Future Center, 90133 Palermo, Italy
| | - Simona Musella
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
| | - Veronica Di Sarno
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
| | - Michele Manfra
- Department of Health Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy;
| | - Carmine Ostacolo
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
| | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
| | - Tania Ciaglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy; (I.C.); (M.R.M.); (S.M.); (V.D.S.); (C.O.); (A.B.); (P.C.)
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5
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Chen Y, Liu Y, Li Y, Yao C, Qu J, Tang J, Chen G, Han Y. Acute exposure to polystyrene nanoplastics induces unfolded protein response and global protein ubiquitination in lungs of mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 280:116580. [PMID: 38865938 DOI: 10.1016/j.ecoenv.2024.116580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/21/2024] [Accepted: 06/08/2024] [Indexed: 06/14/2024]
Abstract
Inhaling microplastics (MPs) and nanoplastics (NPs) in the air can damage lung function. Xenobiotics in the body can cause endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) activation alleviates ER stress. Degradation of unfolded or misfolded proteins is an important pathway for recovering cellular homeostasis. The UPR and protein degradation induced by MPs/NPs in lung tissues are not well understood. Here, we investigated the UPR and protein ubiquitination in the lungs of mice exposed to polystyrene (PS)-NPs and their possible molecular mechanisms leading to protein ubiquitination. Mice were intratracheally administered with 5.6, 17, and 51 mg/kg PS-NPs once for 24 h. Exposure to PS-NPs elevated protein ubiquitination in the lungs of mice in a dose-dependent manner. PS-NPs activated three branches of UPR including inositol-requiring protein 1α (IRE1α), eukaryotic translation initiator factor 2α (eIF2α), and activating transcription factor 6α (ATF6α) in the lungs of mice. However, activated IRE1α did not trigger X-box binding protein 1 (XBP1) mRNA splicing. Exposure to PS-NPs induced an increase in the levels of E3 ubiquitin ligase hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (HRD1) and carboxy terminus of Hsc70 interacting protein (CHIP) in the lungs of mice and BEAS-2B cells. ATF6α siRNA inhibited the levels of HRD1 and CHIP proteins induced by PS-NPs in BEAS-2B cells. These results suggest that ATF6α plays a critical role in increasing ubiquitination of unfolded or misfolded proteins by alleviating PS-NPs induced ER stress through UPR to achieve ER homeostasis in the lungs of mice.
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Affiliation(s)
- Yanhong Chen
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China
| | - Yingqi Liu
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China; Wujiang Center for Disease Control and Prevention, Suzhou, Jiangsu 215299, China
| | - Yanli Li
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China
| | - Chenjuan Yao
- Department of Molecular Oral Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima-Shi, Tokushima 770-8504, Japan
| | - Jianhua Qu
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China
| | - Juan Tang
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China
| | - Gang Chen
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China.
| | - Yu Han
- Department of Occupational Medicine and Environmental Toxicology, College of Public Health, Nantong University, Nantong, Jiangsu 226019, China.
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6
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Deng J, Liu J, Chen W, Liang Q, He Y, Sun G. Effects of Natural Products through Inhibiting Endoplasmic Reticulum Stress on Attenuation of Idiopathic Pulmonary Fibrosis. Drug Des Devel Ther 2024; 18:1627-1650. [PMID: 38774483 PMCID: PMC11108075 DOI: 10.2147/dddt.s388920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 04/23/2024] [Indexed: 05/24/2024] Open
Abstract
With ever-increasing intensive studies of idiopathic pulmonary fibrosis (IPF), significant progresses have been made. Endoplasmic reticulum stress (ERS)/unfolded protein reaction (UPR) is associated with the development and progression of IPF, and targeting ERS/UPR may be beneficial in the treatment of IPF. Natural product is a tremendous source of new drug discovery, and accumulating studies have reported that many natural products show potential therapeutic effects for IPF via modulating one or more branches of the ERS signaling pathway. Therefore, this review focuses on critical roles of ERS in IPF development, and summarizes herbal preparations and bioactive compounds which protect against IPF through regulating ERS.
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Affiliation(s)
- JiuLing Deng
- Department of Pharmacy, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, People’s Republic of China
| | - Jing Liu
- Department of Pharmacy, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, People’s Republic of China
| | - WanSheng Chen
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China
- Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China
| | - Qing Liang
- Department of Pharmacy, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, People’s Republic of China
| | - YuQiong He
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China
- Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China
| | - GuangChun Sun
- Department of Pharmacy, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, People’s Republic of China
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7
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Marathe S, Grotewold E, Otegui MS. Should I stay or should I go? Trafficking of plant extra-nuclear transcription factors. THE PLANT CELL 2024; 36:1524-1539. [PMID: 38163635 PMCID: PMC11062434 DOI: 10.1093/plcell/koad277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/21/2023] [Indexed: 01/03/2024]
Abstract
At the heart of all biological processes lies the control of nuclear gene expression, which is primarily achieved through the action of transcription factors (TFs) that generally contain a nuclear localization signal (NLS) to facilitate their transport into the nucleus. However, some TFs reside in the cytoplasm in a transcriptionally inactive state and only enter the nucleus in response to specific signals, which in plants include biotic or abiotic stresses. These extra-nuclear TFs can be found in the cytosol or associated with various membrane systems, including the endoplasmic reticulum and plasma membrane. They may be integral proteins with transmembrane domains or associate peripherally with the lipid bilayer via acylation or membrane-binding domains. Although over 30 plant TFs, most of them involved in stress responses, have been experimentally shown to reside outside the nucleus, computational predictions suggest that this number is much larger. Understanding how extra-nuclear TFs are trafficked into the nucleus is essential for reconstructing transcriptional regulatory networks that govern major cellular pathways in response to biotic and abiotic signals. Here, we provide a perspective on what is known on plant extranuclear-nuclear TF retention, nuclear trafficking, and the post-translational modifications that ultimately enable them to regulate gene expression upon entering the nucleus.
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Affiliation(s)
- Sarika Marathe
- Department of Botany, University of Wisconsin-Madison, Madison, WI 53706, USA
- Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Erich Grotewold
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824-6473, USA
| | - Marisa S Otegui
- Department of Botany, University of Wisconsin-Madison, Madison, WI 53706, USA
- Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA
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8
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Cheng C, Yuan Y, Yuan F, Li X. Acute kidney injury: exploring endoplasmic reticulum stress-mediated cell death. Front Pharmacol 2024; 15:1308733. [PMID: 38434710 PMCID: PMC10905268 DOI: 10.3389/fphar.2024.1308733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 01/31/2024] [Indexed: 03/05/2024] Open
Abstract
Acute kidney injury (AKI) is a global health problem, given its substantial morbidity and mortality rates. A better understanding of the mechanisms and factors contributing to AKI has the potential to guide interventions aimed at mitigating the risk of AKI and its subsequent unfavorable outcomes. Endoplasmic reticulum stress (ERS) is an intrinsic protective mechanism against external stressors. ERS occurs when the endoplasmic reticulum (ER) cannot deal with accumulated misfolded proteins completely. Excess ERS can eventually cause pathological reactions, triggering various programmed cell death (autophagy, ferroptosis, apoptosis, pyroptosis). This article provides an overview of the latest research progress in deciphering the interaction between ERS and different programmed cell death. Additionally, the report consolidates insights into the roles of ERS in AKI and highlights the potential avenues for targeting ERS as a treatment direction toward for AKI.
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Affiliation(s)
- Cong Cheng
- Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuan Yuan
- Department of Emergency, Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital), Changsha, Hunan, China
| | - Fang Yuan
- Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs, Changsha, Hunan, China
| | - Xin Li
- Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs, Changsha, Hunan, China
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9
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Kohler A, Kohler V. Better Together: Interorganellar Communication in the Regulation of Proteostasis. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2024; 7:25152564241272245. [PMID: 39385949 PMCID: PMC11462569 DOI: 10.1177/25152564241272245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 10/12/2024]
Abstract
An extensive network of chaperones and folding factors is responsible for maintaining a functional proteome, which is the basis for cellular life. The underlying proteostatic mechanisms are not isolated within organelles, rather they are connected over organellar borders via signalling processes or direct association via contact sites. This review aims to provide a conceptual understanding of proteostatic mechanisms across organelle borders, not focussing on individual organelles. This discussion highlights the precision of these finely tuned systems, emphasising the complicated balance between cellular protection and adaptation to stress. In this review, we discuss widely accepted aspects while shedding light on newly discovered perspectives.
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Affiliation(s)
- Andreas Kohler
- Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden
| | - Verena Kohler
- Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden
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10
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Kim G, Lee J, Ha J, Kang I, Choe W. Endoplasmic Reticulum Stress and Its Impact on Adipogenesis: Molecular Mechanisms Implicated. Nutrients 2023; 15:5082. [PMID: 38140341 PMCID: PMC10745682 DOI: 10.3390/nu15245082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/30/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress has the potential to disrupt the signaling of the unfolded protein response (UPR), thereby influencing adipogenesis. This comprehensive review illuminates the molecular mechanisms that underpin the interplay between ER stress and adipogenesis. We delve into the dysregulation of UPR pathways, namely, IRE1-XBP1, PERK and ATF6 in relation to adipocyte differentiation, lipid metabolism, and tissue inflammation. Moreover, we scrutinize how ER stress impacts key adipogenic transcription factors such as proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) along with their interaction with other signaling pathways. The cellular ramifications include alterations in lipid metabolism, dysregulation of adipokines, and aged adipose tissue inflammation. We also discuss the potential roles the molecular chaperones cyclophilin A and cyclophilin B play in adipogenesis. By shedding light on the intricate relationship between ER stress and adipogenesis, this review paves the way for devising innovative therapeutic interventions.
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Affiliation(s)
- Gyuhui Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jiyoon Lee
- Department of Biological Sciences, Franklin College of Arts and Sciences, University of Georgia, Athens, GA 30609, USA;
| | - Joohun Ha
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wonchae Choe
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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11
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Sun Y, Cai M, Liang Y, Zhang Y. Disruption of blood-brain barrier: effects of HIV Tat on brain microvascular endothelial cells and tight junction proteins. J Neurovirol 2023; 29:658-668. [PMID: 37899420 DOI: 10.1007/s13365-023-01179-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/01/2023] [Accepted: 10/12/2023] [Indexed: 10/31/2023]
Abstract
Although the widespread use of antiretroviral therapy (ART) has prolonged the life span of people living with HIV (PLWH), the incidence of HIV-associated neurocognitive disorders (HAND) in PLWH is also gradually increasing, seriously affecting the quality of life for PLWH. However, the pathogenesis of HAND has not been elucidated, which leaves HAND without effective treatment. HIV protein transactivator of transcription (Tat), as an important regulatory protein, is crucial in the pathogenesis of HAND, and its mechanism of HAND has received widespread attention. The blood-brain barrier (BBB) and its cellular component brain microvascular endothelial cells (BMVECs) play a necessary role in protecting the central nervous system (CNS), and their damage associated with Tat is a potential therapeutic target of HAND. In this review, we will study the Tat-mediated damage mechanism of the BBB and present multiple lines of evidence related to BMVEC damage caused by Tat.
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Affiliation(s)
- Yuqing Sun
- Department of Respiratory and Critical Care Medicine, Beijing You An Hospital, Capital Medical University, Beijing, 100069, China
| | - Miaotian Cai
- Department of Respiratory and Critical Care Medicine, Beijing You An Hospital, Capital Medical University, Beijing, 100069, China
| | - Ying Liang
- Department of Respiratory and Critical Care Medicine, Beijing You An Hospital, Capital Medical University, Beijing, 100069, China
| | - Yulin Zhang
- Department of Respiratory and Critical Care Medicine, Beijing You An Hospital, Capital Medical University, Beijing, 100069, China.
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12
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Vived C, Lee-Papastavros A, Aparecida da Silva Pereira J, Yi P, MacDonald TL. β Cell Stress and Endocrine Function During T1D: What Is Next to Discover? Endocrinology 2023; 165:bqad162. [PMID: 37947352 DOI: 10.1210/endocr/bqad162] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/27/2023] [Accepted: 11/07/2023] [Indexed: 11/12/2023]
Abstract
Canonically, type 1 diabetes (T1D) is a disease characterized by autoreactive T cells as perpetrators of endocrine dysfunction and β cell death in the spiral toward loss of β cell mass, hyperglycemia, and insulin dependence. β Cells have mostly been considered as bystanders in a flurry of autoimmune processes. More recently, our framework for understanding and investigating T1D has evolved. It appears increasingly likely that intracellular β cell stress is an important component of T1D etiology/pathology that perpetuates autoimmunity during the progression to T1D. Here we discuss the emerging and complex role of β cell stress in initiating, provoking, and catalyzing T1D. We outline the bridges between hyperglycemia, endoplasmic reticulum stress, oxidative stress, and autoimmunity from the viewpoint of intrinsic β cell (dys)function, and we extend this discussion to the potential role for a therapeutic β cell stress-metabolism axis in T1D. Lastly, we mention research angles that may be pursued to improve β cell endocrine function during T1D. Biology gleaned from studying T1D will certainly overlap to innovate therapeutic strategies for T2D, and also enhance the pursuit of creating optimized stem cell-derived β cells as endocrine therapy.
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Affiliation(s)
- Celia Vived
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | | | - Jéssica Aparecida da Silva Pereira
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Peng Yi
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Tara L MacDonald
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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13
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Moon DO. Calcium's Role in Orchestrating Cancer Apoptosis: Mitochondrial-Centric Perspective. Int J Mol Sci 2023; 24:ijms24108982. [PMID: 37240331 DOI: 10.3390/ijms24108982] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Calcium is an essential intracellular messenger that plays a vital role in controlling a broad range of cellular processes, including apoptosis. This review offers an in-depth analysis of calcium's multifaceted role in apoptosis regulation, focusing on the associated signaling pathways and molecular mechanisms. We will explore calcium's impact on apoptosis through its effects on different cellular compartments, such as the mitochondria and endoplasmic reticulum (ER), and discuss the connection between calcium homeostasis and ER stress. Additionally, we will highlight the interplay between calcium and various proteins, including calpains, calmodulin, and Bcl-2 family members, and the role of calcium in regulating caspase activation and pro-apoptotic factor release. By investigating the complex relationship between calcium and apoptosis, this review aims to deepen our comprehension of the fundamental processes, and pinpointing possible treatment options for illnesses associated with imbalanced cell death is crucial.
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Affiliation(s)
- Dong-Oh Moon
- Department of Biology Education, Daegu University, 201, Daegudae-ro, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of Korea
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14
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Bonsignore G, Martinotti S, Ranzato E. Endoplasmic Reticulum Stress and Cancer: Could Unfolded Protein Response Be a Druggable Target for Cancer Therapy? Int J Mol Sci 2023; 24:ijms24021566. [PMID: 36675080 PMCID: PMC9865308 DOI: 10.3390/ijms24021566] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/04/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Unfolded protein response (UPR) is an adaptive response which is used for re-establishing protein homeostasis, and it is triggered by endoplasmic reticulum (ER) stress. Specific ER proteins mediate UPR activation, after dissociation from chaperone Glucose-Regulated Protein 78 (GRP78). UPR can decrease ER stress, producing an ER adaptive response, block UPR if ER homeostasis is restored, or regulate apoptosis. Some tumour types are linked to ER protein folding machinery disturbance, highlighting how UPR plays a pivotal role in cancer cells to keep malignancy and drug resistance. In this review, we focus on some molecules that have been revealed to target ER stress demonstrating as UPR could be a new target in cancer treatment.
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15
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Niles J, Singh G, Storey KB. Role of unfolded protein response and ER-associated degradation under freezing, anoxia, and dehydration stresses in the freeze-tolerant wood frogs. Cell Stress Chaperones 2023; 28:61-77. [PMID: 36346580 PMCID: PMC9877271 DOI: 10.1007/s12192-022-01307-8] [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: 08/01/2022] [Revised: 08/25/2022] [Accepted: 10/20/2022] [Indexed: 11/09/2022] Open
Abstract
The North American amphibian, wood frogs, Rana sylvatica are the most studied anuran to comprehend vertebrate freeze tolerance. Multiple adaptations support their survival in frigid temperatures during winters, particularly their ability to produce glucose as natural cryoprotectant. Freezing and its component consequences (anoxia and dehydration) induce multiple stresses on cells. Among these is endoplasmic reticulum (ER) stress, a condition spawned by buildup of unfolded or misfolded proteins in the ER. The ER stress causes the unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway that potentially could lead to apoptosis. Immunoblotting was used to assess the responses of major proteins of the UPR and ERAD under freezing, anoxia, and dehydration stresses in the liver and skeletal muscle of the wood frogs. Targets analyzed included activating transcription factors (ATF3, ATF4, ATF6), the growth arrest and DNA damage proteins (GADD34, GADD153), and EDEM (ERAD enhancing α-mannosidase-like proteins) and XBP1 (X-box binding protein 1) proteins. UPR signaling was triggered under all three stresses (freezing, anoxia, dehydration) in liver and skeletal muscle of wood frogs with most tissue/stress responses consistent with an upregulation of the primary targets of all three UPR pathways (ATF4, ATF6, and XBP-1) to enhance the protein folding/refolding capacity under these stress conditions. Only frozen muscle showed preference for proteasomal degradation of misfolded proteins via upregulation of EDEM (ERAD). The ERAD response of liver was downregulated across three stresses suggesting preference for more refolding of misfolded/unfolded proteins. Overall, we conclude that wood frog organs activate the UPR as a means of stabilizing and repairing cellular proteins to best survive freezing exposures.
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Affiliation(s)
- Jacques Niles
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Gurjit Singh
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Kenneth B Storey
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
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16
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Kulkarni A, Muralidharan C, May SC, Tersey SA, Mirmira RG. Inside the β Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis. Endocrinology 2022; 164:bqac184. [PMID: 36317483 PMCID: PMC9667558 DOI: 10.1210/endocr/bqac184] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Indexed: 11/05/2022]
Abstract
The pathogeneses of the 2 major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have witnessed major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β cells in the context of the animal models.
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Affiliation(s)
- Abhishek Kulkarni
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Charanya Muralidharan
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Sarah C May
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Sarah A Tersey
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
| | - Raghavendra G Mirmira
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
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17
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Murase R, Yamamoto A, Hirata Y, Oh-Hashi K. Expression analysis and functional characterization of thioredoxin domain-containing protein 11. Mol Biol Rep 2022; 49:10541-10556. [PMID: 36152228 DOI: 10.1007/s11033-022-07932-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 09/06/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUNDS The endoplasmic reticulum (ER) is a crucial organelle that regulates both the folding, modification and transport of many proteins and senses certain stimuli inside and outside of cells. ER-associated degradation (ERAD), including SEL1L is a crucial mechanism to maintain homeostasis. In this study, we performed comparative proteome analysis in wild-type (wt) and SEL1L-deficient cells. METHODS AND RESULTS We found constitutively high expression of thioredoxin domain-containing protein 11 (TXNDC11) mRNA and protein in our SEL1L-deficient HEK293 cells by RT-PCR and Western blot analysis. The TXNDC11 gene possesses a well-conserved unfolded protein response element (UPRE) around its transcription start site, and ER stress increased TXNDC11 mRNA and luciferase reporter activity via this putative UPRE in HEK293 cells. The amounts of TXNDC11 protein in wild-type and SEL1L-deficient cells with or without thapsigargin (Tg) treatment were parallel to their mRNAs in these cells, which was almost proportional to spliced XBP1 (sXBP1) mRNA expression. The establishment and characterization of TXNDC11-deficient HEK293 cells revealed that the expression of three different ER resident stress sensors, ATF6α, CREB3 and CREB3L2, is regulated by TXNDC11. The rate of disappearance of the three proteins by CHX treatment in wt cells was remarkably different, and the full-length CREB3L2 protein was almost completely degraded within 15 min after CHX treatment. TXNDC11 deficiency increased the expression of each full-length form under resting conditions and delayed their disappearance by CHX treatment. Interestingly, the degree of increase in full-length CREB3/CREB3L2 by TXNDC11 deficiency was apparently higher than that in full-length ATF6α. The increase in these proteins by TXNDC11 deficiency was hardly correlated with the expression of each mRNA. Treatment with ER stress inducers influenced each full-length mature form, and the difference in each full-length form observed in wt and TXNDC11-deficient cells was smaller. CONCLUSION This study demonstrated that TXNDC11 is an ER stress-inducible gene regulated by the IRE1-sXBP1 pathway. In addition, TXNDC11 is involved in the regulation of ATF6α, CREB3 and CREB3L2 protein expression, although the contribution to the stability of these proteins is quite variable. Therefore, its further characterization will provide new insights for understanding protein homeostasis in ER physiology and pathology.
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Affiliation(s)
- Ryoichi Murase
- Graduate School of Natural Science and Technology, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Ayumi Yamamoto
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yoko Hirata
- Graduate School of Natural Science and Technology, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.,United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Kentaro Oh-Hashi
- Graduate School of Natural Science and Technology, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. .,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. .,United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
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18
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Imaizumi Y, Takanuki K, Miyake T, Takemoto M, Hirata K, Hirose M, Oi R, Kobayashi T, Miyoshi K, Aruga R, Yokoyama T, Katagiri S, Matsuura H, Iwasaki K, Kato T, Kaneko MK, Kato Y, Tajiri M, Akashi S, Nureki O, Hizukuri Y, Akiyama Y, Nogi T. Mechanistic insights into intramembrane proteolysis by E. coli site-2 protease homolog RseP. SCIENCE ADVANCES 2022; 8:eabp9011. [PMID: 36001659 PMCID: PMC9401612 DOI: 10.1126/sciadv.abp9011] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/01/2022] [Indexed: 05/31/2023]
Abstract
Site-2 proteases are a conserved family of intramembrane proteases that cleave transmembrane substrates to regulate signal transduction and maintain proteostasis. Here, we elucidated crystal structures of inhibitor-bound forms of bacterial site-2 proteases including Escherichia coli RseP. Structure-based chemical modification and cross-linking experiments indicated that the RseP domains surrounding the active center undergo conformational changes to expose the substrate-binding site, suggesting that RseP has a gating mechanism to regulate substrate entry. Furthermore, mutational analysis suggests that a conserved electrostatic linkage between the transmembrane and peripheral membrane-associated domains mediates the conformational changes. In vivo cleavage assays also support that the substrate transmembrane helix is unwound by strand addition to the intramembrane β sheet of RseP and is clamped by a conserved asparagine residue at the active center for efficient cleavage. This mechanism underlying the substrate binding, i.e., unwinding and clamping, appears common across distinct families of intramembrane proteases that cleave transmembrane segments.
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Affiliation(s)
- Yuki Imaizumi
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Kazunori Takanuki
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Takuya Miyake
- Institute for Life and Medical Sciences, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Mizuki Takemoto
- Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Kunio Hirata
- Life Science Research Infrastructure Group, RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan
| | - Mika Hirose
- Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Rika Oi
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Tatsuya Kobayashi
- Institute for Life and Medical Sciences, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kenichi Miyoshi
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Rie Aruga
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Tatsuhiko Yokoyama
- Institute for Life and Medical Sciences, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shizuka Katagiri
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Hiroaki Matsuura
- Life Science Research Infrastructure Group, RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan
| | - Kenji Iwasaki
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Takayuki Kato
- Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi 980-8575, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi 980-8575, Japan
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi 980-8575, Japan
| | - Michiko Tajiri
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Satoko Akashi
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Osamu Nureki
- Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yohei Hizukuri
- Institute for Life and Medical Sciences, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshinori Akiyama
- Institute for Life and Medical Sciences, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Terukazu Nogi
- Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
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19
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A Platform Technology for Monitoring the Unfolded Protein Response. Methods Mol Biol 2022; 2378:45-67. [PMID: 34985693 PMCID: PMC10053305 DOI: 10.1007/978-1-0716-1732-8_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The unfolded protein response (UPR) is a complex signal transduction pathway that remodels gene expression in response to proteotoxic stress in the endoplasmic reticulum (ER) and is linked to the development of a range of diseases, including Alzheimer's disease, diabetes, and several types of cancer. UPR induction is typically monitored by measuring the expression level of UPR marker genes. Most tools for quantifying gene expression, including DNA microarrays and quantitative PCR with reverse transcription (RT-PCR), produce snapshots of the cell transcriptome, but are not ideal for measurements requiring temporal resolution of gene expression dynamics. Reporter assays for indirect detection of the UPR typically rely on extrachromosomal expression of reporters under the control of minimal or synthetic regulatory sequences that do not recapitulate the native chromosomal context of the UPR target genes. To address the need for tools to monitor chromosomal gene expression that recapitulate gene expression dynamics from the native chromosomal context and generate a readily detectable signal output, we developed a gene signal amplifier platform that links transcriptional and post-translational regulation of a fluorescent output to the expression of a chromosomal gene marker of the UPR. The platform is based on a genetic circuit that amplifies the output signal with high sensitivity and dynamic resolution and is implemented through chromosomal integration of the gene encoding the main control element of the genetic circuit to link its expression to that of the target gene, thereby generating a platform that can be easily adapted to monitor any UPR target through integration of the main control element at the appropriate chromosomal locus. By recapitulating the transcriptional and translational control mechanisms underlying the expression of UPR targets with high sensitivity, this platform provides a novel technology for monitoring the UPR with superior sensitivity and dynamic resolution.
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20
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Ibe NU, Subramanian A, Mukherjee S. Non-canonical activation of the ER stress sensor ATF6 by Legionella pneumophila effectors. Life Sci Alliance 2021; 4:4/12/e202101247. [PMID: 34635501 PMCID: PMC8507491 DOI: 10.26508/lsa.202101247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 12/16/2022] Open
Abstract
Legionella pneumophila secretes toxins into the host cell that induce the non-canonical processing and activation of the ER stress sensor and transcription factor ATF6 via a mechanism that is distinct from the canonical pathway activated by unfolded protein buildup. The intracellular bacterial pathogen Legionella pneumophila (L.p.) secretes ∼330 effector proteins into the host cell to sculpt an ER-derived replicative niche. We previously reported five L.p. effectors that inhibit IRE1, a key sensor of the homeostatic unfolded protein response (UPR) pathway. In this study, we discovered a subset of L.p. toxins that selectively activate the UPR sensor ATF6, resulting in its cleavage, nuclear translocation, and target gene transcription. In a deviation from the conventional model, this L.p.–dependent activation of ATF6 does not require its transport to the Golgi or its cleavage by the S1P/S2P proteases. We believe that our findings highlight the unique regulatory control that L.p. exerts upon the three UPR sensors and expand the repertoire of bacterial proteins that selectively perturb host homeostatic pathways.
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Affiliation(s)
- Nnejiuwa U Ibe
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.,George Williams Hooper Foundation, University of California, San Francisco, San Francisco, CA, USA
| | - Advait Subramanian
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.,George Williams Hooper Foundation, University of California, San Francisco, San Francisco, CA, USA.,Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Shaeri Mukherjee
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA .,George Williams Hooper Foundation, University of California, San Francisco, San Francisco, CA, USA
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21
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Danyukova T, Schöneck K, Pohl S. Site-1 and site-2 proteases: A team of two in regulated proteolysis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119138. [PMID: 34619164 DOI: 10.1016/j.bbamcr.2021.119138] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/12/2021] [Accepted: 09/06/2021] [Indexed: 12/19/2022]
Abstract
The site-1 and site-2 proteases (S1P and S2P) were identified over 20 years ago, and the functions of both have been addressed in numerous studies ever since. Whereas S1P processes a set of substrates independently of S2P, the latter acts in concert with S1P in a mechanism, called regulated intramembrane proteolysis, that controls lipid metabolism and response to unfolded proteins. This review summarizes the molecular roles that S1P and S2P jointly play in these processes. As S1P and S2P deficiencies mainly affect connective tissues, yet with varying phenotypes, we discuss the segregated functions of S1P and S2P in terms of cell homeostasis and maintenance of the connective tissues. In addition, we provide experimental data that point at S2P, but not S1P, as a critical regulator of cell adaptation to proteotoxicity or lipid imbalance. Therefore, we hypothesize that S2P can also function independently of S1P activity.
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Affiliation(s)
- Tatyana Danyukova
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
| | - Kenneth Schöneck
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Sandra Pohl
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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22
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Pachikov AN, Gough RR, Christy CE, Morris ME, Casey CA, LaGrange CA, Bhat G, Kubyshkin AV, Fomochkina II, Zyablitskaya EY, Makalish TP, Golubinskaya EP, Davydenko KA, Eremenko SN, Riethoven JJM, Maroli AS, Payne TS, Powers R, Lushnikov AY, Macke AJ, Petrosyan A. The non-canonical mechanism of ER stress-mediated progression of prostate cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:289. [PMID: 34521429 PMCID: PMC8439065 DOI: 10.1186/s13046-021-02066-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/08/2021] [Indexed: 01/12/2023]
Abstract
Background The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation. Methods Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy. Results Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites. Conclusions We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02066-7.
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Affiliation(s)
- Artem N Pachikov
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.,The Fred and Pamela Buffett Cancer Center, Omaha, NE, 68198, USA
| | - Ryan R Gough
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.,The Fred and Pamela Buffett Cancer Center, Omaha, NE, 68198, USA.,Omaha Western Iowa Health Care System, VA Service, Department of Research Service, Omaha, NE, 68105, USA
| | - Caroline E Christy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mary E Morris
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Carol A Casey
- Omaha Western Iowa Health Care System, VA Service, Department of Research Service, Omaha, NE, 68105, USA.,Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68105, USA
| | - Chad A LaGrange
- Division of Urologic Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ganapati Bhat
- School of Basic and Applied Sciences, Dayananda Sagar University, Bangalore, Karnataka, 560078, India
| | - Anatoly V Kubyshkin
- Department of Pathological Physiology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Iryna I Fomochkina
- Department of Pathological Physiology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Evgeniya Y Zyablitskaya
- Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Tatiana P Makalish
- Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Elena P Golubinskaya
- Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Kateryna A Davydenko
- Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Sergey N Eremenko
- Saint Luc's Clinique, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051
| | - Jean-Jack M Riethoven
- Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.,Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.,The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
| | - Amith S Maroli
- The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.,Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
| | - Thomas S Payne
- Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.,The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
| | - Robert Powers
- The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.,Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
| | - Alexander Y Lushnikov
- Nanoimaging Core Facility, University of Nebraska Medical Center, Omaha, NE, 68105, USA
| | - Amanda J Macke
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Armen Petrosyan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. .,The Fred and Pamela Buffett Cancer Center, Omaha, NE, 68198, USA. .,Omaha Western Iowa Health Care System, VA Service, Department of Research Service, Omaha, NE, 68105, USA.
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23
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Fang C, Weng T, Hu S, Yuan Z, Xiong H, Huang B, Cai Y, Li L, Fu X. IFN-γ-induced ER stress impairs autophagy and triggers apoptosis in lung cancer cells. Oncoimmunology 2021; 10:1962591. [PMID: 34408924 PMCID: PMC8366549 DOI: 10.1080/2162402x.2021.1962591] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Interferon-gamma (IFN-γ) is a major effector molecule of immunity and a common feature of tumors responding to immunotherapy. Active IFN-γ signaling can directly trigger apoptosis and cell cycle arrest in human cancer cells. However, the mechanisms underlying these actions remain unclear. Here, we report that IFN-γ rapidly increases protein synthesis and causes the unfolded protein response (UPR), as evidenced by the increased expression of glucose-regulated protein 78, activating transcription factor-4, and c/EBP homologous protein (CHOP) in cells treated with IFN-γ. The JAK1/2-STAT1 and AKT-mTOR signaling pathways are required for IFN-γ-induced UPR. Endoplasmic reticulum (ER) stress promotes autophagy and restores homeostasis. Surprisingly, in IFN-γ-treated cells, autophagy was impaired at the step of autophagosome-lysosomal fusion and caused by a significant decline in the expression of lysosomal membrane protein-1 and −2 (LAMP-1/LAMP-2). The ER stress inhibitor 4-PBA restored LAMP expression in IFN-γ-treated cells. IFN-γ stimulation activated the protein kinase-like ER kinase (PERK)-eukaryotic initiation factor 2a subunit (eIF2α) axis and caused a reduction in global protein synthesis. The PERK inhibitor, GSK2606414, partially restored global protein synthesis and LAMP expression in cells treated with IFN-γ. We further investigated the functional consequences of IFN-γ-induced ER stress. We show that inhibition of ER stress significantly prevents IFN-γ-triggered apoptosis. CHOP knockdown abrogated IFN-γ-mediated apoptosis. Inhibition of ER stress also restored cyclin D1 expression in IFN-γ-treated cells. Thus, ER stress and the UPR caused by IFN-γ represent novel mechanisms underlying IFN-γ-mediated anticancer effects. This study expands our understanding of IFN-γ-mediated signaling and its cellular actions in tumor cells.
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Affiliation(s)
- Can Fang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Weng
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaojie Hu
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiwei Yuan
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Xiong
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bing Huang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yixin Cai
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lequn Li
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangning Fu
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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24
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Chen JH, Wu CH, Chiang CK. Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis. Int J Mol Sci 2021; 22:ijms22168674. [PMID: 34445377 PMCID: PMC8395452 DOI: 10.3390/ijms22168674] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called “ER stress”. Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.
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Affiliation(s)
- Jia-Huang Chen
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan; (J.-H.C.); (C.-H.W.)
| | - Chia-Hsien Wu
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan; (J.-H.C.); (C.-H.W.)
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan
| | - Chih-Kang Chiang
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan; (J.-H.C.); (C.-H.W.)
- Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei 100225, Taiwan
- Center for Biotechnology, National Taiwan University, Taipei 10672, Taiwan
- Correspondence: ; Tel.: +886-2-2312-3456 (ext. 88347)
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25
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Lemarié M, Chatonnet F, Caron G, Fest T. Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy. Front Immunol 2021; 12:671998. [PMID: 33995412 PMCID: PMC8117215 DOI: 10.3389/fimmu.2021.671998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/12/2021] [Indexed: 01/13/2023] Open
Abstract
Antibody therapy, where artificially-produced immunoglobulins (Ig) are used to treat pathological conditions such as auto-immune diseases and cancers, is a very innovative and competitive field. Although substantial efforts have been made in recent years to obtain specific and efficient antibodies, there is still room for improvement especially when considering a precise tissular targeting or increasing antigen affinity. A better understanding of the cellular and molecular steps of terminal B cell differentiation, in which an antigen-activated B cell becomes an antibody secreting cell, may improve antibody therapy. In this review, we use our recently published data about human B cell differentiation, to show that the mechanisms necessary to adapt a metamorphosing B cell to its new secretory function appear quite early in the differentiation process i.e., at the pre-plasmablast stage. After characterizing the molecular pathways appearing at this stage, we will focus on recent findings about two main processes involved in antibody production: unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We’ll show that many genes coding for factors involved in UPR and ER stress are induced at the pre-plasmablast stage, sustaining our hypothesis. Finally, we propose to use this recently acquired knowledge to improve productivity of industrialized therapeutic antibodies.
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Affiliation(s)
- Maud Lemarié
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France
| | - Fabrice Chatonnet
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France.,Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
| | - Gersende Caron
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France.,Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
| | - Thierry Fest
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France.,Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
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26
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Hien LT, Back SH. Establishment of a reporter system for monitoring activation of the ER stress transducer ATF6β. Biochem Biophys Res Commun 2021; 558:1-7. [PMID: 33894672 DOI: 10.1016/j.bbrc.2021.04.052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 04/13/2021] [Indexed: 11/19/2022]
Abstract
ATF6 has two isoforms, ATF6α and ATF6β, which are ubiquitously expressed type II transmembrane glycoproteins in the endoplasmic reticulum (ER). While the regulatory mechanisms and transcriptional roles of ATF6α in response to ER stress have been well-studied, those of its paralogue ATF6β are less understood. Moreover, there is no specific cell-based reporter assay to monitor ATF6β activation. Here, we developed a new cell-based reporter system that can monitor activation of endogenous ATF6β. This system expresses a chimeric protein containing a synthetic transcription factor followed by the transmembrane domain and C-terminal luminal domain of ATF6β. Under ER stress conditions, the chimeric protein was cleaved by regulated intramembrane proteolysis (RIP) to liberate the N-terminal synthetic transcription factor, which induced luciferase expression in the HeLa Luciferase Reporter cell line. This new stable reporter cell line will be an innovative tool to investigate RIP of ATF6β.
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Affiliation(s)
- Le Thi Hien
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, South Korea
| | - Sung Hoon Back
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, South Korea.
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27
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Gallot YS, Bohnert KR. Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy. Int J Mol Sci 2021; 22:2567. [PMID: 33806433 PMCID: PMC7961896 DOI: 10.3390/ijms22052567] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.
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Affiliation(s)
- Yann S. Gallot
- LBEPS, Univ Evry, IRBA, Université Paris Saclay, 91025 Evry, France
| | - Kyle R. Bohnert
- Kinesiology Department, St. Ambrose University, Davenport, IA 52803, USA
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28
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Yuan Q, Xu T, Chen Y, Qu W, Sun D, Liu X, Sun L. MiR-185-5p ameliorates endoplasmic reticulum stress and renal fibrosis by downregulation of ATF6. J Transl Med 2020; 100:1436-1446. [PMID: 32514126 DOI: 10.1038/s41374-020-0447-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 05/22/2020] [Accepted: 05/24/2020] [Indexed: 02/07/2023] Open
Abstract
Endoplasmic reticulum (ER) stress is considered an important factor in the formation of fibrosis. Therefore, modulation of ER stress may represent a promising therapeutic strategy in renal fibrosis. MiR-185-5p has been identified to be implicated in TGF-β1-induced renal fibrosis; however, it is largely unknown whether and how miR-185-5p regulates ER stress in renal fibrosis. In this study, we demonstrated that miR-185-5p directly bound to ATF6, an ER stress-related protein, and downregulated the expression thereof. We subsequently constructed an in vitro model of renal fibrosis using HK2 cells treated with TGF-β1, and found that miR-185-5p attenuated ER stress and dedifferentiation of tubular epithelia by suppression of ATF6. In addition, we constructed an in vivo mouse model using unilateral urethral obstruction (UUO). Our in vivo findings showed that miR-185-5p reduced the expression of ER stress-related proteins and inhibited epithelial dedifferentiation via downregulation of ATF6, thereby improving UUO-induced renal fibrosis. Overall, our findings revealed that miR-185-5p exerts beneficial effects in renal fibrosis. Thus, the miR-185-5p/ATF6 regulatory pathway may be a potential target for therapeutic intervention in renal fibrosis.
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Affiliation(s)
- Quan Yuan
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China
| | - Tianhua Xu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Ying Chen
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Wei Qu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Dan Sun
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Xiaodan Liu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China
| | - Li Sun
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
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29
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McCurdy EP, Chung KM, Benitez-Agosto CR, Hengst U. Promotion of Axon Growth by the Secreted End of a Transcription Factor. Cell Rep 2020; 29:363-377.e5. [PMID: 31597097 DOI: 10.1016/j.celrep.2019.08.101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/02/2019] [Accepted: 08/29/2019] [Indexed: 12/27/2022] Open
Abstract
Axon growth is regulated externally by attractive and repulsive cues generated in the environment. In addition, intrinsic pathways govern axon development, although the extent to which axons themselves can influence their own growth is unknown. We find that dorsal root ganglion (DRG) axons secrete a factor supporting axon growth and identify it as the C terminus of the ER stress-induced transcription factor CREB3L2, which is generated by site 2 protease (S2P) cleavage in sensory neurons. S2P and CREB3L2 knockdown or inhibition of axonal S2P interfere with the growth of axons, and C-terminal CREB3L2 is sufficient to rescue these effects. C-terminal CREB3L2 forms a complex with Shh and stabilizes its association with the Patched-1 receptor on developing axons. Our results reveal a neuron-intrinsic pathway downstream of S2P that promotes axon growth.
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Affiliation(s)
- Ethan P McCurdy
- Integrated Program in Cellular, Molecular and Biomedical Studies, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Kyung Min Chung
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Carlos R Benitez-Agosto
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Ulrich Hengst
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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30
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Zhou Y, Tong Z, Jiang S, Zheng W, Zhao J, Zhou X. The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation. Cells 2020; 9:cells9051219. [PMID: 32423023 PMCID: PMC7291288 DOI: 10.3390/cells9051219] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 12/26/2022] Open
Abstract
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.
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Affiliation(s)
- Yang Zhou
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China
- Correspondence:
| | - Zhizi Tong
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
| | - Songhong Jiang
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
| | - Wenyan Zheng
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
| | - Jianjun Zhao
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Xiangmei Zhou
- State Key Laboratories for Agrobiotechnology, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
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31
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Characterization of Endoplasmic Reticulum (ER) in Human Pluripotent Stem Cells Revealed Increased Susceptibility to Cell Death upon ER Stress. Cells 2020; 9:cells9051078. [PMID: 32357563 PMCID: PMC7291192 DOI: 10.3390/cells9051078] [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: 03/06/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/19/2022] Open
Abstract
Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have a well-orchestrated program for differentiation and self-renewal. However, the structural features of unique proteostatic-maintaining mechanisms in hPSCs and their features, distinct from those of differentiated cells, in response to cellular stress remain unclear. We evaluated and compared the morphological features and stress response of hPSCs and fibroblasts. Compared to fibroblasts, electron microscopy showed simpler/fewer structures with fewer networks in the endoplasmic reticulum (ER) of hPSCs, as well as lower expression of ER-related genes according to meta-analysis. As hPSCs contain low levels of binding immunoglobulin protein (BiP), an ER chaperone, thapsigargin treatment sharply increased the gene expression of the unfolded protein response. Thus, hPSCs with decreased chaperone function reacted sensitively to ER stress and entered apoptosis faster than fibroblasts. Such ER stress-induced apoptotic processes were abolished by tauroursodeoxycholic acid, an ER-stress reliever. Hence, our results revealed that as PSCs have an underdeveloped structure and express fewer BiP chaperone proteins than somatic cells, they are more susceptible to ER stress-induced apoptosis in response to stress.
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32
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Rozpędek-Kamińska W, Siwecka N, Wawrzynkiewicz A, Wojtczak R, Pytel D, Diehl JA, Majsterek I. The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases. Int J Mol Sci 2020; 21:E2108. [PMID: 32204380 PMCID: PMC7139310 DOI: 10.3390/ijms21062108] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 12/11/2022] Open
Abstract
Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism-accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.
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Affiliation(s)
- Wioletta Rozpędek-Kamińska
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (W.R.-K.); (N.S.); (A.W.); (R.W.)
| | - Natalia Siwecka
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (W.R.-K.); (N.S.); (A.W.); (R.W.)
| | - Adam Wawrzynkiewicz
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (W.R.-K.); (N.S.); (A.W.); (R.W.)
| | - Radosław Wojtczak
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (W.R.-K.); (N.S.); (A.W.); (R.W.)
| | - Dariusz Pytel
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; (D.P.); (J.A.D.)
| | - J. Alan Diehl
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; (D.P.); (J.A.D.)
| | - Ireneusz Majsterek
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (W.R.-K.); (N.S.); (A.W.); (R.W.)
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33
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Afrin T, Diwan D, Sahawneh K, Pajerowska-Mukhtar K. Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet. JOURNAL OF EXPERIMENTAL BOTANY 2020; 71:1659-1667. [PMID: 31679034 DOI: 10.1093/jxb/erz487] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/21/2019] [Indexed: 05/20/2023]
Abstract
The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.
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Affiliation(s)
- Taiaba Afrin
- Department of Biology, University of Alabama at Birmingham, Birmingham, USA
| | - Danish Diwan
- Department of Biology, University of Alabama at Birmingham, Birmingham, USA
| | - Katrina Sahawneh
- Department of Biology, University of Alabama at Birmingham, Birmingham, USA
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Martelli AM, Paganelli F, Chiarini F, Evangelisti C, McCubrey JA. The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias. Cancers (Basel) 2020; 12:cancers12020333. [PMID: 32024211 PMCID: PMC7072709 DOI: 10.3390/cancers12020333] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/24/2020] [Accepted: 01/27/2020] [Indexed: 02/06/2023] Open
Abstract
The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.
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Affiliation(s)
- Alberto M. Martelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy;
- Correspondence: ; Tel.: +39-051-209-1580
| | - Francesca Paganelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Francesca Chiarini
- CNR Institute of Molecular Genetics, 40136 Bologna, Italy; (F.C.); (C.E.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Camilla Evangelisti
- CNR Institute of Molecular Genetics, 40136 Bologna, Italy; (F.C.); (C.E.)
- IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - James A. McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA;
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Kim JI, Kaufman RJ, Back SH, Moon JY. Development of a Reporter System Monitoring Regulated Intramembrane Proteolysis of the Transmembrane bZIP Transcription Factor ATF6α. Mol Cells 2019; 42:783-793. [PMID: 31707777 PMCID: PMC6883980 DOI: 10.14348/molcells.2019.0104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/11/2019] [Accepted: 09/30/2019] [Indexed: 12/20/2022] Open
Abstract
When endoplasmic reticulum (ER) functions are perturbed, the ER induces several signaling pathways called unfolded protein response to reestablish ER homeostasis through three ER transmembrane proteins: inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Although it is important to measure the activity of ATF6 that can indicate the status of the ER, no specific cell-based reporter assay is currently available. Here, we report a new cell-based method for monitoring ER stress based on the cleavage of ATF6α by sequential actions of proteases at the Golgi apparatus during ER stress. A new expressing vector was constructed by using fusion gene of GAL4 DNA binding domain (GAL4DBD) and activation domain derived from herpes simplex virus VP16 protein (VP16AD) followed by a human ATF6α N-terminal deletion variant. During ER stress, the GAL4DBD-VP16AD(GV)-hATF6α deletion variant was cleaved to liberate active transcription activator encompassing GV-hATF6α fragment which could translocate into the nucleus. The translocated GV-hATF6α fragment strongly induced the expression of firefly luciferase in HeLa Luciferase Reporter cell line containing a stably integrated 5X GAL4 site-luciferase gene. The established double stable reporter cell line HLR-GV-hATF6α(333) represents an innovative tool to investigate regulated intramembrane proteolysis of ATF6α. It can substitute active pATF6(N) binding motif-based reporter cell lines.
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Affiliation(s)
- Jin-Ik Kim
- Department of Biochemistry & Health Sciences, Changwon National University, Changwon 51140,
Korea
| | - Randal J. Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037,
USA
| | - Sung Hoon Back
- School of Biological Sciences, University of Ulsan, Ulsan 44610,
Korea
| | - Ja-Young Moon
- Department of Biochemistry & Health Sciences, Changwon National University, Changwon 51140,
Korea
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Matsuhisa K, Saito A, Cai L, Kaneko M, Okamoto T, Sakaue F, Asada R, Urano F, Yanagida K, Okochi M, Kudo Y, Matsumoto M, Nakayama KI, Imaizumi K. Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis. FASEB J 2019; 34:865-880. [DOI: 10.1096/fj.201901748r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/04/2019] [Accepted: 10/15/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Koji Matsuhisa
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
- Department of Stress Protein Processing Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Atsushi Saito
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
- Department of Stress Protein Processing Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Longjie Cai
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Masayuki Kaneko
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Takumi Okamoto
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Fumika Sakaue
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
- Department of Stress Protein Processing Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Rie Asada
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
- Department of Medicine Division of Endocrinology Metabolism, and Lipid Research Washington University School of Medicine St. Louis MO USA
| | - Fumihiko Urano
- Department of Medicine Division of Endocrinology Metabolism, and Lipid Research Washington University School of Medicine St. Louis MO USA
| | - Kanta Yanagida
- Neuropsychiatry Department of Integrated Medicine Division of Internal Medicine Osaka University Graduate School of Medicine Osaka Japan
| | - Masayasu Okochi
- Neuropsychiatry Department of Integrated Medicine Division of Internal Medicine Osaka University Graduate School of Medicine Osaka Japan
| | - Yukitsuka Kudo
- Department of Gerontology and Geriatrics Institute of Development, Aging and Cancer Tohoku University Sendai Japan
| | - Masaki Matsumoto
- Department of Molecular and Cellular Biology Medical Institute of Bioregulation Kyushu University Fukuoka Japan
| | - Keiichi I. Nakayama
- Department of Molecular and Cellular Biology Medical Institute of Bioregulation Kyushu University Fukuoka Japan
| | - Kazunori Imaizumi
- Department of Biochemistry Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
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Oka OBV, van Lith M, Rudolf J, Tungkum W, Pringle MA, Bulleid NJ. ERp18 regulates activation of ATF6α during unfolded protein response. EMBO J 2019; 38:e100990. [PMID: 31368601 PMCID: PMC6670016 DOI: 10.15252/embj.2018100990] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 05/03/2019] [Accepted: 05/20/2019] [Indexed: 01/08/2023] Open
Abstract
Activation of the ATF6α signaling pathway is initiated by trafficking of ATF6α from the ER to the Golgi apparatus. Its subsequent proteolysis releases a transcription factor that translocates to the nucleus causing downstream gene activation. How ER retention, Golgi trafficking, and proteolysis of ATF6α are regulated and whether additional protein partners are required for its localization and processing remain unresolved. Here, we show that ER-resident oxidoreductase ERp18 associates with ATF6α following ER stress and plays a key role in both trafficking and activation of ATF6α. We find that ERp18 depletion attenuates the ATF6α stress response. Paradoxically, ER stress accelerates trafficking of ATF6α to the Golgi in ERp18-depleted cells. However, the translocated ATF6α becomes aberrantly processed preventing release of the soluble transcription factor. Hence, we demonstrate that ERp18 monitors ATF6α ER quality control to ensure optimal processing following trafficking to the Golgi.
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Affiliation(s)
- Ojore BV Oka
- Institute of Molecular, Cell and Systems BiologyCollege of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Marcel van Lith
- Institute of Molecular, Cell and Systems BiologyCollege of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Jana Rudolf
- Inserm U1035/BMGICUniversity of BordeauxBordeauxFrance
| | - Wanida Tungkum
- Institute of Molecular, Cell and Systems BiologyCollege of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Marie Anne Pringle
- Institute of Molecular, Cell and Systems BiologyCollege of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
| | - Neil J Bulleid
- Institute of Molecular, Cell and Systems BiologyCollege of Medical Veterinary and Life SciencesUniversity of GlasgowGlasgowUK
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Porcine circovirus type 2 ORF5 protein induces endoplasmic reticulum stress and unfolded protein response in porcine alveolar macrophages. Arch Virol 2019; 164:1323-1334. [PMID: 30877450 DOI: 10.1007/s00705-019-04185-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 01/19/2019] [Indexed: 01/12/2023]
Abstract
Porcine circovirus type 2 (PCV2) is the essential infectious agent causing porcine circovirus-associated disease (PCVD) in pigs and one of the important viruses that severely jeopardize the swine husbandry industry. PCV2 elicits the unfolded protein response (UPR) via activation of the PERK pathway, and its capsid protein (Cap) has also been found to induce UPR with subsequent activation of apoptosis. The open reading frame 5 (ORF5) protein is a recently discovered non-structural protein, and its function in PCV2 pathogenesis remains unknown. The aim of this study was to determine whether the PCV2 ORF5 protein could induce endoplasmic reticulum stress (ERS) and UPR in porcine alveolar macrophages (PAMs). pEGFP-tagged ORF5 protein was transiently overexpressed in PAMs. Transmission electron microscopy (TEM) was employed to examine changes in ER morphology, and quantitative real-time PCR and western blotting analysis were used to measure UPR-related cell signaling alterations. We found that the ORF5 protein triggers swelling and degranulation of the ER and upregulates the expression of ERS markers. Further experiments demonstrated that the PCV2 ORF5 protein induces ERS and UPR via the PERK (RNA-activated protein kinase-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6) and IRE1 (inositol requiring enzyme 1) signaling pathways. Together with previous studies, we provide new information on the ERS-UPR induced by the PCV2 ORF5 protein.
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Ahn N, Koh J, Kim K. Endoplasmic Reticulum Stress of Skeletal Muscle and Exercise Training Effects in Aging and Obesity. THE ASIAN JOURNAL OF KINESIOLOGY 2018. [DOI: 10.15758/ajk.2018.20.3.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Burman A, Tanjore H, Blackwell TS. Endoplasmic reticulum stress in pulmonary fibrosis. Matrix Biol 2018; 68-69:355-365. [PMID: 29567124 DOI: 10.1016/j.matbio.2018.03.015] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/15/2018] [Accepted: 03/16/2018] [Indexed: 12/15/2022]
Abstract
Endoplasmic reticulum (ER) stress is associated with development and progression of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). ER stress was first implicated in the pathogenesis of IPF >15 years ago with the discovery of disease-causing mutations in surfactant protein C, which result in a misfolded gene product in type II alveolar epithelial cells (AECs). ER stress and the unfolded protein response (UPR) have been linked to lung fibrosis through regulation of AEC apoptosis, epithelial-mesenchymal transition, myofibroblast differentiation, and M2 macrophage polarization. Although progress has been made in understanding the causes and consequences of ER stress in IPF and a number of chronic fibrotic disorders, further studies are needed to identify key factors that induce ER stress in important cell types and define critical down-stream processes and effector molecules that mediate ER stress-related phenotypes. This review discusses potential causes of ER stress induction in the lungs and current evidence linking ER stress to fibrosis in the context of individual cell types: AECs, fibroblasts, and macrophages. As our understanding of the relationship between ER stress and lung fibrosis continues to evolve, future studies will examine new strategies to modulate UPR pathways for therapeutic benefit.
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Affiliation(s)
- Ankita Burman
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Harikrishna Tanjore
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Timothy S Blackwell
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Veterans Affairs Medical Center, Nashville, TN, USA.
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41
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Oh-Hashi K, Soga A, Naruse Y, Takahashi K, Kiuchi K, Hirata Y. Elucidating post-translational regulation of mouse CREB3 in Neuro2a cells. Mol Cell Biochem 2018; 448:287-297. [PMID: 29455434 DOI: 10.1007/s11010-018-3333-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/09/2018] [Indexed: 12/30/2022]
Abstract
CREB3 is an ER membrane-bound transcription factor; however, post-translational regulation of CREB3, including expression, processing, and activation, is not fully characterized. We therefore constructed several types of mouse CREB3 expression genes and elucidated their expression in Neuro2a cells by treatment with stimuli and co-transfection with genes associated with ER-Golgi homeostasis, such as mutant Sar1 [H79G], GRP78, and KDEL receptor 1 (KDELR1). Interestingly, treatment of Neuro2a cells expressing Flag-tagged full-length CREB3 with monensin and nigericin induced the expression of the approximately 50 kDa N-terminal fragment; however, its cleavage was not parallel to the levels of GADD153 and LC3-II. Co-transfection of full-length CREB3 together with Sar1 [H79G], GRP78, or KDELR1 showed that only Sar1 [H79G] induced expression of the cleaved form, and KDELR1 dramatically decreased the expression of the full-length form. Accordingly, Sar1 [H79G]- and KDELR1-overexpression influenced GAL4-CREB3-dependent luciferase activities. To understand the activation of CREB3 under more pathophysiological conditions, we focused on the effect of metal ions on CREB3 cleavage in Neuro2a cells. Among the six metal ions we tested, only copper ion stabilized full-length CREB3 expression. Copper ion also increased its N-terminal form and GAL4-CREB3-dependent luciferase activity, which was accompanied by the increase in the ubiquitinated proteins in Neuro2a cells. Taken together, CREB3 expression is regulated by multiple ER-Golgi resident factors in a post-translational manner, but its processing is not directly associated with ER stress and autophagic dysfunction. This finding is especially true for the unique action of the copper ion on CREB3 stabilization and processing in parallel to aberration of ubiquitin-proteasome system, which might provide new insights into understanding the mechanisms of intractable disorders.
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Affiliation(s)
- Kentaro Oh-Hashi
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. .,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
| | - Ayano Soga
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yoshihisa Naruse
- Department of Natural Science, Medical Education and Research Center, Meiji University of Integrative Medicine, Hiyoshi-cho, Nantan-shi, Kyoto, 629-0392, Japan
| | - Kanto Takahashi
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Kazutoshi Kiuchi
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yoko Hirata
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.,Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
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Kim SY, Kyaw YY, Cheong J. Functional interaction of endoplasmic reticulum stress and hepatitis B virus in the pathogenesis of liver diseases. World J Gastroenterol 2017; 23:7657-7665. [PMID: 29209107 PMCID: PMC5703926 DOI: 10.3748/wjg.v23.i43.7657] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 09/01/2017] [Accepted: 11/01/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is a non-cytopathic virus that causes acute and chronic inflammatory liver diseases, often leading to the pathogenesis of hepatocellular carcinoma (HCC). Although many studies for the roles of HBV on pathogenesis of the liver diseases, such as non-alcoholic fatty liver disease (NAFLD), hepatic inflammation, cirrhosis, and HCC, have been reported, the mechanisms are not fully understood. Endoplasmic reticulum (ER) and mitochondria have the protective mechanisms to restore their damaged function by intrinsic or extrinsic stresses, but their chronic dysfunctions are associated with the pathogenesis of the various diseases. Furthermore, HBV can affect intra- or extracellular homeostasis through induction of ER and mitochondrial dysfunctions, leading to liver injury. Therefore, the mechanism by which HBV induces ER or mitochondrial stresses may be a therapeutic target for treatment of liver diseases.
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Affiliation(s)
- So Young Kim
- Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea
| | - Yi Yi Kyaw
- Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea
| | - Jaehun Cheong
- Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea
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Park JW, Choi WG, Lee PJ, Chung SW, Kim BS, Chung HT, Cho S, Kim JH, Kang BH, Kim H, Kim HP, Back SH. The novel resveratrol derivative 3,5-diethoxy-3',4'-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro. Acta Pharmacol Sin 2017; 38:1486-1500. [PMID: 28795692 DOI: 10.1038/aps.2017.106] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023]
Abstract
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a well-known polyphenol that is present in grapes, peanuts, pine seeds, and several other plants. Resveratrol exerts deleterious effects on various types of human cancer cells. Here, we analyzed the cell death-inducing mechanisms of resveratrol-006 (Res-006), a novel resveratrol derivative in human liver cancer cells in vitro. Res-006 was more effectively suppressed the viability of HepG2 human hepatoma cells than resveratrol (the IC50 values were 67.2 and 354.8 μmol/L, respectively). Co-treatment with the ER stress regulator 4-phenylbutyrate (0.5 mmol/L) or the ROS inhibitor N-acetyl-L-cysteine (NAC, 1 mmol/L) significantly attenuated Res-006-induced HepG2 cell death, suggesting that pro-apoptotic ER stress and/or ROS may govern the Res-006-induced HepG2 cell death. We further revealed that treatment of HepG2 cells with Res-006 (65 μmol/L) immediately elicited the dysregulation of mitochondrial dynamics and the accumulation of mitochondrial ROS. It also collapsed the mitochondrial membrane potential and further induced ER stress and cell death. These events, except for the change in mitochondrial morphology, were prevented by the exposure of the HepG2 cells to the mitochondrial ROS scavenger, Mito-TEMPO (300-1000 μmol/L). The results suggest that Res-006 may kill HepG2 cells through cell death pathways, including the ER stress initiated by mitochondrial ROS accumulation. The cell death induced by this novel resveratrol derivative involves crosstalk between the mitochondria and ER stress mechanisms.
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Role of the unfolded protein response in tumor cell characteristics and cancer outcome. Curr Opin Oncol 2017; 29:41-47. [PMID: 27845970 DOI: 10.1097/cco.0000000000000339] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW In the present review, we discuss the possible role of the unfolded protein response (UPR) in the acquisition of tumor cell characteristics and in the prognosis of cancer outcome, which could assist and contribute to the development of more promising therapeutic strategies. RECENT FINDINGS Accumulating evidence supports the idea that alteration of endoplasmic reticulum proteostasis is a key player in cancer development and aggressiveness. Some UPR components were reported as independent prognostic biomarker. Recent evidence supports a relationship between the UPR activation status and prognosis of tumors. This may represent an interesting avenue for better characterization of carcinogenesis and tumor type. SUMMARY The contribution of the UPR to the characteristics of malignant tumors is complex and dependent on both intrinsic (e.g. oncogene addiction) and extrinsic (e.g. hypoxia) contexts. Through adaptation to severe microenvironmental conditions, UPR branches are generally a survival strategy for cancer cells, which are able to cope with this challenging context. We address the question of whether the activation status of the UPR is related to tumor properties and discuss the role of the UPR in the clinical context.
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Taniguchi M, Yoshida H. TFE3, HSP47, and CREB3 Pathways of the Mammalian Golgi Stress Response. Cell Struct Funct 2017; 42:27-36. [PMID: 28179603 DOI: 10.1247/csf.16023] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The capacity of each organelle in eukaryotic cells is tightly regulated in accordance with cellular demands by specific regulatory systems, which are generically termed organelle autoregulation. The Golgi stress response is one of the systems of organelle autoregulation and it augments the capacity of Golgi function if this becomes insufficient (Golgi stress). Recently, several pathways of the mammalian Golgi stress response have been identified, specifically the TFE3, HSP47, and CREB3 pathways. This review summarizes the essential parts of the Golgi stress response from the perspective of the organelle autoregulation.
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Affiliation(s)
- Mai Taniguchi
- Department of Molecular Biochemistry, Graduate School of Life Science, University of Hyogo
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Papaioannou A, Chevet E. Driving Cancer Tumorigenesis and Metastasis Through UPR Signaling. Curr Top Microbiol Immunol 2017; 414:159-192. [PMID: 28710693 DOI: 10.1007/82_2017_36] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In the tumor microenvironment, cancer cells encounter both external and internal factors that can lead to the accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER) lumen, thus causing ER stress. When this happens, an adaptive mechanism named the Unfolded Protein Response (UPR) is triggered to help the cell cope with this change and restore protein homeostasis in the ER. Sequentially, one would expect that the activation of the three UPR branches, driven namely by IRE1, PERK, and ATF6, are crucial for the adaptation of cancer cells to the changing environment and thus for their survival and further propagation. Indeed, in the last few years, an increasing amount of studies has shown the implication of UPR signaling in different aspects of carcinogenesis and tumor progression. Features such as sustaining proliferation and resistance to cell death, genomic instability, altered metabolism, increased inflammation and tumor-immune infiltration, invasion and metastasis, and angiogenesis, defined as "the hallmarks of cancer", can be regulated by the UPR machinery. At the same time, new potential therapeutic interventions applicable to different kinds of cancers are being revealed. In order to describe the emerging role of UPR in cancer biology, these are the points that will be discussed in this chapter.
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Affiliation(s)
- Alexandra Papaioannou
- Inserm U1242 «Chemistry, Oncogenesis, Stress and Signaling», University of Rennes 1, Rennes, France.,Centre de Lutte contre le Cancer Eugène Marquis, Avenue de la bataille Flandres Dunkerque, 35000, Rennes, France
| | - Eric Chevet
- Inserm U1242 «Chemistry, Oncogenesis, Stress and Signaling», University of Rennes 1, Rennes, France.
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Bahar E, Kim H, Yoon H. ER Stress-Mediated Signaling: Action Potential and Ca(2+) as Key Players. Int J Mol Sci 2016; 17:ijms17091558. [PMID: 27649160 PMCID: PMC5037829 DOI: 10.3390/ijms17091558] [Citation(s) in RCA: 179] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 09/06/2016] [Accepted: 09/09/2016] [Indexed: 01/24/2023] Open
Abstract
The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca(2+)) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca(2+) regulates cell death both at the early and late stages of apoptosis. Severe Ca(2+) dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca(2+) (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca(2+) and action potential in ER stress-mediated apoptosis.
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Affiliation(s)
- Entaz Bahar
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Gyeongnam, Korea.
| | - Hyongsuk Kim
- Department of Electronics Engineering, Chonbuk National University, Jeonju 54896, Jeonbuk, Korea.
| | - Hyonok Yoon
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Gyeongnam, Korea.
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Gallagher CM, Garri C, Cain EL, Ang KKH, Wilson CG, Chen S, Hearn BR, Jaishankar P, Aranda-Diaz A, Arkin MR, Renslo AR, Walter P. Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch. eLife 2016; 5. [PMID: 27435960 PMCID: PMC4954757 DOI: 10.7554/elife.11878] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 05/26/2016] [Indexed: 12/14/2022] Open
Abstract
The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination. DOI:http://dx.doi.org/10.7554/eLife.11878.001 Newly made proteins must be folded into specific three-dimensional shapes before they can perform their roles in cells. Many proteins are folded in a cell compartment called the endoplasmic reticulum. The cell closely monitors the quality of the work done by this compartment. If the endoplasmic reticulum has more proteins to fold than it can handle, unfolded or misfolded proteins accumulate and trigger a stress response called the unfolded protein response. This increases the capacity of the endoplasmic reticulum to fold proteins to match the demand. However, if the stress persists, then the unfolded protein response instructs the cell to die to protect the rest of the body. A protein called ATF6α is one of three branches of the unfolded protein response. This protein is found in the endoplasmic reticulum where it is inactive. Endoplasmic stress causes ATF6α to move from the endoplasmic reticulum to another compartment called the Golgi apparatus. There, two enzymes cut ATF6α to release a fragment of the protein that then moves to the nucleus to increase the production of the machinery needed to fold proteins in the endoplasmic reticulum. Errors in protein folding can cause serious diseases in humans and other animals. Drugs that target ATF6α might be able to regulate part of the unfolded protein response to treat these diseases. However, no drugs that act on ATF6α had been identified. Now, two groups of researchers have independently identified small molecules that specifically target ATF6α. Gallagher et al. screened over 100,000 compounds for their ability to reduce the activity of ATF6α-regulated genes. The experiments reveal that a class of small molecules termed Ceapins can selectively block the activity of ATF6α during endoplasmic reticulum stress, but had no effect on other proteins involved in the unfolded protein response. Furthermore, when human cells experiencing stress were treated with Ceapins, a greater number of cells died in comparison to cells that had not received Ceapins. An accompanying study by Gallagher and Walter reports on the mechanism by which Ceapins act on ATF6α. Independently, Plate et al. identified a type of small molecule that can activate ATF6. Together, the findings of Gallagher et al. and Plate et al. may lead to the development of new drugs for treating diseases associated with incorrect protein folding in the endoplasmic reticulum. DOI:http://dx.doi.org/10.7554/eLife.11878.002
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Affiliation(s)
- Ciara M Gallagher
- Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
| | - Carolina Garri
- Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States.,Fundación Ciencia Para la Vida, Santiago, Chile
| | - Erica L Cain
- Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
| | - Kenny Kean-Hooi Ang
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Christopher G Wilson
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Steven Chen
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Brian R Hearn
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Priyadarshini Jaishankar
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Andres Aranda-Diaz
- Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
| | - Michelle R Arkin
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Adam R Renslo
- Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
| | - Peter Walter
- Department of Biochemistry and Biophysics, Howard Hughes MedicaI Institute, University of California, San Francisco, United States
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Gallagher CM, Walter P. Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress. eLife 2016; 5. [PMID: 27435962 PMCID: PMC4954756 DOI: 10.7554/elife.11880] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 05/22/2016] [Indexed: 02/07/2023] Open
Abstract
The membrane-bound transcription factor ATF6α is activated by proteolysis during endoplasmic reticulum (ER) stress. ATF6α target genes encode foldases, chaperones, and lipid biosynthesis enzymes that increase protein-folding capacity in response to demand. The off-state of ATF6α is maintained by its spatial separation in the ER from Golgi-resident proteases that activate it. ER stress induces trafficking of ATF6α. We discovered Ceapins, a class of pyrazole amides, as selective inhibitors of ATF6α signaling that do not inhibit the Golgi proteases or other UPR branches. We show that Ceapins block ATF6α signaling by trapping it in ER-resident foci that are excluded from ER exit sites. Removing the requirement for trafficking by pharmacological elimination of the spatial separation of the ER and Golgi apparatus restored cleavage of ATF6α in the presence of Ceapins. Washout of Ceapins resensitized ATF6α to ER stress. These results suggest that trafficking of ATF6α is regulated by its oligomeric state. DOI:http://dx.doi.org/10.7554/eLife.11880.001 Newly made proteins must be folded into specific three-dimensional shapes before they can perform their roles in cells. Many proteins are folded in a cell compartment called the endoplasmic reticulum. The cell closely monitors the quality of the work done by this compartment. If the endoplasmic reticulum has more proteins to fold than it can handle, unfolded or misfolded proteins accumulate and trigger a stress response called the unfolded protein response. This increases the capacity of the endoplasmic reticulum to fold proteins to match the demand. However, if the stress persists, then the unfolded protein response instructs the cell to die to protect the rest of the body. A protein called ATF6α is one of three branches of the unfolded protein response. This protein is found in the endoplasmic reticulum where it is inactive. Endoplasmic stress causes ATF6α to move from the endoplasmic reticulum to another compartment called the Golgi apparatus. There, two enzymes cut ATF6α to release a fragment of the protein that then moves to the nucleus to increase the production of the machinery needed to fold proteins in the endoplasmic reticulum. In a related study, Gallagher et al. identified a group of small molecules called Ceapins, which inhibit ATF6α activity. Here, Gallagher and Walter investigate how Ceapins act on ATF6α. The experiments show that Ceapin causes ATF6α molecules to form clusters that prevent the protein from moving to the Golgi apparatus by keeping it away from the machinery that moves proteins between these compartments. When the enzymes that cut ATF6α are sent to the endoplasmic reticulum, Ceapin treatment no longer prevents ATF6α activation, which shows that these small molecules specifically inhibit the stress-induced movement of ATF6α. When Ceapins are washed out of cells, the ATF6α clusters fall apart and ATF6α can now move to the Golgi. These experiments show that ATF6α is actively held in the endoplasmic reticulum by a mechanism that is stabilized by Ceapins. Gallagher and Walter propose that the small clusters of ATF6α in unstressed cells act to keep this protein in the endoplasmic reticulum. However, when cells experience stress, the ATF6α clusters fall apart to allow the protein to move to the Golgi. The next steps following on from this work are to find out what these clusters are, how they are influenced by endoplasmic reticulum stress and exactly how the Ceapins stabilize these clusters. DOI:http://dx.doi.org/10.7554/eLife.11880.002
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Affiliation(s)
- Ciara M Gallagher
- Howard Hughes MedicaI Institute, University of California, San Francisco, San Francisco, United States.,Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
| | - Peter Walter
- Howard Hughes MedicaI Institute, University of California, San Francisco, San Francisco, United States.,Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
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Abstract
Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle, is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under stress and inflammatory conditions, ER loses homeostasis in its function, which is termed ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once stress is beyond the compensatory capacity of UPR or protracted, apoptosis would be initiated by triggering cell injuries, even cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidence that ER stress participates in the pathogenesis of sepsis. In this review, we summarize current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma-hemorrhage and ischemia/reperfusion injury. We also discuss the potential implications of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.
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