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He Z, Liu Q, Wang Y, Zhao B, Zhang L, Yang X, Wang Z. The role of endoplasmic reticulum stress in type 2 diabetes mellitus mechanisms and impact on islet function. PeerJ 2025; 13:e19192. [PMID: 40166045 PMCID: PMC11956770 DOI: 10.7717/peerj.19192] [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: 12/18/2024] [Accepted: 02/26/2025] [Indexed: 04/02/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder characterized by insulin resistance and dysfunction of islet cells. Endoplasmic reticulum (ER) stress plays a crucial role in the pathogenesis and progression of T2DM, especially in the function and survival of β-cells. β-cells are particularly sensitive to ER stress because they require substantial insulin synthesis and secretion energy. In the early stages of T2DM, the increased demand for insulin exacerbates β-cell ER stress. Although the unfolded protein response (UPR) can temporarily alleviate this stress, prolonged or excessive stress leads to pancreatic cell dysfunction and apoptosis, resulting in insufficient insulin secretion. This review explores the mechanisms of ER stress in T2DM, particularly its impact on islet cells. We discuss how ER stress activates UPR signaling pathways to regulate protein folding and degradation, but when stress becomes excessive, these pathways may contribute to β-cell death. A deeper understanding of how ER stress impacts islet cells could lead to the development of novel T2DM treatment strategies aimed at improving islet function and slowing disease progression.
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Affiliation(s)
- Zhaxicao He
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Qian Liu
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Yan Wang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Bing Zhao
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Lumei Zhang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Xia Yang
- Tianshui Hospital of Traditional Chinese Medicine, Tianshui, China
| | - Zhigang Wang
- Gansu University of Chinese Medicine, Lanzhou, China
- Tianshui Hospital of Traditional Chinese Medicine, Tianshui, China
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2
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Acosta-Alvear D, Harnoss JM, Walter P, Ashkenazi A. Homeostasis control in health and disease by the unfolded protein response. Nat Rev Mol Cell Biol 2025; 26:193-212. [PMID: 39501044 DOI: 10.1038/s41580-024-00794-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2024] [Indexed: 02/27/2025]
Abstract
Cells rely on the endoplasmic reticulum (ER) to fold and assemble newly synthesized transmembrane and secretory proteins - essential for cellular structure-function and for both intracellular and intercellular communication. To ensure the operative fidelity of the ER, eukaryotic cells leverage the unfolded protein response (UPR) - a stress-sensing and signalling network that maintains homeostasis by rebalancing the biosynthetic capacity of the ER according to need. The metazoan UPR can also redirect signalling from cytoprotective adaptation to programmed cell death if homeostasis restoration fails. As such, the UPR benefits multicellular organisms by preserving optimally functioning cells while removing damaged ones. Nevertheless, dysregulation of the UPR can be harmful. In this Review, we discuss the UPR and its regulatory processes as a paradigm in health and disease. We highlight important recent advances in molecular and mechanistic understanding of the UPR that enable greater precision in designing and developing innovative strategies to harness its potential for therapeutic gain. We underscore the rheostatic character of the UPR, its contextual nature and critical open questions for its further elucidation.
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Affiliation(s)
| | - Jonathan M Harnoss
- Department of General, Visceral, Thoracic and Transplant Surgery, University Hospital Giessen, Giessen, Germany
| | - Peter Walter
- Altos Labs, Inc., Bay Area Institute of Science, Redwood City, CA, USA.
| | - Avi Ashkenazi
- Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
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3
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Luchetti N, Smith KM, Matarrese MAG, Loppini A, Filippi S, Chiodo L. A statistical mechanics investigation of unfolded protein response across organisms. Sci Rep 2024; 14:27658. [PMID: 39532983 PMCID: PMC11557608 DOI: 10.1038/s41598-024-79086-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Living systems rely on coordinated molecular interactions, especially those related to gene expression and protein activity. The Unfolded Protein Response is a crucial mechanism in eukaryotic cells, activated when unfolded proteins exceed a critical threshold. It maintains cell homeostasis by enhancing protein folding, initiating quality control, and activating degradation pathways when damage is irreversible. This response functions as a dynamic signaling network, with proteins as nodes and their interactions as edges. We analyze these protein-protein networks across different organisms to understand their intricate intra-cellular interactions and behaviors. In this work, analyzing twelve organisms, we assess how fundamental measures in network theory can individuate seed proteins and specific pathways across organisms. We employ network robustness to evaluate and compare the strength of the investigated protein-protein interaction networks, and the structural controllability of complex networks to find and compare the sets of driver nodes necessary to control the overall networks. We find that network measures are related to phylogenetics, and advanced network methods can identify main pathways of significance in the complete Unfolded Protein Response mechanism.
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Affiliation(s)
- Nicole Luchetti
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy.
- Center for Life Nano- & Neuro-Science, Italian Institute of Technology, Viale Regina Elena 291, Rome, 00161, Italy.
| | - Keith M Smith
- Computer and Information Sciences, University of Strathclyde, 26 Richmond Street, Glasgow, G1 1XH, United Kingdom
| | - Margherita A G Matarrese
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy
| | - Alessandro Loppini
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy
| | - Simonetta Filippi
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy.
- National Institute of Optics, National Research Council, Largo Enrico Fermi 6, Florence, 50125, Italy.
- International Center for Relativistic Astrophysics Network, Piazza della Repubblica 10, Pescara, 65122, Italy.
| | - Letizia Chiodo
- Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, Rome, 00128, Italy
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4
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Ernst R, Renne MF, Jain A, von der Malsburg A. Endoplasmic Reticulum Membrane Homeostasis and the Unfolded Protein Response. Cold Spring Harb Perspect Biol 2024; 16:a041400. [PMID: 38253414 PMCID: PMC11293554 DOI: 10.1101/cshperspect.a041400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
The endoplasmic reticulum (ER) is the key organelle for membrane biogenesis. Most lipids are synthesized in the ER, and most membrane proteins are first inserted into the ER membrane before they are transported to their target organelle. The composition and properties of the ER membrane must be carefully controlled to provide a suitable environment for the insertion and folding of membrane proteins. The unfolded protein response (UPR) is a powerful signaling pathway that balances protein and lipid production in the ER. Here, we summarize our current knowledge of how aberrant compositions of the ER membrane, referred to as lipid bilayer stress, trigger the UPR.
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Affiliation(s)
- Robert Ernst
- Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany
- Preclinical Center for Molecular Signaling (PZMS), Medical Faculty, Saarland University, 66421 Homburg, Germany
| | - Mike F Renne
- Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany
- Preclinical Center for Molecular Signaling (PZMS), Medical Faculty, Saarland University, 66421 Homburg, Germany
| | - Aamna Jain
- Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany
- Preclinical Center for Molecular Signaling (PZMS), Medical Faculty, Saarland University, 66421 Homburg, Germany
| | - Alexander von der Malsburg
- Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany
- Preclinical Center for Molecular Signaling (PZMS), Medical Faculty, Saarland University, 66421 Homburg, Germany
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Yue F, Xu J, Meng L, Wang Q, Tan M, Zhang A, Yan S, Jiang D. A new insight into Cd exposure-induced hemocyte reduction in Lymantria dispar larvae: Involvement of the ROS-ATF6-ER stress-apoptosis pathway. JOURNAL OF HAZARDOUS MATERIALS 2024; 469:134061. [PMID: 38508113 DOI: 10.1016/j.jhazmat.2024.134061] [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: 01/27/2024] [Revised: 03/07/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024]
Abstract
Hemocytes are important targets for heavy metal-induced immunotoxicity in insects. This study aimed to investigate the mechanism by which cadmium (Cd) exposure affects the hemocyte count in Lymantria dispar larvae. The results showed that the number of larval hemocytes was significantly decreased under Cd exposure, accompanied by a significant increase in the apoptosis rate and the expression of Caspase-3. The endoplasmic reticulum (ER) of hemocytes in the Cd-treated group showed irregular swelling. Expression levels of ER stress indicator genes (CHOP, Bip1, Bip2, Bip3, and Bip4) were significantly higher in the Cd-treated group. Among the three pathways that potentially mediate ER stress, only the key genes in the ATF6 pathway (ATF6, S1P-1, S1P-2, and WFS1) exhibited differential responses to Cd exposure. Cd exposure significantly increased the levels of reactive oxygen species (ROS) and the expression of oxidative stress-related genes (CNCC, P38, and ATF2) in hemocytes. Studies using inhibitors confirmed that apoptosis mediated the decrease in hemocyte count, ER stress mediated apoptosis, ATF6 pathway mediated ER stress, and ROS or oxidative stress mediated ER stress through the activation of the ATF6 pathway. Taken together, the ROS-ATF6-ER stress-apoptosis pathway is responsible for the reduction in the hemocyte count of Cd-treated L. dispar larvae.
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Affiliation(s)
- Fusen Yue
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China; Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin 150040, PR China
| | - Jinsheng Xu
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China; Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin 150040, PR China
| | - Linyi Meng
- School of Forestry, Beihua University, Jilin 132013, PR China
| | - Qi Wang
- Forest Conservation Institute, Chinese Academy of Forestry, Harbin 150040, PR China
| | - Mingtao Tan
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China; Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin 150040, PR China
| | - Aoying Zhang
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China; Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin 150040, PR China
| | - Shanchun Yan
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China; Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin 150040, PR China
| | - Dun Jiang
- School of Forestry, Northeast Forestry University, Harbin 150040, PR China; Key Laboratory of Sustainable Forest Ecosystem Management-Ministry of Education, Northeast Forestry University, Harbin 150040, PR China.
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6
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Vivacqua G, Mancinelli R, Leone S, Vaccaro R, Garro L, Carotti S, Ceci L, Onori P, Pannarale L, Franchitto A, Gaudio E, Casini A. Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders. Neurogastroenterol Motil 2024; 36:e14780. [PMID: 38462652 DOI: 10.1111/nmo.14780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 01/27/2024] [Accepted: 03/03/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND Different studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis. PURPOSE In this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut-to-brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders.
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Affiliation(s)
- Giorgio Vivacqua
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Stefano Leone
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Rosa Vaccaro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Ludovica Garro
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Simone Carotti
- Integrated Research Center (PRAAB), Campus Biomedico University of Roma, Rome, Italy
| | - Ludovica Ceci
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Arianna Casini
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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Hazari Y, Chevet E, Bailly-Maitre B, Hetz C. ER stress signaling at the interphase between MASH and HCC. Hepatology 2024:01515467-990000000-00844. [PMID: 38626349 DOI: 10.1097/hep.0000000000000893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/28/2024] [Indexed: 04/18/2024]
Abstract
HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here, we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the unfolded protein response in HCC, such as cancer therapy, are also discussed.
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Affiliation(s)
- Younis Hazari
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Department of Biotechnology, University of Kashmir, Srinagar, India
| | - Eric Chevet
- Inserm U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Béatrice Bailly-Maitre
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Team "Metainflammation and Hematometabolism", Metabolism Department, France
- Université Côte d'Azur, INSERM, U1065, C3M, 06200 Nice, France
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Buck Institute for Research on Aging, Novato, California, USA
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8
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Ikeda T, Ishikawa T, Ninagawa S, Okada T, Ono M, Mori K. Proteomic analysis of fatty liver induced by starvation of medaka fish larvae. Cell Struct Funct 2023; 48:123-133. [PMID: 37380437 PMCID: PMC10915113 DOI: 10.1247/csf.23014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 06/23/2023] [Indexed: 06/30/2023] Open
Abstract
When medaka fish (Oryzias latipes) larvae are grown in the absence of exogenous nutrition, the liver becomes dark and positive to Oil Red O staining from 7 days post-hatch (dph). We determined the mechanism of this starvation-induced development of fatty liver by proteomic analysis using livers obtained from larvae grown in the presence or absence of 2% glucose at 5 dph. Results showed that changes in the expression levels of enzymes involved in glycolysis or the tricarboxylic acid cycle were modest, whereas the expression levels of enzymes involved in amino acid catabolism or β-oxidation of fatty acids were significantly elevated, suggesting that they become major energy sources under starvation conditions. Expression levels of enzymes for the uptake and β-oxidation of fatty acids as well as synthesis of triacylglycerol were elevated, whereas those for the synthesis of cholesterol as well as export of cholesterol and triacylglycerol were decreased under starvation conditions, which explains the accumulation of triacylglycerol in the liver. Our results provide the basis for future research to understand how gene malfunction(s) affects the development of fatty liver, which can lead to nonalcoholic steatohepatitis and then to liver cirrhosis.Key words: amino acid catabolism, β-oxidation, triacylglycerol, cholesterol, export.
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Affiliation(s)
- Tomoyo Ikeda
- Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
| | - Tokiro Ishikawa
- Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
| | - Satoshi Ninagawa
- Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
| | - Tetsuya Okada
- Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
| | - Masaya Ono
- National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Kazutoshi Mori
- Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
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Hou XX, Li YW, Song JL, Zhang W, Liu R, Yuan H, Feng TT, Jiang ZY, Li WT, Zhu CL. Cryptotanshinone induces apoptosis of activated hepatic stellate cells via modulating endoplasmic reticulum stress. World J Gastroenterol 2023; 29:2616-2627. [PMID: 37213406 PMCID: PMC10198054 DOI: 10.3748/wjg.v29.i17.2616] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/28/2023] [Accepted: 04/10/2023] [Indexed: 05/23/2023] Open
Abstract
BACKGROUND Cryptotanshinone (CPT) has wide biological functions, including anti-oxidative, antifibrosis, and anti-inflammatory properties. However, the effect of CPT on hepatic fibrosis is unknown.
AIM To investigate the effects of CPT treatment on hepatic fibrosis and its underlying mechanism of action.
METHODS Hepatic stellate cells (HSCs) and normal hepatocytes were treated with different concentrations of CPT and salubrinal. The CCK-8 assay was used to determine cell viability. Flow cytometry was used to measure apoptosis and cell cycle arrest. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analyses were used to measure mRNA levels and protein expression of endoplasmic reticulum stress (ERS) signaling pathway related molecules, respectively. Carbon tetrachloride (CCL4) was used to induce in vivo hepatic fibrosis in mice. Mice were treated with CPT and salubrinal, and blood and liver samples were collected for histopathological examination.
RESULTS We found that CPT treatment significantly reduced fibrogenesis by modulating the synthesis and degradation of the extracellular matrix in vitro. CPT inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in cultured HSCs. Furthermore, we found that CPT promoted apoptosis of activated HSCs by upregulating expression of ERS markers (CHOP and GRP78) and activating ERS pathway molecules (PERK, IRE1α, and ATF4), which were inhibited by salubrinal. Inhibition of ERS by salubrinal partially eliminated the therapeutic effect of CPT in our CCL4-induced hepatic fibrosis mouse model.
CONCLUSION CPT can promote apoptosis of HSCs and alleviate hepatic fibrosis through modulating the ERS pathway, which represents a promising strategy for treating hepatic fibrosis.
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Affiliation(s)
- Xiao-Xue Hou
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Yu-Wen Li
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Jia-Li Song
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Wen Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Rui Liu
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570000, Hainan Province, China
| | - Hui Yuan
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Tian-Tong Feng
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Zheng-Yi Jiang
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
| | - Wen-Ting Li
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570000, Hainan Province, China
| | - Chuan-Long Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China
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Abstract
The endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, undergoes a rapid, reversible and inactivating post-translational modification. This covalent modification complements the slower, conventional unfolded protein response (UPR) in matching the supply of active Hsp70 chaperone to the protein folding demand within the ER lumen. Long believed to be ADP-ribosylation, we now know this modification to be AMPylation (adenylylation) of BiP's threonine 518. Here, we review the discovery of the responsible enzyme (the Fic domain-containing protein FICD), the structural and biochemical basis of the inactivating modification and the discovery of FICD's dual role as the enzyme that both AMPylates and deAMPylates BiP. The structural basis of BiP recognition by FICD and recent in vitro insights into oligomeric state-mediated regulation of FICD's antagonistic enzymatic activities are also reviewed, the latter in the context of how such a regulatory system may arise in cells. Last, we consider the physiological significance of BiP AMPylation and speculate on the fitness benefits of this metazoan-specific adaptation.
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Affiliation(s)
- Luke A Perera
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom
| | - David Ron
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom
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