The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis
The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis
Abstract Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.
Kroemer Guido、Urra Hery、Milani Mateus、Pihan Philippe、Baxter Reese、Huang Menghao、Vihinen Helena、Bailly-maitre Beatrice、Plate Lars、Diaz Javier、Ratziu Vlad、Hengstler Jan G.、Criollo Alfredo、Garcia Lopez Valeria A.、Dong X Charlie、Aprahamia Fanny、Jokitalo Eija、Batista-Gonzalez Ana、Tamburini Giovanni、Hazari Younis、Foufelle Fabienne、Maiers Jessica L、Godoy Patricio、Hetz Claudio、Durand Sylvere
Metabolomics and Cell Biology Platforms, UMS AMMICa Gustave Roussy Cancer Campus||Centre de Recherche des Cordeliers, Universit¨| de Paris, Sorbonne Universit¨|, INSERM U1138, Institut Universitaire de France||Institut du Cancer Paris CARPEM, Department of BiologyBiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of ChileBiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of ChileBiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of ChileDepartment of Medicine, Indiana University School of MedicineDeparment of Biochemisry and Molecular Biology, Indiana University School of MedicineElectron Microscopy Unit, Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki HelsinkiUniversit¨| C?te d?ˉAzur, INSERMDepartment of Biological Sciences, Vanderbilt University||Department of Chemistry, Vanderbilt UniversityBiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of ChileCentre de Recherche des Cordeliers Sorbonne Universit¨|, Universit¨| de Paris||Institute of Cardiometabolism and Nutrition||Sorbonne Universit¨|, Assistance Publique-H?pitaux De Paris FranceLeibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo)Instituto de Investigaci¨?n en Ciencias Odontol¨?gicas (ICOD), Facultad de Odontolog¨aa, Universidad de ChileDepartment of Biological Sciences, Vanderbilt UniversityDeparment of Biochemisry and Molecular Biology, Indiana University School of MedicineMetabolomics and Cell Biology Platforms, UMS AMMICa Gustave Roussy Cancer Campus||Centre de Recherche des Cordeliers, Universit¨| de Paris, Sorbonne Universit¨|, INSERM U1138, Institut Universitaire de FranceElectron Microscopy Unit, Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki HelsinkiInstituto de Investigaci¨?n en Ciencias Odontol¨?gicas (ICOD), Facultad de Odontolog¨aa, Universidad de ChileBiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of ChileBiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of ChileCentre de Recherche des Cordeliers Sorbonne Universit¨|, Universit¨| de Paris||Institute of Cardiometabolism and NutritionDepartment of Medicine, Indiana University School of MedicineLeibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo)Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile||FONDAP Center for Geroscience (GERO), Brain Health and Metabolism||Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile||Buck Institute for Research on AgingMetabolomics and Cell Biology Platforms, UMS AMMICa Gustave Roussy Cancer Campus||Centre de Recherche des Cordeliers, Universit¨| de Paris, Sorbonne Universit¨|, INSERM U1138, Institut Universitaire de France
基础医学分子生物学生物化学
collagenliver fibrosisUPRIRE1PDIA1/P4HB
Kroemer Guido,Urra Hery,Milani Mateus,Pihan Philippe,Baxter Reese,Huang Menghao,Vihinen Helena,Bailly-maitre Beatrice,Plate Lars,Diaz Javier,Ratziu Vlad,Hengstler Jan G.,Criollo Alfredo,Garcia Lopez Valeria A.,Dong X Charlie,Aprahamia Fanny,Jokitalo Eija,Batista-Gonzalez Ana,Tamburini Giovanni,Hazari Younis,Foufelle Fabienne,Maiers Jessica L,Godoy Patricio,Hetz Claudio,Durand Sylvere.The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis[EB/OL].(2025-03-28)[2025-06-14].https://www.biorxiv.org/content/10.1101/2023.05.02.538835.点此复制
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