title: IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions.
abstract: The endoplasmic reticulum (ER) has emerged as a critical regulator of cell survival. IRE1 is a transmembrane protein with kinase and RNase activities that is localized to the ER and that promotes resistance to ER stress. We showed a mechanism by which IRE1 conferred protection against ER stress-mediated cell death. IRE1 signaling prevented ER membrane permeabilization mediated by Bax and Bak and cell death in cells experiencing ER stress. Suppression of IRE1 signaling triggered by its kinase activity led to the accumulation of the BH3 domain-containing protein Bnip3, which in turn triggered the oligomerization of Bax and Bak in the ER membrane and ER membrane permeabilization. Consequently, in response to ER stress, cells deficient in IRE1 were susceptible to leakage of ER contents, which was associated with the accumulation of calcium in mitochondria, oxidative stress in the cytosol, and ultimately cell death. Our results reveal a role for IRE1 in preventing a cell death-initializing step that emanates from the ER and provide a potential target for treating diseases characterized by ER stress, including diabetes and Wolfram syndrome.
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.affiliation: Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xiucui
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Murphy
authors.affiliation: Programs in Molecular, Cell and Cancer Biology, Molecular Medicine, and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA. John Cochran VA Medical Center, St. Louis, MO 63106, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. urano@dom.wustl.edu.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010539:Permeability; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014929:Wolfram Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: C508686:BNip3 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases