title: Pathogenic Mechanism of Diabetes Development Due to Dysfunction of Unfolded Protein Response.
abstract: The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and membrane proteins are folded and assembled. Various stresses cause the accumulation of unfolded or misfolded proteins in the ER, resulting in ER dysfunction. This condition is termed ER stress. To cope with ER stress, cells activate a signaling pathway termed the unfolded protein response (UPR). Recently, accumulating evidence suggests that the UPR plays a pivotal role in pancreatic β cells. Pancreatic β cells producing a large amount of insulin are highly sensitive when the UPR is impaired. In mammalian cells, three principal ER stress sensors, PERK, IRE1, and ATF6, initiate the UPR. Activated PERK attenuates protein translation through eIF2α phosphorylation to cope with the ER stress. PERK KO mice develop diabetes by 2-4 weeks of age due to progressive β-cell loss. IRE1α noncanonically splices the XBP1 mRNA, leading to the upregulation of the ERAD components and ER molecular chaperones. This pathway is constitutively activated in pancreatic β cells. To clarify the physiological role of the IRE1α pathway in β cells, we generated pancreatic-β-cell-specific IRE1α-conditional KO (cKO) mice and IRE1α-cKO insulinoma cell lines. Here, we show that IRE1α is required for the upregulation of insulin-folding enzymes in pancreatic β cells to balance insulin-folding enzymes with insulin.
authors.affiliation: Nara Institute of Science and Technology, Graduate School of Biological Sciences, Laboratory of Molecular and Cell Genetics.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Michiko
authors.initials: M
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
mesh_terms: D051702:Activating Transcription Factor 6 / Q000502:physiology; D000818:Animals; D003920:Diabetes Mellitus / Q000209:etiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*; D019892:eIF-2 Kinase / Q000502:physiology
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D015852:Eukaryotic Initiation Factor-2; D007328:Insulin; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases