title: Endoplasmic reticulum oxidoreductin-1α (Ero1α) improves folding and secretion of mutant proinsulin and limits mutant proinsulin-induced endoplasmic reticulum stress.
abstract: Upon chronic up-regulation of proinsulin synthesis, misfolded proinsulin can accumulate in the endoplasmic reticulum (ER) of pancreatic β-cells, promoting ER stress and type 2 diabetes mellitus. In Mutant Ins-gene-induced Diabetes of Youth (MIDY), misfolded mutant proinsulin impairs ER exit of co-expressed wild-type proinsulin, limiting insulin production and leading to eventual β-cell death. In this study we have investigated the hypothesis that increased expression of ER oxidoreductin-1α (Ero1α), despite its established role in the generation of H2O2, might nevertheless be beneficial in limiting proinsulin misfolding and its adverse downstream consequences. Increased Ero1α expression is effective in promoting wild-type proinsulin export from cells co-expressing misfolded mutant proinsulin. In addition, we find that upon increased Ero1α expression, some of the MIDY mutants themselves are directly rescued from ER retention. Secretory rescue of proinsulin-G(B23)V is correlated with improved oxidative folding of mutant proinsulin. Indeed, using three different variants of Ero1α, we find that expression of either wild-type or an Ero1α variant lacking regulatory disulfides can rescue mutant proinsulin-G(B23)V, in parallel with its ability to provide an oxidizing environment in the ER lumen, whereas beneficial effects were less apparent for a redox-inactive form of Ero1. Increased expression of protein disulfide isomerase antagonizes the rescue provided by oxidatively active Ero1. Importantly, ER stress induced by misfolded proinsulin was limited by increased expression of Ero1α, suggesting that enhancing the oxidative folding of proinsulin may be a viable therapeutic strategy in the treatment of type 2 diabetes.
authors.affiliation: From the Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
authors.forename: Jordan
authors.initials: J
authors.lastname: Wright
authors.forename: Julia
authors.initials: J
authors.lastname: Birk
authors.forename: Leena
authors.initials: L
authors.lastname: Haataja
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Ramming
authors.forename: Michael A
authors.initials: MA
authors.lastname: Weiss
authors.forename: Christian
authors.initials: C
authors.lastname: Appenzeller-Herzog
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding
chemical_list: D008562:Membrane Glycoproteins; D011384:Proinsulin; D006861:Hydrogen Peroxide; C405327:ERO1A protein, human; D010088:Oxidoreductases
keywords: Diabetes; Disulfide; Endoplasmic Reticulum (ER); Insulin Synthesis; Mutant Ins-gene-induced Diabetes of Youth; Oxidative Folding; β-Cell
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