Endoplasmic Reticulum Oxidoreductin-1α (Ero1α) Improves Folding and Secretion of Mutant Proinsulin and Limits Mutant Proinsulin-induced Endoplasmic Reticulum Stress
Year: 2013
Type: article
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 H 2 O 2 , 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. Background: Mutant proinsulin-G(B23)V is defective in formation of native disulfide bonds. Results: Overexpression of Ero1α partially rescues secretion of mutant proinsulin-G(B23)V. Conclusion: Enhanced ER oxidation is of potential benefit to proinsulin folding. Significance: Diseases involving proinsulin misfolding might be ameliorated by techniques augmenting protein oxidation in the ER of pancreatic β-cells.
Source: Journal of Biological Chemistry
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: National Science Foundation, University of Michigan, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Michigan Diabetes Research and Training Center, How mutations in proinsulin cause diabetes: a protein-misfolding disease, Michigan Medical Scientist Training Program, G301048564, G438186345, Systems and Integrative Biology Training Program, G5760820354, Michigan Diabetes Research Center, G67213621, G7178668192, Rescued Secretion of Misfolded Mutant Proinsulin, Proinsulin Trafficking for Insulin Biosynthesis, G9000030401, G9000060903, G9000301458
OpenAlex ID: W2064288138