ArticleThe Journal of biological chemistry2013
Endoplasmic reticulum oxidoreductin-1α (Ero1α) improves folding and secretion of mutant proinsulin and limits mutant proinsulin-induced endoplasmic reticulum stress.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice.GeroScience · 2025Article
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Endoplasmic reticulum oxidoreductin 1α as a potential therapeutic target in diseases: from oxidative protein folding to pathophysiological mechanisms.Frontiers in pharmacology · 2025Review
- A metabolic redox relay supports ER proinsulin export in pancreatic islet β cells.JCI insight · 2024Article
- Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.Protein science : a publication of the Protein Society · 2024Article
- Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer.Journal of experimental & clinical cancer research : CR · 2024Review
- Article
- Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction.Nature communications · 2023Article
- From glucose sensing to exocytosis: takes from maturity onset diabetes of the young.Frontiers in endocrinology · 2023Review
- Homocysteine facilitates endoplasmic reticulum stress and apoptosis of hepatocytes by suppressing ERO1α expression via cooperation between DNMT1 and G9a.Cell biology international · 2022Article
- ERO1-PDI Redox Signaling in Health and Disease.Antioxidants & redox signaling · 2021Review
- ERO1α mediates endoplasmic reticulum stress-induced apoptosis via microRNA-101/EZH2 axis in colon cancer RKO and HT-29 cells.Human cell · 2021Article
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
- Evolution of insulin at the edge of foldability and its medical implications.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Role of the ERO1-PDI interaction in oxidative protein folding and disease.Pharmacology & therapeutics · 2020Review
- "Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.The Journal of biological chemistry · 2020Article
- Article
- Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes.Annals of the New York Academy of Sciences · 2018Review
- A Bystander Mechanism Explains the Specific Phenotype of a Broadly Expressed Misfolded Protein.PLoS genetics · 2016Article
- Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
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.
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Registered trials
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