Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth
- 1 May 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (5), 954-964
- https://doi.org/10.2337/db19-1106
Abstract
Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene-induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in beta-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.Funding Information
- National Institutes of Health (R01-DK-48280, R24-DK-110973, R01-DK-04949)
- Natural Science Foundation of China (81830025, 81620108004, 81570699)
This publication has 38 references indexed in Scilit:
- Control of Precursor Maturation and Disposal Is an Early Regulative Mechanism in the Normal Insulin Production of Pancreatic β-CellsPLOS ONE, 2011
- Mutant INS-Gene Induced Diabetes of Youth: Proinsulin Cysteine Residues Impose Dominant-Negative Inhibition on Wild-Type Proinsulin TransportPLOS ONE, 2010
- Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youthTrends in Endocrinology & Metabolism, 2010
- ERO1-β, a pancreas-specific disulfide oxidase, promotes insulin biogenesis and glucose homeostasisThe Journal of cell biology, 2010
- Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesisProceedings of the National Academy of Sciences of the United States of America, 2010
- Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secretedBiochemical and Biophysical Research Communications, 2010
- Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitusJCI Insight, 2008
- The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and DiabetesEndocrine Reviews, 2008
- Proinsulin maturation, misfolding, and proteotoxicityProceedings of the National Academy of Sciences of the United States of America, 2007
- Insulin gene mutations as a cause of permanent neonatal diabetesProceedings of the National Academy of Sciences of the United States of America, 2007