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https://hdl.handle.net/2440/118047
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Type: | Journal article |
Title: | Chaperone-driven degradation of a misfolded proinsulin mutant in parallel with restoration of wild-type insulin secretion |
Author: | Cunningham, C. He, K. Arunagiri, A. Paton, A. Paton, J. Arvan, P. Tsai, B. |
Citation: | Diabetes, 2017; 66(3):741-753 |
Publisher: | American Diabetes Association |
Issue Date: | 2017 |
ISSN: | 0012-1797 1939-327X |
Statement of Responsibility: | Corey N. Cunningham, Kaiyu He, Anoop Arunagiri, Adrienne W. Paton, James C. Paton, Peter Arvan and Billy Tsai |
Abstract: | In heterozygous patients with a diabetic syndrome called mutant INS gene-induced diabetes of youth (MIDY), there is decreased insulin secretion when mutant proinsulin expression prevents wild-type (WT) proinsulin from exiting the endoplasmic reticulum (ER), which is essential for insulin production. Our previous results revealed that mutant Akita proinsulin is triaged by ER-associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shifting Akita proinsulin from high-molecular weight (MW) complexes toward smaller oligomeric species that are competent to undergo ERAD. Strikingly, overexpressing Grp170 also liberates WT proinsulin, which is no longer trapped in these high-MW complexes, enhancing ERAD of Akita proinsulin and restoring WT insulin secretion. Our data reveal that Grp170 participates in preparing mutant proinsulin for degradation while enabling WT proinsulin escape from the ER. In principle, selective destruction of mutant proinsulin offers a rational approach to rectify the insulin secretion problem in MIDY. |
Keywords: | Cell Line, Tumor Endoplasmic Reticulum Animals Humans Rats Diabetes Mellitus Insulin Proinsulin Glycoproteins Molecular Chaperones Protein Folding Heterozygote Mutation HSP70 Heat-Shock Proteins Insulin-Secreting Cells Gene Knockdown Techniques HEK293 Cells Endoplasmic Reticulum-Associated Degradation Insulin Secretion |
Rights: | © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. |
DOI: | 10.2337/db16-1338 |
Published version: | http://dx.doi.org/10.2337/db16-1338 |
Appears in Collections: | Aurora harvest 3 Molecular and Biomedical Science publications |
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