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- Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion.
Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion.
Citation | “Chaperone-Driven Degradation Of A Misfolded Proinsulin Mutant In Parallel With Restoration Of Wild-Type Insulin Secretion.”. Diabetes, pp. 741-753. . |
Center | University of Michigan |
Author | Corey N Cunningham, Kaiyu He, Anoop Arunagiri, Adrienne W Paton, James C Paton, Peter Arvan, Billy Tsai |
Abstract |
In heterozygous patients with a diabetic syndrome called mutant 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 proinsulin is triaged by ER-associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shifting 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 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. |
Year of Publication |
2017
|
Journal |
Diabetes
|
Volume |
66
|
Issue |
3
|
Number of Pages |
741-753
|
Date Published |
12/2017
|
ISSN Number |
1939-327X
|
DOI |
10.2337/db16-1338
|
Alternate Journal |
Diabetes
|
PMID |
28028074
|
PMCID |
PMC5319713
|
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