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Diabetes. 2017 Mar;66(3):741-753. doi: 10.2337/db16-1338. Epub 2016 Dec 27.

Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion.

Author information

1
Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI.
2
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI.
3
Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI.
4
Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, Australia.
5
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI btsai@umich.edu parvan@med.umich.edu.
6
Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI btsai@umich.edu parvan@med.umich.edu.

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.

PMID:
28028074
PMCID:
PMC5319713
DOI:
10.2337/db16-1338
[Indexed for MEDLINE]
Free PMC Article

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