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Mol Biol Cell. 2015 Oct 1;26(19):3413-23. doi: 10.1091/mbc.E15-01-0034. Epub 2015 Aug 12.

PDI reductase acts on Akita mutant proinsulin to initiate retrotranslocation along the Hrd1/Sel1L-p97 axis.

Author information

1
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109.
2
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109 Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109.
3
Division of Metabolism Endocrinology and Diabetes, Comprehensive Diabetes Center, University of Michigan Medical School, Ann Arbor, MI 48109.
4
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109 Division of Metabolism Endocrinology and Diabetes, Comprehensive Diabetes Center, University of Michigan Medical School, Ann Arbor, MI 48109 btsai@umich.edu) parvan@med.umich.edu).
5
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109 Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109 btsai@umich.edu) parvan@med.umich.edu).

Abstract

In mutant INS gene-induced diabetes of youth (MIDY), characterized by insulin deficiency, MIDY proinsulin mutants misfold and fail to exit the endoplasmic reticulum (ER). Moreover, these mutants bind and block ER exit of wild-type (WT) proinsulin, inhibiting insulin production. The ultimate fate of ER-entrapped MIDY mutants is unclear, but previous studies implicated ER-associated degradation (ERAD), a pathway that retrotranslocates misfolded ER proteins to the cytosol for proteasomal degradation. Here we establish key ERAD machinery components used to triage the Akita proinsulin mutant, including the Hrd1-Sel1L membrane complex, which conducts Akita proinsulin from the ER lumen to the cytosol, and the p97 ATPase, which couples the cytosolic arrival of proinsulin with its proteasomal degradation. Surprisingly, we find that protein disulfide isomerase (PDI), the major protein oxidase of the ER lumen, engages Akita proinsulin in a novel way, reducing proinsulin disulfide bonds and priming the Akita protein for ERAD. Efficient PDI engagement of Akita proinsulin appears linked to the availability of Hrd1, suggesting that retrotranslocation is coordinated on the lumenal side of the ER membrane. We believe that, in principle, this form of diabetes could be alleviated by enhancing the targeting of MIDY mutants for ERAD to restore WT insulin production.

PMID:
26269577
PMCID:
PMC4591687
DOI:
10.1091/mbc.E15-01-0034
[Indexed for MEDLINE]
Free PMC Article

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