title: Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion.
abstract: In heterozygous patients with a diabetic syndrome called mutantINSgene-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 mutantAkitaproinsulin is triaged by ER-associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shiftingAkitaproinsulin 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 ofAkitaproinsulin 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.
authors.affiliation: Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI.|Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Corey N
authors.initials: CN
authors.lastname: Cunningham
authors.affiliation: Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: He
authors.affiliation: Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Anoop
authors.initials: A
authors.lastname: Arunagiri
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, Australia.
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI btsai@umich.edu parvan@med.umich.edu.|Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.affiliation: Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI btsai@umich.edu parvan@med.umich.edu.|Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Billy
authors.initials: B
authors.lastname: Tsai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000235:genetics*; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D018832:Molecular Chaperones; D009154:Mutation; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D051381:Rats
chemical_list: D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; D007328:Insulin; D018832:Molecular Chaperones; C098410:glucose-regulated protein 170; D011384:Proinsulin