Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling.

Autor:	Ghiasi SM; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Dahlby T; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Hede Andersen C; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Haataja L; Division of Metabolism, Endocrinology, & Diabetes, University of Michigan Medical Center, Ann Arbor, MI., Petersen S; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Omar-Hmeadi M; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Yang M; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Pihl C; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Bresson SE; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Khilji MS; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Klindt K; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Cheta O; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Perone MJ; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Buenos Aires, Argentina., Tyrberg B; Translational Science, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Prats C; Center for Healthy Ageing, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Barg S; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Tengholm A; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden., Arvan P; Division of Metabolism, Endocrinology, & Diabetes, University of Michigan Medical Center, Ann Arbor, MI., Mandrup-Poulsen T; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Marzec MT; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark michal@sund.ku.dk.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2019 Apr; Vol. 68 (4), pp. 747-760. Date of Electronic Publication: 2019 Jan 22.
DOI:	10.2337/db18-0671
Abstrakt:	Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is underinvestigated. Here, we have explored the importance of glucose-regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 coimmunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life, and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activated protein kinase R-like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion. (© 2019 by the American Diabetes Association.)
Databáze:	MEDLINE
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