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

Author:

Ghiasi Seyed Mojtaba1ORCID,Dahlby Tina1,Hede Andersen Caroline1,Haataja Leena2,Petersen Sólrun1,Omar-Hmeadi Muhmmad3,Yang Mingyu3,Pihl Celina1,Bresson Sophie Emilie1,Khilji Muhammad Saad1,Klindt Kristian1,Cheta Oana1,Perone Marcelo J.14,Tyrberg Björn5,Prats Clara6ORCID,Barg Sebastian3,Tengholm Anders3ORCID,Arvan Peter2,Mandrup-Poulsen Thomas1ORCID,Marzec Michal Tomasz1ORCID

Affiliation:

1. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2. Division of Metabolism, Endocrinology, & Diabetes, University of Michigan Medical Center, Ann Arbor, MI

3. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

4. Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Buenos Aires, Argentina

5. Translational Science, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

6. Center for Healthy Ageing, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

Abstract

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.

Funder

Danish Council for Independent Research

Augustinus Foundation

Dagmar Marshall Foundation

A.P. Møller Foundation

Kirsten and Freddy Johansen Foundation

Eva and Hans Carl Holm Foundation

Danish Diabetes Academy

Zealand Pharma A/S

Swedish Research Council

Diabetesfonden

Family Ernfors Foundation

NovoNordisk Foundation

National Institutes of Health

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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