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

• DOI: 10.2337/db18-0671
• Publication Date: 2019-01-22T20:17:08Z
• Authors: Seyed Mojtaba Ghiasi; Tina Dahlby; Caroline Hede And...; Leena Haataja; Sólrun Petersen; Muhmmad Omar-Hmeadi; Mingyu Yang; Celina Pihl; Sophie Emilie Bre...; Muhammad Saad Khilji; Kristian Klindt; Oana Cheta; Marcelo J. Perone; Björn Tyrberg; Clara Prats; Sebastian Barg; Anders Tengholm; Peter Arvan; Thomas Mandrup-Po...; Michal Tomasz Marzec
• Keywords: Proinsulin; Chaperone (clinical)

Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in handling wild-type is underinvestigated. Here, we have explored importance glucose-regulated 94 (GRP94), a prominent ER known fold insulin-like growth factors, within β-cells. We found that GRP94 coimmunoprecipitated with and inhibition function and/or expression reduced glucose-dependent insulin secretion, shortened half-life, lowered intracellular levels. This phenotype was accompanied by post-ER misprocessing higher numbers enlarged granules contained amorphic material immunogold staining for mature insulin. Insulin granule exocytosis accelerated twofold, but secreted had diminished bioactivity. Moreover, knockdown or knockout β-cells selectively activated kinase R–like (PERK), without increasing apoptosis Finally, mRNA overexpressed islets from patients type 2 diabetes. conclude crucial secretion.