The endoplasmic reticulum chaperone glucose-regulated protein 94 is essential for proinsulin handling

GHIASI, SM; DAHLBY, T; ANDERSEN, CH; HAATAJA, L; PETERSEN, S; OMAR-HMEADI, M; YANG, M; PIHL, C; BRESSON, SE; KHILJI, MS; KLINDT, K; CHETA, O; PERONE, MJ; TYRBERG, B; PRATS, C; BARG, S; TENGHOLM, A; ARVAN, P; MANDRUP-POULSEN, T; MARZEC, MT

DIABETES

AMER DIABETES ASSOC

Año: 2019 vol. 68 p. 747 - 760

0012-1797

Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, therole of protein chaperones in the handling of wild-type proinsulin is under-investigated. Here, we haveexplored the importance of glucose regulated protein 94 (GRP94), a prominent ER chaperone known tofold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 coimmunoprecipitatedwith proinsulin and that inhibition of GRP94 function and/or expression reducedglucose-dependent insulin secretion, shortened proinsulin half-life and lowered intracellular proinsulinand insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and highernumbers of enlarged insulin granules that contained amorphic material with reduced immunogoldstaining for mature insulin. Insulin granule exocytosis was two-fold accelerated but the secreted insulinhad diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activatedProtein Kinase R-like Endoplasmic Reticulum Kinase (PERK), without increasing apoptosis levels.Finally, GRP94 mRNA was overexpressed in islets from T2D patients. We conclude that GRP94 is achaperone crucial for proinsulin handling and insulin secretion.