A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1α Activation in Pancreatic β Cells

Autophosphorylation of inositol-requiring enzyme 1 alpha (IRE1 alpha) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic beta cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1 alpha in a glucose-stimulated or endoplasmic reticulum (ER) stress-responsive manner in pancreatic beta cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1 alpha, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1 alpha by PP2A, thereby inhibiting glucose-stimulated IRE1 alpha activation and attenuating IRE1 alpha-dependent increases in insulin production. Moreover, IRE1 alpha activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1 alpha signaling pathway in pancreatic beta cells.