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Autophosphorylation of inositol-requiring enzyme 1α (IRE1α) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic β cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1α in a glucose-stimulated or endoplasmic reticulum (ER) stress–responsive manner in pancreatic β cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1α, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1α by PP2A, thereby inhibiting glucose-stimulated IRE1α activation and attenuating IRE1α-dependent increases in insulin production. Moreover, IRE1α activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key …