Cdc37/Hsp90 Protein-mediated Regulation of IRE1α Protein Activity in Endoplasmic Reticulum Stress Response and Insulin Synthesis in INS-1 Cells

IRE1 alpha is an endoplasmic reticulum (ER) localized signaling molecule critical for unfolded protein response. During ER stress, IRE1 alpha activation is induced by oligomerization and autophosphorylation in its cytosolic domain, a process triggered by dissociation of an ER luminal chaperone, binding immunoglobulin-protein (BiP), from IRE1 alpha. In addition, inhibition of a cytosolic chaperone protein Hsp90 also induces IRE1 alpha oligomerization and activation in the absence of an ER stressor. Here, we report that the Hsp90 cochaperone Cdc37 directly interacts with IRE1 alpha through a highly conserved cytosolic motif of IRE1 alpha. Cdc37 knockdown or disruption of Cdc37 interaction with IRE1 alpha significantly increased basal IRE1 alpha activity. In INS-1 cells, Hsp90 inhibition and disruption of IRE1 alpha-Cdc37 interaction both induced an ER stress response and impaired insulin synthesis and secretion. These data suggest that Cdc37-mediated direct interaction between Hsp90/Cdc37 and an IRE1 alpha cytosolic motif is important to maintain basal IRE1 alpha activity and contributes to normal protein homeostasis and unfolded protein response under physiological stimulation.