Cdc37/Hsp90 protein-mediated regulation of IRE1? protein activity in endoplasmic reticulum stress response and insulin synthesis in INS-1 cells.

ABSTRACT: IRE1? is an endoplasmic reticulum (ER) localized signaling molecule critical for unfolded protein response. During ER stress, IRE1? 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?. In addition, inhibition of a cytosolic chaperone protein Hsp90 also induces IRE1? oligomerization and activation in the absence of an ER stressor. Here, we report that the Hsp90 cochaperone Cdc37 directly interacts with IRE1? through a highly conserved cytosolic motif of IRE1?. Cdc37 knockdown or disruption of Cdc37 interaction with IRE1? significantly increased basal IRE1? activity. In INS-1 cells, Hsp90 inhibition and disruption of IRE1?-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? cytosolic motif is important to maintain basal IRE1? activity and contributes to normal protein homeostasis and unfolded protein response under physiological stimulation.

SUBMITTER: Ota A 

PROVIDER: S-EPMC3307264 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature