Doctor of Philosophy, University of California Los Angeles (2009)
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.
View details for DOI 10.1074/jbc.M111.331264
View details for Web of Science ID 000300791800019
View details for PubMedID 22199355