When the cells are exposed to endoplasmic reticulum (ER) stress,incorrectly folded proteins accumulate in the ER lumen.To maintain celluar homeostasis,cells cause unfolded protein response(UPR),which induces transcriptional activation of genes encoding ER-resident molecular chaperones,including BiP.The ER transmembrane protein IRE1 containing both kinase and ribonuclease activities,plays important roles in sensing the ER stress and tranducting the signals from ER to cytosol/nucleus.Here we report both the activation mechanism and the role of ribonulease domain of IRE1.First we present more direct evidence of the BiP-dependent IRE1 regulation model using yeast BiP mutants:mutations stabilizing BiP association with IRE1 impaired UPR signaling even under condiction of ER stress,while mutations disrupting this association constitutively activate UPR pathway.This result suggests that the dissociation and association of BiP to IRE1 directly regulates the degree of IRE1 activation.Second,chimeric protein analyses of RNase regeion between IRE1α and IRE1β showed that RNase domain of IRE1βcarries the activities of the cleavage of 28S rRNA and cytotoxicity,whereas RNase domain of IRE1α has the activity of UPR induction.These results suggest that the different function between IRE1α and IRE1β depends on the different activity of RNase region.