Anti-IRE1/ERN1: Mouse IRE1/ERN1 Antibody

The structural analysis of the luminal stress-sensing domain of yeast IRE1 provided insights into IRE1 activation under ER stress. Upon UPR activation, the luminal domain of IRE1 undergoes oligomerization, which brings the cytosolic kinase domains into juxtaposition allowing their activation by transautophosphorylation and cofactor binding. Though an otherwise conventional protein kinase, the only known phosphorylation substrate of IRE1 is itself. The trans-autophosphorylation of IRE1 somehow unmasks its effector function by triggering conformational changes that activate the RNase domain of the enzyme, which is to cleave a conserved mRNA substrate and produce the homeostatic transcription factor XBP1s. In addition, IRE1α’s RNase also causes endonucleolytic decay of many ER-localized mRNAs, including those encoding chaperones, as early events culminating in apoptosis.³ IRE1 signaling attenuates after prolonged ER stress. IRE1 then enters a refractive state even if ER stress remains unmitigated. Attenuation includes dissolution of IRE1 clusters, IRE1 dephosphorylation, and decline in endoribonuclease activity. Thus IRE1 activity is governed by a timer that may be important in switching the UPR from the initially cytoprotective phase to the apoptotic mode. Moreover, it has been demonstrated that the duration of PERK and IRE1 signaling varied markedly after the imposition of protein misfolding. The sustained PERK signaling was detrimental to cell viability whereas the equivalent duration of IRE1 signaling was not; suggesting that extended PERK activity contributes to the cell death that occurs with chronic ER stress.⁴