IRE1α and PERK are both upstream UPR master kinases whose activation levels correlate directly with ER unfolded protein levels. Together, IRE1α and PERK may utilize the levels and duration of autophosphorylation to control homeostatic-apoptotic switching. Under low/remediable levels of ER stress, self-association of IRE1α through its lumenal domain extinguishes as adaptive UPR outputs from XBP1s re-establish homeostasis (Figure 7A). However, under irremediable ER stress, high-order oligomerization through IRE1α’s lumenal domains leads to kinase hyper-phosphorylation, and acquisition of relaxed specificity in the RNase. Endonucleolytic destruction of RNAs localizing to the ER membrane during co-translational translocation in close proximity to hyperactive IRE1αRNase occurs under irremediable ER stress, and is mimicked when overexpressing WT- IRE1α; instead, forcible activation of IRE1α (I642G) under 1NM-PP1 more closely mimics an adaptive UPR, primarily constrained to XBP1 splicing. Thus IRE1α RNase hyperactivation leading to ER-localized mRNA decay actually amplifies and promotes ER stress-mediated cell death (Han et al., 2009)(Figure S4D). Opposite to its direct effects on destabilizing ER-localized mRNAs, IRE1α RNase activation may also cleave specific miRs, and in doing so indirectly stabilize specific mRNA targets needed
