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 to promote cell death. In this scenario, adaptive outputs through XBP1 mRNA splicing may become eclipsed and irrelevant as destructive IRE1α signaling dominates in a terminal UPR (Figure 7B). A therapeutic strategy to shut down IRE1α RNase entirely should therefore reduce destructive outputs under irremediable ER stress. Consistent with this notion, the tool compound STF-083010, which selectively targets the IRE1α RNase activity (Papandreou et al., 2010), markedly reduces TXNIP induction and downstream IL-1β maturation and secretion. We interpret these results as proof-of-concept that targeting the hyperactive IRE1α RNAse can disrupt cell destructive endpoints in the terminal UPR. It is likely that the active component of STF-083010 is the salicylaldehyde that rapid hydrolysis of its sulfonylimine unmasks (Volkmann et al., 2011). Aldehydes are inherently unstable in vivo and may limit the utility of this compound class. The future development of more drug-like inhibitors will allow these concepts to be effectively explored in vivo for amelioration of ER stress disease endpoints.
