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. Author manuscript; available in PMC: 2010 Aug 7.
Published in final edited form as: Cell. 2009 Aug 7;138(3):562–575. doi: 10.1016/j.cell.2009.07.017

Figure 7. Model For Divergent IRE1α RNase Outputs and their Modulation by Kinase Inhibitors.

Figure 7

(A) Pseudokinase IRE1α activation. Overproduction of IRE1α (I642G) causes it to cluster in the ER, allowing 1NM-PP1 to allosterically activate the RNase when it binds the engineered kinase pocket. While these two steps are depicted as separable, when provided 1NM-PP1 during IRE1α (I642G) overproduction, XBP1 mRNA splicing is identical to that occurring during overproduction of WT IRE1α—the phosphotransfer activation mode, (B). Oligomerization of the kinase/RNase domains in phosphorylated IRE1α is depicted as higher-order than in IRE1α (I642G) under 1NM-PP1. Relaxed specificity of the RNase pocket in phosphorylated IRE1α promotes ER-localized mRNA decay. IRE1α (I642G) under 1NM-PP1 is maintained in a tight conformation that restricts activity to XBP1 splicing, thus averting ER mRNA decay, (A). (C) KIRAs: kinase-inhibiting RNase attenuators of IRE1α. KIRAs reduce IRE1α autophosphorylation, thus reducing kinase/RNase oligomerization and tempering ER-localized mRNA decay; KIRAs permit, and even enhance XBP1 mRNA splicing, because they still satisfy the kinase ligand requirement in endogenous IRE1α.