FIG 8.

Model of activation of ER stress response by both Ire1 and Kin kinases. The ER-resident kinase/RNase Ire1 resides across the ER membrane. (Both the NH₃⁺-terminal luminal and cytoplasmic kinase/RNase domains are colored teal.) Under conditions of ER stress, Ire1 cleaves out an intron (orange line) in the HAC1 pre-mRNA. The resulting mature mRNA translates the Hac1 protein (Hac1p) that activates transcription of the UPR genes in the nucleus. In parallel, the protein kinase Kin1 or Kin2 (shown by blue with both the NH₃⁺-terminal and KA1 regions likely to anchor the endomembrane) is coactivated. There are two possible ways Kin1 and Kin2 functionally contribute to the HAC1-mediated UPR. First, Kin1/Kin2 binds directly to the 3′UTR element of HAC1 mRNA and promotes targeting to the ER stress signaling site, splicing, and translational repression. Second, Kin1/Kin2 phosphorylates a protein substrate (substrate shown by “S^kin,” and phosphorylation is indicated by “P”), a component of the 3′UTR-RNP complex that modulates both mRNA targeting and translation. Alternatively, the Kin1/Kin2 substrate constitutes a novel signaling cascade (denoted by “?” in a box) and transactivates the UPR genes in the nucleus. The sensing mechanism for Kin2 is unknown and is shown by “?”