Research ArticleCell Biology

Phosphorylation of Pal2 by the protein kinases Kin1 and Kin2 modulates HAC1 mRNA splicing in the unfolded protein response in yeast

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Science Signaling  25 May 2021:
Vol. 14, Issue 684, eaaz4401
DOI: 10.1126/scisignal.aaz4401

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HAC-king an ER stress response

ER stress induces an evolutionarily conserved response that initiates the alternative splicing of the mRNA encoding Hac1 in yeast and XBP1 in mammals. Hac1 or XBP1 then mediates the unfolded protein response (UPR) to restore ER homeostasis. The kinases Kin1 and Kin2 are required for the UPR, and Ghosh et al. uncovered the substrate of these kinases. Kin1 and Kin2 directly phosphorylated the endocytic adaptor protein Pal2, which bound to and promoted the processing of HAC1 mRNA. These results identify components in a mechanism that ensures the cytosolic splicing of HAC1 mRNA to generate a critical effector of the UPR.


During cellular stress in the budding yeast Saccharomyces cerevisiae, an endoplasmic reticulum (ER)–resident dual kinase and RNase Ire1 splices an intron from HAC1 mRNA in the cytosol, thereby releasing its translational block. Hac1 protein then activates an adaptive cellular stress response called the unfolded protein response (UPR) that maintains ER homeostasis. The polarity-inducing protein kinases Kin1 and Kin2 contribute to HAC1 mRNA processing. Here, we showed that an RNA-protein complex that included the endocytic proteins Pal1 and Pal2 mediated HAC1 mRNA splicing downstream of Kin1 and Kin2. We found that Pal1 and Pal2 bound to the 3′ untranslated region (3′UTR) of HAC1 mRNA, and a yeast strain lacking both Pal1 and Pal2 was deficient in HAC1 mRNA processing. We also showed that Kin1 and Kin2 directly phosphorylated Pal2, and that a nonphosphorylatable Pal2 mutant could not rescue the UPR defect in a pal1Δ pal2Δ strain. Thus, our work uncovers a Kin1/2-Pal2 signaling pathway that coordinates HAC1 mRNA processing and ER homeostasis.

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