An Evolutionarily Conserved Ypk1/SGK1 Kinase Pathway Regulates the Unfolded Protein Response by Modulating the Ire1 Protein Abundance

The unfolded protein response (UPR) is a cellular mechanism that maintains protein homeostasis (proteostasis) under conditions of endoplasmic reticulum (ER) stress. The dual kinase/RNase Ire1 is a conserved regulator of the UPR, mediating the unconventional cytosolic splicing of HAC1 mRNA in yeast and XBP1 mRNA in human cells. The resulting spliced HAC1/XBP1 transcript encodes a transcription factor that induces the expression of protein-folding chaperones and stress-responsive genes, thereby restoring proteostasis. In our previous work, we showed that the MAP kinase Slt2 (homolog of human ERKs) contributes to UPR signaling by promoting IRE1 expression through the transcription factor Rlm1 (homolog of human MEF2C). Here, we demonstrate that Hac1 expression is reduced in yeast strains deficient in essential protein kinase Cdc28, Pkc1, Rio2, Tor2, Pkh1, or Ypk1, suggesting that these kinases also serve as UPR regulators. We focused on the kinase Ypk1, the yeast ortholog of human SGK1 (serum/glucocorticoid-regulated kinase 1). We provide genetic and biochemical evidence that Ypk1/SGK1 acts upstream of the Pkc1/PKC{delta} signaling pathway and is required for maintaining IRE1 protein abundance in both yeast and human cells. Collectively, our results identify an evolutionarily conserved Ypk1/SGK1 signaling pathway that regulates the HAC1 and XBP1 mRNA splicing by modulating the Ire1 protein abundance.