Kinases Kin1 and Kin2 pleiotropically modulate splicing and translation of HAC1 mRNA (746.2)

Abstract

Most nascent proteins fold and mature in the endoplasmic reticulum (ER). From the ER, matured proteins are packed inside a membrane‐bound vesicle that buds from the ER, travels and fuses with their target destination, thereby delivering the cargo protein. Stresses that disrupt ER function cause an over‐accumulation of un‐folded proteins in the ER, a state referred to as ER stress. To adapt to ER stress, cells activate a network of signaling pathways collectively called the unfolded protein response (UPR). The UPR in yeast Saccharomyces cerevisiae is initiated by a dual kinase/RNase Ire1 that removes an inhibitory intron from HAC1 pre‐mRNA, resulting in expression of Hac1 protein, a transcriptional activator of several UPR genes involved in adapting to ER stress. We have discovered that protein kinases Kin1 and Kin2 are dosage suppressors of a HAC1 allele that is devoid of a consensus element in the 3’ un‐translated region of pre‐mRNA. We have further discovered that both splicing and translation of HAC1 mRNA are reduced in a strain lacking kin1 and kin2 kinases, suggesting that the Ire1‐Hac1 signaling pathway is pleotropically regulated by Kin kinases. These Kin kinases have been reported to regulate polarized exocytosis and vesicular transport of proteins in yeast cells. Thus, our results revealed a novel role of Kin kinases in the yeast UPR.