The highly conserved yeast cell wall integrity mitogen-activated protein kinase pathway regulates cellular responses to cell wall and membrane stress. We report that this pathway is activated and essential for viability under growth conditions that alter both the abundance and pattern of synthesis and turnover of membrane phospholipids, particularly phosphatidylinositol and phosphatidylcholine. Mutants defective in this pathway exhibit a choline-sensitive inositol auxotrophy, yet fully derepress INO1 and other Opi1p-regulated genes when grown in the absence of inositol. Under these growth conditions, Mpk1p is transiently activated by phosphorylation and stimulates the transcription of known targets of Mpk1p signaling, including genes regulated by the Rlm1p transcription factor. mpk1⌬ cells also exhibit severe defects in lipid metabolism, including an abnormal accumulation of phosphatidylcholine, diacylglycerol, triacylglycerol, and free sterols, as well as aberrant turnover of phosphatidylcholine. Overexpression of the NTE1 phospholipase B gene suppresses the choline-sensitive inositol auxotrophy of mpk1⌬ cells, whereas overexpression of other phospholipase genes has no effect on this phenotype. These results indicate that an intact cell wall integrity pathway is required for maintaining proper lipid homeostasis in yeast, especially when cells are grown in the absence of inositol.

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Rapid genome‐wide changes in the transcription of hundreds of genes in yeast cells occur in response to changes in lipid metabolism that accompany the provision of inositol, the immediate precursor to phosphatidylinositol (1, 2). Changes in the synthesis and turnover of lipids that accompany these transcriptional responses include decreases in phosphatidic acid and CDP‐diacylglycerol and an increase in the rate of phosphatidylinositol synthesis and phosphatidylcholine turnover (3, 4). These changes in the patterns of synthesis or turnover of these lipids influence several major signaling pathways and transcriptional networks. Moreover, the Protein Kinase C pathway is involved in maintaining lipid homeostasis in cells deprived of inositol when choline is present. A screen of viable gene deletion mutants for phenotypes associated with misregulation of lipid metabolism identified many mutants defective in several major stress response pathways. We will discuss the roles of these signaling pathways in cellular homeostasis under conditions of changing lipid metabolism.This work is supported by NIH grant GM‐19629.