A Functional Relationship Between Plb1‐Mediated Phosphatidylcholine Turnover and Sphingolipid Homeostasis in Saccharomyces cerevisiae

Abstract

Plb1 is a B‐type phospholipase that acts on phosphatidylcholine (PC). Localization studies have found Plb1 to be primarily at the endoplasmic reticulum and secreted from the cell. We have shown previously that Plb1 activity and expression are up‐regulated by loss of Ypk1, the yeast homolog of the human serum‐ and glucocorticoid‐ induced kinase (Sgk1). In addition, Plb1 overexpression is known to rescue the lethality of a ypk1ts ypk2Δ mutant. Ypk1 is a serine/threonine protein kinase that affects several membrane events, including plasma membrane flippase activity and sphingolipid homeostasis. Employing the serine palmitoyltransferse inhibitor, myriocin, and genetic mutants, we report that overexpression of Plb1 compensates for diminished sphingolipid biosynthesis in various strain backgrounds. To probe this result further, we examined the effect of Plb1 overexpression on signaling pathways known to affect, or be affected by, altered sphingolipid metabolism. Overexpression of Plb1 results in up‐regulation of the Unfolded Protein Response (UPR) and up‐regulation of INO1, a gene encoding inositol 3‐phosphate synthase, the rate limiting step in inositol biosynthesis. We are examining both the mechanism by which PC turnover up‐regulates the UPR and INO1 expression, as well as how that up‐regulation affects flux through sphingolipid biosynthesis. Our findings indicate a functional relationship between PC turnover and sphingolipid homeostasis.Support or Funding InformationNIH GM104876 to JPV