SPHINGOID BASE 1-PHOSPHATE PHOSPHATASE - A KEY REGULATOR OF SPHINGOLIPID METABOLISM AND STRESS-RESPONSE

The sphingolipid metabolites ceramide and sphingosine-1-phosphate are second messengers with opposing roles in mammalian cell growth arrest and survival; their relative cellular level has been proposed to be a rheostat that determines the fate of cells. This report demonstrates t hat this rheostat is an evolutionarily conserved stress-regulatory mec hanism that influences growth and survival of yeast. Although the role of sphingosine-1-phosphate in yeast was not previously examined, accu mulation of ceramide has been shown to induce G(1) arrest and cell dea th. We now have identified a gene in Saccharomyces cerevisiae, LBP1, t hat regulates the levels of phosphorylated sphingoid bases and ceramid e. LBP1 was cloned from a yeast mutant that accumulated phosphorylated long-chain sphingoid bases and diverted sphingoid base intermediates from sphingolipid pathways to glycerophospholipid biosynthesis. LBP1 a nd its homolog, LBP2, encode very hydrophobic proteins that contain a novel conserved sequence motif for lipid phosphatases, and both have l ong-chain sphingoid base phosphate phosphatase activity. In vitro char acterization of Lbp1p shows that this phosphatase is Mg2+-independent with high specificity for phosphorylated long-chain bases, phytosphing osine and sphingosine. The deletion of LBP1 results in the accumulatio n of phosphorylated long-chain sphingoid bases and reduced ceramide le vels. Moreover, deletion of LBP1 and LBP2 results in dramatically enha nced survival upon severe heat shock. Thus, these phosphatases play a previously unappreciated role in regulating ceramide and phosphorylate d sphingoid base levels in yeast, and they modulate stress responses t hrough sphingolipid metabolites in a manner that is reminiscent of the ir effects on mammalian cells.