Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response

Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):150-5. doi: 10.1073/pnas.95.1.150.

Abstract

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 that this rheostat is an evolutionarily conserved stress-regulatory mechanism that influences growth and survival of yeast. Although the role of sphingosine-1-phosphate in yeast was not previously examined, accumulation of ceramide has been shown to induce G1 arrest and cell death. We now have identified a gene in Saccharomyces cerevisiae, LBP1, that regulates the levels of phosphorylated sphingoid bases and ceramide. 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 and its homolog, LBP2, encode very hydrophobic proteins that contain a novel-conserved sequence motif for lipid phosphatases, and both have long-chain sphingoid base phosphate phosphatase activity. In vitro characterization of Lbp1p shows that this phosphatase is Mg2+-independent with high specificity for phosphorylated long-chain bases, phytosphingosine and sphingosine. The deletion of LBP1 results in the accumulation of phosphorylated long-chain sphingoid bases and reduced ceramide levels. Moreover, deletion of LBP1 and LBP2 results in dramatically enhanced survival upon severe heat shock. Thus, these phosphatases play a previously unappreciated role in regulating ceramide and phosphorylated sphingoid base levels in yeast, and they modulate stress responses through sphingolipid metabolites in a manner that is reminiscent of their effects on mammalian cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antifungal Agents / metabolism
  • Cloning, Molecular
  • Hot Temperature
  • Lysophospholipids*
  • Magnesium / metabolism
  • Models, Chemical
  • Molecular Sequence Data
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins*
  • Sphingolipids / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Tetrahydronaphthalenes / metabolism

Substances

  • Antifungal Agents
  • Lysophospholipids
  • Saccharomyces cerevisiae Proteins
  • Sphingolipids
  • Tetrahydronaphthalenes
  • australifungin
  • sphingosine 1-phosphate
  • LCB3 protein, S cerevisiae
  • YSR3 protein, S cerevisiae
  • Phosphoric Monoester Hydrolases
  • Magnesium
  • Sphingosine

Associated data

  • GENBANK/Z28278
  • GENBANK/Z49410