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 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.
Mandala
S M
SM
Department of Biochemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. suzanne_mandala@merck.com
Thornton
R
R
Tu
Z
Z
Kurtz
M B
MB
Nickels
J
J
Broach
J
J
Menzeleev
R
R
Spiegel
S
S
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000378:metabolism; D003001:Cloning, Molecular; D006358:Hot Temperature; D008246:Lysophospholipids; D008274:Magnesium / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism
D000935:Antifungal Agents; D008246:Lysophospholipids; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; D013764:Tetrahydronaphthalenes; C094344:australifungin; C060506:sphingosine 1-phosphate; C110252:LCB3 protein, S cerevisiae; C503018:YSR3 protein, S cerevisiae; D010744:Phosphoric Monoester Hydrolases; D008274:Magnesium; D013110:Sphingosine