Sphingoid base 1-phosphate phosphatase: A key regulator of sphingolipid metabolism and stress response
Sphingoid base 1-phosphate phosphatase: A key regulator of sphingolipid metabolism and stress response
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DOI：
10.1073/pnas.95.1.150
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发表时间：
1998-01-06
影响因子：
11.1
通讯作者：
Spiegel, S
中科院分区：
文献类型：
--
作者：
Mandala, SM;Thornton, R;Spiegel, S
鞘磷脂代谢物神经酰胺和1-磷酸鞘氨醇是哺乳动物细胞生长停滞和存活的第二信使，它们的相对细胞水平被认为是决定细胞命运的变阻器。这份报告表明，这种变阻器是一种进化上保守的压力调节机制，影响酵母的生长和生存。尽管神经氨醇-1-磷酸在酵母中的作用以前没有被研究过，但神经酰胺的积累已经被证明可以诱导G(1)期停滞和细胞死亡。我们现在已经在酿酒酵母中发现了一个基因，LBP1，它调节磷酸化的狮身人面像碱基和神经酰胺的水平。LBP1是从一个酵母突变体中克隆出来的，该突变体积累了长链狮身人面像碱基的磷酸化，并将狮身人面像碱基的中间产物从鞘磷脂途径转移到甘油磷脂的生物合成中。LBP1及其同源物LBP2编码非常疏水的蛋白质，含有一个新的脂磷酸酶保守序列基序，并且都具有长链狮身人面像碱性磷酸酶活性。Lbp1p的体外特性表明，该磷酸酶不依赖于镁离子，对磷酸化的长链碱基、植酸鞘氨醇和鞘氨醇具有高度的专一性。LBP1的缺失导致磷酸化的长链狮身人面像碱基的积累和神经酰胺水平的降低。此外，LBP1和LBP2的缺失可显著提高严重热休克患者的存活率。因此，这些磷酸酶在调节酵母中神经酰胺和磷酸化的狮身人面像碱基水平方面发挥了以前未被认识的作用，它们通过鞘磷脂代谢产物调节应激反应，其方式使人想起它们对哺乳动物细胞的影响。
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 G(1) 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.