Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis.
Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis.
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DOI：
10.1083/jcb.200203123
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发表时间：
2002-09-16
期刊：
影响因子：
--
通讯作者：
Spiegel S
中科院分区：
文献类型：
--
作者：
Le Stunff H;Galve-Roperh I;Peterson C;Milstien S;Spiegel S
鞘鞘醇-1-磷酸（S1P）是一种具有生物活性的鞘脂代谢物，通过与G蛋白偶联受体家族结合或作为细胞内第二信使调节多种生物过程。哺乳动物S1P磷酸酶（SPP-1），可降解S1P终止其作用，最近克隆了基于同源性的脂质磷酸水解酶，该酶调节酵母中磷酸化的鞘基水平。共聚焦显微镜令人惊讶地显示，表位标记的SPP-1是细胞内的，并与内质网标记钙连联蛋白共定位。SPP-1活性和蛋白主要富集于细胞膜内，质膜表达较低。用S1P处理SPP-1转染物显著增加神经酰胺水平，主要在细胞膜内，降低存活，增强凋亡。值得注意的是，尽管双氢- s1p是SPP-1的良好底物，但它没有引起显著的神经酰胺积累或增加细胞凋亡。神经酰胺合成酶抑制剂伏马菌素B1完全阻断S1P诱导的神经酰胺积累，而丝氨酸棕榈酰基转移酶抑制剂肉豆蔻素仅部分减少S1P诱导的神经酰胺积累，这是神经酰胺从头合成的第一步。此外，S1P，而非二氢S1P，刺激了[3H]棕榈酸盐（丝氨酸棕榈酰转移酶和神经酰胺合成酶的底物）与c16 -神经酰胺的结合。总之，我们的研究结果表明SPP-1以前所未有的方式调节鞘脂生物合成，并准备影响细胞命运。
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein–coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin B1, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate.
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DOI：
10.1083/jcb.200105033
发表时间：
2001-12-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Funato K;Riezman H
通讯作者：
Riezman H
影响因子：
4.1
作者：
Mao, CG;Saba, JD;Obeid, LM
通讯作者：
Obeid, LM
影响因子：
4.8
作者：
Gudz, TI;Tserng, KY;Hoppel, CL
通讯作者：
Hoppel, CL
影响因子：
4.8
作者：
Jenkins, GM;Richards, A;Hannun, Y
通讯作者：
Hannun, Y
影响因子：
4.8
作者：
Cuvillier, O;Edsall, L;Spiegel, S
通讯作者：
Spiegel, S