Palmitoylation of the sphingosine 1-phosphate receptor S1P1 is involved in its signaling functions and internalization
Palmitoylation of the sphingosine 1-phosphate receptor S1P1 is involved in its signaling functions and internalization
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DOI：
10.1111/j.1365-2443.2009.01319.x
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发表时间：
2009-08-01
期刊：
影响因子：
2.1
通讯作者：
Kihara, Akio
中科院分区：
文献类型：
--
作者：
Ohno, Yusuke;Ito, Ayako;Kihara, Akio
脂质介质鞘氨醇1-磷酸（S1 P）通过与其受体（S1 P（1）-S1 P（5））结合来调节几种细胞过程，这些受体是异源三聚体G蛋白偶联受体。在这里，我们报告说，所有的S1 P受体棕榈酰化。在S1 P（1）中，胞质尾区的三个Cys残基被棕榈酰化。我们使用野生型S1 P（1）或非棕榈酰化突变体S1 P（1）过度产生的模型细胞来检查S1 P（1）棕榈酰化的作用。与野生型S1 P（1）相比，非棕榈酰化的S1 P（1）表现出与天然配体S1 P相似的结合亲和力，但低于合成配体FTY 720磷酸盐（FTY 720-P），FTY 720是免疫调节剂FTY 720的活性形式。然而，非棕榈酰化的S1 P（1）的下游信号传导受到S1 P和FTY 720-P刺激的类似影响。此外，与野生型蛋白相比，在S1 P刺激下，突变的非棕榈酰化S1 P（1）的内化被延迟。这种效果在FTY 720-P刺激下更加明显。S1 P（1）及其突变体的磷酸化也存在类似的差异。这些发现可能为FTY 720药理作用的分子机制提供见解。最后，野生型S1 P（1）的棕榈酰化在S1 P处理后增加，表明S1 P（1）在其配体刺激后经历棕榈酰化/脱棕榈酰化循环。
The lipid mediator sphingosine 1-phosphate (S1P) regulates several cellular processes through binding to its receptors (S1P(1)-S1P(5)), which are heterotrimeric G protein-coupled receptors. Here, we report that all S1P receptors are palmitoylated. In S1P(1), three Cys residues in the cytoplasmic tail are palmitoylated. We examined the roles of palmitoylation of S1P(1) using model cells in which wild-type S1P(1) or a non-palmitoylated mutant S1P(1) was overproduced. Compared with wild-type S1P(1), the non-palmitoylated S1P(1) exhibited binding affinity similar to the natural ligand S1P but lower to the synthetic ligand FTY720 phosphate (FTY720-P), the active form of the immunomodulator FTY720. However, downstream signaling of non-palmitoylated S1P(1) was similarly affected by S1P and FTY720-P stimulation. Moreover, upon stimulation with S1P, internalization of the mutant non-palmitoylated S1P(1) was retarded, compared with that of the wild-type protein. This effect was much more pronounced with FTY720-P stimulation. Similar differences were observed for the phosphorylation of S1P(1) and its mutant. These findings may provide insights into the molecular mechanisms of the pharmacological effects of FTY720. Finally, palmitoylation of wild-type S1P(1) increased upon treatment with S1P, suggesting that S1P(1) undergoes a palmitoylation/depalmitoylation cycle after stimulation by its ligands.