DHHC5-mediated palmitoylation of S1P receptor subtype 1 determines G-protein coupling.
DHHC5-mediated palmitoylation of S1P receptor subtype 1 determines G-protein coupling.
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DOI：
10.1038/s41598-017-16457-4
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发表时间：
2017-11-29
影响因子：
4.6
通讯作者：
Nakamura SI
中科院分区：
文献类型：
--
作者：
Badawy SMM;Okada T;Kajimoto T;Ijuin T;Nakamura SI
鞘氨醇1-磷酸（S1P）是一种多效性脂质介质，主要通过g蛋白偶联S1P受体（S1PRs）参与免疫细胞运输和血管通透性的调节。然而，S1PRs如何与g蛋白偶联的机制尚不清楚。在这里，我们发现S1P1R原型亚型的棕榈酰化是随后抑制g蛋白（Gi）偶联的先决条件。我们已经确定DHHC5是S1P1R棕榈酰化的酶。在基础条件下，S1P1R与质膜（PM）中的DHHC5功能相关，并被完全棕榈酰化，从而实现Gi偶联。刺激后，受体内化，在PM中留下DHHC5，导致S1P1R的去棕榈酰化。我们还发现，虽然生理激动剂s1p诱导的内吞S1P1R很容易循环回PM，但药理学fty720 -p诱导的内吞S1P1R阳性囊泡在后期与DHHC5相关，持续在那里传递Gi信号。这表明FTY720-P在PM中关闭S1P信号，而在细胞内连续打开S1P信号。我们提出dhhc5介导的S1P1R棕榈酰化以时空方式决定Gi偶联及其信号传导。
Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator involved in the regulation of immune cell trafficking and vascular permeability acting mainly through G-protein-coupled S1P receptors (S1PRs). However, mechanism underlying how S1PRs are coupled with G-proteins remains unknown. Here we have uncovered that palmitoylation of a prototypical subtype S1P1R is prerequisite for subsequent inhibitory G-protein (Gi) coupling. We have identified DHHC5 as an enzyme for palmitoylation of S1P1R. Under basal conditions, S1P1R was functionally associated with DHHC5 in the plasma membranes (PM) and was fully palmitoylated, enabling Gi coupling. Upon stimulation, the receptor underwent internalisation leaving DHHC5 in PM, resulting in depalmitoylation of S1P1R. We also revealed that while physiological agonist S1P-induced endocytosed S1P1R readily recycled back to PM, pharmacological FTY720-P-induced endocytosed S1P1R-positive vesicles became associated with DHHC5 in the later phase, persistently transmitting Gi signals there. This indicates that FTY720-P switches off the S1P signal in PM, while switching on its signal continuously inside the cells. We propose that DHHC5-mediated palmitoylation of S1P1R determines Gi coupling and its signalling in a spatio/temporal manner.
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影响因子：
4.8
作者：
Lobo, S;Greentree, WK;Deschenes, RJ
通讯作者：
Deschenes, RJ
影响因子：
2.9
作者：
Loisel, TP;Adam, L;Bouvier, M
通讯作者：
Bouvier, M
影响因子：
3.9
作者：
Pyne, S;Long, JS;Pyne, NJ
通讯作者：
Pyne, NJ
影响因子：
2.9
作者：
NG, GYK;GEORGE, SR;ODOWD, BF
通讯作者：
ODOWD, BF
DOI：
10.1083/jcb.200206120
发表时间：
2002-10-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Roth AF;Feng Y;Chen L;Davis NG
通讯作者：
Davis NG