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首页> 外文期刊>Cellular Signalling >GGA3 interacts with L-type prostaglandin D synthase and regulates the recycling and signaling of the DP1 receptor for prostaglandin D-2 in a Rab4-dependent mechanism
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GGA3 interacts with L-type prostaglandin D synthase and regulates the recycling and signaling of the DP1 receptor for prostaglandin D-2 in a Rab4-dependent mechanism

机译：GGA3与L型前列腺素D合成酶相互作用，并在RAB4依赖机制中调节前列腺素D-2的DP1受体的再循环和信号传导

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摘要

Mechanisms controlling the recycling of G protein-coupled receptors (GPCRs) remain largely unclear. We report that GGA3 (Golgi-associated, gamma adaptin ear containing, ADP-ribosylation factor-binding protein 3) regulates the recycling and signaling of the PGD(2) receptor DP1 through a new mechanism. An endogenous interaction between DP1 and GGA3 was detected by co-immunoprecipitation in HeLa cells. The interaction was promoted by DP1 agonist stimulation, which was supported by increased DP1-GGA3 colocalization in confocal microscopy. Pulldown assays showed that GGA3 interacts with the intracellular loop 2 and C-terminus of DP1, whereas the receptor interacts with the VHS domain of GGA3. The Arf-binding deficient GGA3 N194A mutant had the same effect as wild-type GGA3 on DP1 trafficking, suggesting a new mechanism for GGA3 in recycling. Depletion of Rab4 inhibited the GGA3 effect on DP1 recycling, revealing a Rab4-dependent mechanism. Interestingly, depletion of L-PGDS (L-type prostaglandin synthase, the enzyme that produces the agonist for DP1) impaired the ability of GGA3 to mediate DP1 recycling, while GGA3 knockdown prevented L-PGDS from promoting DP1 recycling, indicating that both proteins function interdependently. A novel interaction was observed between co-immunoprecipitated endogenous L-PGDS and GGA3 proteins in HeLa cells, and in vitro using purified recombinant proteins. Redistribution of L-PGDS towards GGA3- and Rab4-positive vesicles was induced by DP1 activation. Silencing of GGA3 inhibited ERK1/2 activation following DP1 stimulation. Altogether, our data reveal a novel function for GGA3, in a newly described association with L-PGDS, in the recycling and signaling of a GPCR, namely DP1.
机译：控制G蛋白偶联受体（GPCR）再循环的机制仍然不清楚。我们报告了GGA3（Golgi相关的，γ适应蛋白耳，ADP-核糖基化因子结合蛋白3）通过新机制调节PGD（2）受体DP1的再循环和信号传导。通过HeLa细胞中的共免疫沉淀检测DP1和GGA3之间的内源性相互作用。 DP1激动剂刺激促进了相互作用，其通过增加了共聚焦显微镜的DP1-GGA3分层化的增加。下拉测定表明，GGA3与DP1的细胞内环2和C末端相互作用，而受体与GGA3的VHS结构域相互作用。 ARF结合缺陷GGA3 N194A突变体具有与DP1贩运的野生型GGA3的效果相同，表明GGA3在回收中的新机制。 RAB4的耗竭抑制了对DP1回收的GGA3影响，揭示了RAB4依赖性机制。有趣的是，L-PGDS（L型前列腺素合酶，产生DP1的激动剂的酶）耗尽损害了GGA3介导DP1再循环的能力，而GGA3敲低阻止L-PGDS促进DP1再循环，表明这两种蛋白质功能相互依存。在HeLa细胞中共免疫沉淀的内源L-PGDS和GGA3蛋白之间观察到新的相互作用，并使用纯化的重组蛋白在体外。 DP1活化诱导促进L-PGDS向GGA3和RAB4阳性囊泡的再分布。在DP1刺激后，GGA3的沉默抑制ERK1 / 2激活。完全，我们的数据显示了GGA3的新功能，在新描述的与L-PGDS中，在GPCR的再循环和信令中，即DP1。

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