Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments.
Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments.
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DOI：
10.1074/jbc.m113.526350
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发表时间：
2014-02-14
期刊：
影响因子：
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通讯作者：
Hanyaloglu AC
中科院分区：
文献类型：
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作者：
Jean-Alphonse F;Bowersox S;Chen S;Beard G;Puthenveedu MA;Hanyaloglu AC
背景：配体诱导内化后，GPCR通过不同的受体基序和蛋白质相互作用进行分类。结果：不同的GPCR靶向于前早期内体区室，用于其分选和MAPK信号传导。结论：GPCR分选基序及其相互作用蛋白在内体靶向和受体信号传导中提供特异性。意义：我们描述了一个在前所未有的空间水平上重新编程GPCR信号的系统。G蛋白偶联受体（GPCRs）的胞后分选是由其高度多样的受体序列基序与其相互作用蛋白之间的相互作用驱动的，所述相互作用蛋白例如突触后密度蛋白（PSD 95）、果蝇盘大肿瘤抑制因子（Dlg 1）、闭锁小带-1蛋白（zo-1）（PDZ）结构域蛋白。然而，这些不同的相互作用是否提供了潜在的功能特异性，除了驱动排序，是未知的。在这里，我们确定了GPCR，回收通过不同的PDZ配体/PDZ蛋白对，利用其回收机制，主要是针对内体定位和信号传导的特异性。促黄体生成素受体（LHR）和β2-肾上腺素能受体（B2 AR）是两种被分类到受调节的再循环途径的GPCR，它们经历不同的运输到不同的内体区室。与B2 AR运输到早期内体（EE）不同，LHR内化到不同的前早期内体（pre-EE）以进行再循环。前EE本地化需要的LHR C-末端尾部与PDZ蛋白GAIP相互作用蛋白C末端的相互作用，抑制其交通EE。将LHR重新路由到EE，或将EE定位的GPCR重新路由到前EE，在空间上重新编程MAPK信号传导。此外，LHR介导的MAPK信号转导的激活需要内化，并在EE隔室丧失后维持。我们建议GPCR分选序列和相互作用的蛋白质之间的组合特异性决定了GPCR信号活性的前所未有的时空控制。
Background: Following ligand-induced internalization, GPCRs are sorted by diverse receptor motifs and protein interactions. Results: Distinct GPCRs are targeted to a pre-early endosome compartment for their sorting and MAPK signaling. Conclusion: GPCR sorting motifs and their interacting proteins provide specificity in endosomal targeting and receptor signaling. Significance: We describe a system to reprogram GPCR signaling at an unprecedented spatial level. Postendocytic sorting of G protein-coupled receptors (GPCRs) is driven by their interactions between highly diverse receptor sequence motifs with their interacting proteins, such as postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), zonula occludens-1 protein (zo-1) (PDZ) domain proteins. However, whether these diverse interactions provide an underlying functional specificity, in addition to driving sorting, is unknown. Here we identify GPCRs that recycle via distinct PDZ ligand/PDZ protein pairs that exploit their recycling machinery primarily for targeted endosomal localization and signaling specificity. The luteinizing hormone receptor (LHR) and β2-adrenergic receptor (B2AR), two GPCRs sorted to the regulated recycling pathway, underwent divergent trafficking to distinct endosomal compartments. Unlike B2AR, which traffics to early endosomes (EE), LHR internalizes to distinct pre-early endosomes (pre-EEs) for its recycling. Pre-EE localization required interactions of the LHR C-terminal tail with the PDZ protein GAIP-interacting protein C terminus, inhibiting its traffic to EEs. Rerouting the LHR to EEs, or EE-localized GPCRs to pre-EEs, spatially reprograms MAPK signaling. Furthermore, LHR-mediated activation of MAPK signaling requires internalization and is maintained upon loss of the EE compartment. We propose that combinatorial specificity between GPCR sorting sequences and interacting proteins dictates an unprecedented spatiotemporal control in GPCR signal activity.