Biased agonists of the chemokine receptor CXCR3 differentially signal through Gα <sub>i</sub> :β-arrestin complexes
Biased agonists of the chemokine receptor CXCR3 differentially signal through Gα <sub>i</sub> :β-arrestin complexes
复制标题
趋化因子受体 CXCR3 的偏向激动剂通过 Gα :β-arrestin 复合物发出差异信号
DOI：
10.1126/scisignal.abg5203
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发表时间：
2022
影响因子：
7.3
通讯作者：
Rajagopal Sudarshan
中科院分区：
文献类型：
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作者：
Zheng Kevin;Smith Jeffrey S.;Eiger Dylan S.;Warman Anmol;Choi Issac;Honeycutt Christopher C.;Boldizsar Noelia;Gundry Jaimee N.;Pack Thomas F.;Inoue Asuka;Caron Marc G.;Rajagopal Sudarshan
G 蛋白偶联受体 (GPCR) 是最大的细胞表面受体家族，通过近端效应器、G 蛋白和 β-抑制蛋白发出信号，影响几乎所有生物过程。 G 蛋白和 β-arrestin 信号通路在很大程度上被认为是可分离的；然而，Gα 蛋白和 β-arrestins 之间的直接相互作用已被描述为独特的 GPCR 信号通路的一部分。在这些复合物中，Gαi/o（而非其他 Gα 蛋白亚型）直接与 β-arrestin 相互作用，无论与 GPCR 偶联的典型 Gα 蛋白如何。在这里，我们报道了 CXCR3 的内源性偏向趋化因子激动剂（CXCL9、CXCL10 和 CXCL11）与两种小分子偏向激动剂一起，差异形成了 Gαi:β-arrestin 复合物。 Gαi:β-抑制蛋白复合物的形成与 G 蛋白激活或 β-抑制蛋白招募没有很好的相关性。 β-抑制蛋白生物传感器证明，促进 Gαi:β-抑制蛋白复合物形成的配体产生相似的 β-抑制蛋白构象。我们还发现，Gαi:β-arrestin 复合物并不与丝裂原激活蛋白激酶 ERK 偶联，正如在 V2 加压素受体等其他受体中观察到的那样，但与网格蛋白接头蛋白 AP-2 偶联，这表明这些复合物存在上下文依赖性信号传导。这些发现强化了 Gαi:β-arrestin 复合物形成是一种独特的 GPCR 信号通路的观点，并增强了我们对偏向激动谱的理解。
G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have largely been considered separable; however, direct interactions between Gα proteins and β-arrestins have been described that appear to be part of a distinct GPCR signaling pathway. Within these complexes, Gαi/o, but not other Gα protein subtypes, directly interacts with β-arrestin, regardless of the canonical Gα protein that is coupled to the GPCR. Here, we report that the endogenous biased chemokine agonists of CXCR3 (CXCL9, CXCL10, and CXCL11), together with two small-molecule biased agonists, differentially formed Gαi:β-arrestin complexes. Formation of the Gαi:β-arrestin complexes did not correlate well with either G protein activation or β-arrestin recruitment. β-arrestin biosensors demonstrated that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We also found that Gαi:β-arrestin complexes did not couple to the mitogen-activated protein kinase ERK, as is observed with other receptors such as the V2 vasopressin receptor, but did couple with the clathrin adaptor protein AP-2, which suggests context-dependent signaling by these complexes. These findings reinforce the notion that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of the spectrum of biased agonism.