The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction
The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction
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DOI：
10.1074/jbc.m109.092106
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发表时间：
2010-03-05
影响因子：
4.8
通讯作者：
Gerard, Norma P.
中科院分区：
文献类型：
--
作者：
Bamberg, Claire E.;Mackay, Charles R.;Gerard, Norma P.
补体过敏毒素C5 a是宿主防御的促炎组分，其通过两种鉴定的受体C5 a受体（C5 aR）和C5 L2起作用。C5 aR是一种经典的G蛋白偶联受体，而C5 L2在结构上同源，但缺乏G蛋白偶联。在人类中性粒细胞中，我们发现C5 L2主要在细胞内，而C5 aR在质膜上表达。共聚焦分析显示配体结合后内化的C5 aR与C5 L2和β-抑制蛋白共定位。C5 L2的抗体阻断导致C5 a介导的趋化性和ERK 1/2磷酸化显著增加，但不改变C5 a介导的钙动员，支持其在β-抑制蛋白途径调节中的作用。C5 L2与β-抑制蛋白的结合通过细胞免疫共沉淀测定来证实。C5 L2阻断对人多形核白细胞中的配体摄取或C5 aR内吞作用也没有影响，将其作用与该细胞类型中的快速再循环或清除受体的作用区分开来。因此，这是天然存在的七跨膜片段受体的第一个例子，该受体既与G蛋白特异性解偶联，又是通过β-抑制蛋白途径的信号转导的负调节剂。在生理上，这些特性为宿主防御的额外微调提供了可能性。
The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and beta-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the beta-arrestin pathway. Association of C5L2 with beta-arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the beta-arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.