Biased signaling of G protein-coupled receptors - From a chemokine receptor CCR7 perspective
Biased signaling of G protein-coupled receptors - From a chemokine receptor CCR7 perspective
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DOI：
10.1016/j.ygcen.2017.07.004
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发表时间：
2018-03-01
影响因子：
2.7
通讯作者：
Hjorto, Gertrud M.
中科院分区：
文献类型：
--
作者：
Jorgensen, Astrid Sissel;Rosenkilde, Mette M.;Hjorto, Gertrud M.
趋化因子（趋化细胞因子）及其相关的G蛋白偶联受体（GPCR）以协调一致的方式发挥作用，控制免疫细胞在时间和空间上的定位。配体和受体的混杂性，以及趋化因子系统内的偏向信号传导，增加了如何控制基于细胞的免疫系统的复杂性。偏倚有三种形式：配体偏倚、受体偏倚和组织偏倚。偏置信号越来越多地被认为在促进免疫细胞趋化性的微调协调中发挥重要作用。在目前的审查中，我们讨论了最近的研究结果与配体和组织偏向信号的CCR 7和总结什么是已知的偏见在其他趋化因子受体。CCR 7由T细胞亚群和成熟树突状细胞（DC）表达。CCR 7与其两个内源性配体CCL 19和CCL 21（其中CCL 21的羧基末端尾显示出非常强的糖胺聚糖（GAG）结合）一起在协调成熟抗原呈递DC和初始T细胞之间的相遇中起核心作用，所述相遇通常发生在淋巴结（LN）中。该过程是抗原特异性T细胞介导的免疫应答起始的先决条件。因此，CCR 7及其配体是启动基于细胞的免疫应答的关键参与者。CCL 19和CCL 21对CCR 7表现出不同的相互作用和对接模式，导致不同的CCR 7构象稳定，从而优先激活不同的细胞内信号传导途径（即配体偏好）。一般来说，CCL 19似乎产生强的时间信号，而CCL 21产生较弱但更持久的信号。这两种配体的组织差异表达，以及第三种配体“无尾-CCL 21”的产生，通过DC特异性蛋白酶活性（组织偏好），协调DC和T细胞LN的归巢和引发，每个配体发挥重叠但又不同的作用。角色。(C)2017爱思唯尔公司All rights reserved.
Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space. Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how the cell based immune system is controlled. Bias comes in three forms; ligand-, receptor- and tissue-bias. Biased signaling is increasingly being recognized as playing an important role in contributing to the fine-tuned coordination of immune cell chemotaxis. In the current review we discuss the recent findings related to ligand- and tissue-biased signaling of CCR7 and summarize what is known about bias at other chemokine receptors. CCR7 is expressed by a subset of T-cells and by mature dendritic cells (DCs). Together with its two endogenous ligands CCL19 and CCL21, of which the carboxy terminal tail of CCL21 displays an extraordinarily strong glycosaminoglycan (GAG) binding, CCR7 plays a central role in coordinating the meeting between mature antigen presenting DCs and naive T-cells which normally takes place in the lymph nodes (LNs). This process is a prerequisite for the initiation of an antigen-specific T-cell mediated immune response. Thus CCR7 and its ligands are key players in initiating cell-based immune responses. CCL19 and CCL21 display differential interaction- and docking-modes for CCR7 leading to stabilization of different CCR7 conformations and hereby preferential activation of distinct intracellular signaling pathways (i.e. ligand bias). In general CCL19 seems to generate a strong temporal signal, whereas CCL21 generates a weaker, but more persistent signal. Tissue differential expression of these two ligands, and the generation of a third ligand "tailless-CCL21", through DC specific protease activity (tissue bias), orchestrates DC and T-cell LN homing and priming, with each ligand serving overlapping, but also distinct roles. (C) 2017 Elsevier Inc. All rights reserved.