β-拘留蛋白2的活性调控机制

Advances in the Regulation of β-Arrestin 2 Activity

β-拘留蛋白2(β-arrestin2)是arrestins家族的一个成员,广泛表达于全身组织,其不仅可以调节大多数G蛋白偶联受体(G-protein coupled receptors,GPCRs)的脱敏、内化,还能调节多种非GPCRs的内化,或作为支架蛋白质参与MAPK、PI3K/AKT等信号通路。越来越多的研究发现,β-arrestin2在肿瘤、自身免疫性疾病、纤维化疾病、心血管疾病、代谢性疾病等多种疾病进展过程中表达异常,提示其可能在疾病的病理过程中发挥重要的调控作用。β-arrestin2功能的发挥不仅与其在细胞中的表达水平有关,更依赖于对其活性的调控。但对于β-arrestin2的活性如何被调控,以及其活性如何影响其生物学功能的关注较少。近年来,陆续有研究报道了β-arrestin2可发生磷酸化、泛素化、SUMO化、S-亚硝基化等翻译后修饰,探讨了其翻译后修饰的可能位点,并发现翻译后修饰可影响β-arrestin2的细胞定位、调节受体内吞的作用、β-arrestin2与信号分子的相互作用及下游信号通路,对了解β-arrestin2活性调控在细胞中的作用具有重要意义。本文在介绍β-arrestin2的结构特征及其参与的信号转导通路的基础上,对近年来β-arrestin2的翻译后修饰等活性调节机制的研究进展进行综述,以期为以β-arrestin2为可能靶点的药物开发提供参考。

β-Arrestin 2, a member of the arrestin family, is widely expressed in tissues. It not only mediates the desensitization, internalization of most G-protein coupled receptors(GPCRs), but also regulates the internalization of some non-GPCRs, or functions as a scaffold protein to be involved in signaling pathways such as MAPK, PI3 K/AKT, etc. Growing evidence has showed that β-arrestin 2 is abnormally expressed in malignant tumors, autoimmune, fibrotic, cardiovascular and metabolic diseases, etc, suggesting its important role in the progression of these diseases. Besides its abnormal expression in cells, the function of β-arrestin 2 is also related to its activity. However, the regulatory mechanisms of β-arrestin 2 activity and consequent effects are less known. Recent studies have revealed that β-arrestin 2 undergoes post-translational modifications such as phosphorylation, ubiquitination, SUMOylation, S-nitrosylation, which affect the cellular localization of β-arrestin 2, the function of regulating the endocytosis of receptors, the interaction between β-arrestin 2 and downstream signaling molecules, which are of great significance to understand the regulation of β-arrestin 2 activity in cells. In this review, the structure of β-arrestin 2 and β-arrestin 2-mediated signal transduction were introduced, then the advance in the post-translational modifications of β-arrestin 2, as well as the mechanism involved were summarized. We aim to provide reference for the development of drugs targeting β-arrestin 2.