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MG53是人类疾病的“双刃剑”

张岩, 吴鸿昆, 吕凤祥, 肖瑞平

北京大学分子医学研究所生物膜国家重点实验室；北大-清华生命科学中心；代谢及心血管分子医学北京市重点实验室，北京 100871

摘要

Mitsugumin 53 (MG53)，又名Trim72，是一种在心肌和骨骼肌中大量表达的TRIM家族成员。MG53不仅在多种重要的生理学功能中发挥作用，也是多种疾病的关键致病因素。首先，MG53通过促进细胞膜修复从而维持心肌和骨骼肌细胞的完整性。其次，MG53通过活化PI3K-Akt-GSK3β和ERK1/2细胞生存信号通路，参与心肌缺血预适应和后适应保护作用；而且外源性给予MG53重组蛋白，能够保护包括心脏、骨骼肌、肺脏、肾脏和皮肤在内的多种器官的缺血/再灌注和机械损伤。更重要的是，MG53能够作为E3连接酶，介导胰岛素受体和胰岛素受体底物1的降解，进而引起胰岛素抵抗和代谢性疾病(例如2型糖尿病)及其心血管并发症。另外，MG53还能够抑制骨骼肌分化。总之，在把MG53作为一个人类疾病的治疗靶点的时候，需要综合考虑其多种生物功能和机制，从而最大化其有益作用，并尽量避免其副作用。本综述系统地总结目前对MG53生物学功能，尤其是其作为临床疾病的治疗靶点的研究进展。

关键词： MG53; 缺血/再灌注损伤; 胰岛素抵抗; 脂代谢

分类号：R33

MG53 is a double-edged sword for human diseases

ZHANG Yan, WU Hong-Kun, LV Feng-Xiang, XIAO Rui-Ping

State Key Laboratory of Membrane Biology, Institute of Molecular Medicine； Peking-Tsinghua Center for Life Sciences and Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China

Abstract

Mitsugumin 53 (MG53), also named Trim72, is a multi-functional TRIM-family protein, which is abundantly expressed in cardiac and skeletal muscle. It has been shown that MG53 not only plays important physiological roles but also acts as a crucial pathogenic factor of various diseases. First, MG53 preserves cardiac and skeletal muscle integrity via facilitating plasma membrane repair. Second, MG53 is essentially involved in cardiac ischemic preconditioning and postconditioning by activating PI3K-Akt-GSK3β and ERK1/2 cell survival signaling pathways. Moreover, systemic delivery of recombinant MG53 is able to abolish mechanic or ischemia-reperfusion (I/R)-induced injury of multiple organs, including heart, skeletal muscle, lung, kidney and skin. Importantly, MG53 acts as an E3 ligase to mediate the degradation of insulin receptor and insulin receptor substrate-1, and subsequently induces insulin resistance and metabolic diseases such as type-2 diabetes and its cardiovascular complications. In addition, MG53 negatively regulates myogenesis. As a potential therapeutic target of human diseases, multiple facets of MG53 biological function and mechanisms of
action should be taken into the consideration to maximize its beneficial effects and minimize potential side-effects. Here in this review, we intend to comprehensively summarize the current progresses on the biological functions of MG53, focusing on its clinical value as a therapeutic target.

Key words: MG53; ischemia/reperfusion injury; insulin resistance; lipid metabolism

收稿日期：2016-02-24　　录用日期：2016-04-21

通讯作者：张岩　　E-mail: zhangyan9876@pku.edu.cn

引用本文：

张岩, 吴鸿昆, 吕凤祥, 肖瑞平. MG53是人类疾病的“双刃剑”[J]. 生理学报 2016; 68 (4): 505-516.

ZHANG Yan, WU Hong-Kun, LV Feng-Xiang, XIAO Rui-Ping. MG53 is a double-edged sword for human diseases. Acta Physiol Sin 2016; 68 (4): 505-516 (in Chinese with English abstract).