蛋白降解N端规则通路的研究进展  

Progress on the role of N-end rule pathways in protein degradation

作　　者：许纳新 刘永[1] 汪毅 凌树宽 XU Na-Xin;LIU Yong;WANG Yi;LING Shu-Kuan(Academy of Sports Human Sciences,Beijing Sport University,Beijing 100084,China;Department of Sports,Renmin University of China,Beijing 100872,China;Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health),Wenzhou 325000,China)

机构地区：[1]北京体育大学运动人体科学院,北京100084 [2]中国人民大学体育部,北京100872 [3]瓯江实验室(再生调控与眼脑健康浙江省实验室),温州325000

出　　处：《生理学报》2024年第6期987-1000,共14页Acta Physiologica Sinica

摘　　要：N端规则通路是一种由泛素-蛋白酶体系统介导的,能通过识别蛋白质N端特定的残基对目标蛋白进行特异性降解的一种蛋白降解方式。在N端规则通路中发挥关键性作用的残基被称为降解子(degron),由于其往往是蛋白质N端的不稳定残基,所以又被叫做N端降解子(N-degron)。目前在真核生物体内,已被发现的N端规则通路包括N端精氨酸化规则通路(Arg/N端规则通路)、N端乙酰化规则通路(Ac/N端规则通路)、N端脯氨酸规则通路(Pro/N端规则通路)以及近年来最新发现的N端甘氨酸规则通路(Gly/N端规则通路)。Ac/N端规则通路靶向含有N端乙酰化(Nt-乙酰化)残基的蛋白质;Arg/N端规则通路则靶向一些未乙酰化的残基并涉及N端的精氨酸化;对于一些N端氨基酸为Pro和Gly的蛋白来说,它们既不能被乙酰化修饰也不能通过Arg/N端通路被识别,因而主要通过Pro/N端规则通路和Gly/N端规则通路被识别和降解。通过N端规通路介导的降解对特定蛋白质进行调节在大量生理和病理过程中发挥了重要作用,包括心血管发育,神经发生,生殖细胞减数分裂、精子发生、HPV感染及细胞凋亡等。本文综述了已知的N端规则通路的作用和机制,并探讨其与疾病发生的关系。作为一种独立的蛋白降解系统,N端规则通路仍包含了无数的生物学秘密等待着挖掘,对这些通路的全面理解可能会为各种疾病揭示新的治疗靶点。The N-end rule pathway is a protein degradation pathway mediated by the ubiquitin-proteasome system,which specifically targets and degrades target proteins by recognizing specific residues at the N-terminus of the proteins.The residues which play a crucial role in the N-end rule pathway are called degrons,also known as N-degrons,as they are usually unstable at the N-terminal end of the protein.Currently,several N-end rule pathways have been identified in the eukaryotes,including the Arg/N-end rule,Ac/N-end rule,and Pro/N-end rule pathways,as well as the recently discovered Gly/N-end rule pathway.The Ac/N-end rule pathway targets proteins containing N-terminal acetylation(Nt-acetylation)residues.The Arg/N-end rule pathway,on the other hand,targets certain unacetylated residues and involves N-terminal arginylation.For proteins with N-terminal proline(Pro)and glycine(Gly)residues,they are neither modified by acetylation nor recognized through the Arg/N-end rule pathway.Therefore,these proteins are primarily recognized and degraded through the Pro/N-end rule pathway and the Gly/N-end rule pathway.The regulation of specific proteins through N-end rule pathway-mediated degradation plays an important role in numerous physiological and pathological processes,such as cardiovascular development,neurogenesis,meiosis,spermatogenesis,HPV infection,and cell apoptosis.In this review,we summarize the role and mechanisms of several known N-end rule pathways and discuss their relationship with certain diseases.As an independent protein degradation system,the N-end rule pathways still hold countless biological secrets waiting for exploring.The comprehensive understanding of these pathways could potentially uncover novel therapeutic targets for various diseases.

关 键 词：N端规则通路 E3泛素连接酶 泛素化降解 

分 类 号：R73[医药卫生—肿瘤]