Pup-蛋白酶体系统的作用机制和生物学功能  

The Mechanism and Biological Functions of Pup-proteasome System

作　　者：戴炜 李梦淼 张俊杰[1] DAI Wei;LI Meng-Miao;ZHANG Jun-Jie(Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education,College of Life Sciences,Beijing Normal University,Beijing 100875,China;College of Life Sciences,Liaoning Normal University,Dalian 116081,China)

机构地区：[1]北京师范大学生命科学学院,细胞增殖及调控生物学教育部重点实验室,北京100875 [2]辽宁师范大学生命科学学院,大连116081

出　　处：《生物化学与生物物理进展》2023年第4期725-739,共15页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(32171138,81972604);细胞增殖及调控生物学教育部重点实验室开放课题资助项目。

摘　　要：Pup-蛋白酶体系统(Pup-proteasome system,PPS)是原核生物的一种翻译后蛋白质修饰降解体系,在去酰胺酶(deamidase of Pup,Dop)和蛋白酶体辅助因子A(proteasome accessory factorA,PafA)两种酶的作用下,原核生物类泛素蛋白(prokaryotic ubiquitin-like protein,Pup)可以标记靶蛋白,并介导靶蛋白经蛋白酶体降解。在分枝杆菌中PPS参与氧化应激、营养缺乏、热激、DNA损伤等多种应激反应,并在金属离子稳态调控、毒素-抗毒素系统(toxin-antitoxin system,TA system)的调节以及抵抗宿主免疫等过程中发挥作用。PPS与结核分枝杆菌(Mycobacterium tuberculosis,Mtb)的持留性和致病性直接相关,因此PPS中的PafA、Dop和蛋白酶体均是抗结核药物开发的新靶点,筛选针对PPS的小分子抑制剂将成为新型抗结核药物研发的一个新途径。此外,Paf A催化的蛋白质Pup化被应用于生物技术的研发,形成了一种新的邻近标记技术——基于Pup化的邻近标记技术(pupylation-based interaction tagging,PUP-IT),应用于蛋白质相互作用的研究。本文综述了Pup-蛋白酶体系统的作用机制及其生物学功能研究的进展,并探讨了该系统在抗结核药物和生物技术研发中的应用前景。The Pup-proteasome system(PPS)is a prokaryotic post-translational protein degradation pathway,in which prokaryotic ubiquitin-like protein(Pup)is activated by deamidase of Pup(Dop)and covalently linked to target proteins by proteasome accessory factor A(Paf A),and then the Pup-labeled target proteins are degraded by proteasome.PPS in mycobacteria is involved in the reactions to a various stress conditions,such as oxidative stress,nutritional deficiency,heat stress,and DNA damage,and participates in the regulation of metal ion homeostasis,toxin-antitoxin system,and host immune resistance.It has been reported that PPS is closely related to the retention and pathogenicity of Mycobacterium tuberculosis,therefore the PPS components,PafA,Dop and proteasome,have emerged as new targets for anti-tuberculosis drug development.Several small molecule inhibitors targeting PPS have been identified as the potential novel anti-tuberculosis drugs.In addition,PafAcatalyzed protein pupylation has been applied in biotechnology research,and developed into a new proximity labeling method,named pupylation-based interaction tagging(PUP-IT),which has been successfully used in the study of protein-protein interactions.This article reviews the research progress in the mechanism of action and biological functions of PPS,as well as the research progress in PPS inhibitors and PPS biotechnology applications.

关 键 词：Pup-蛋白酶体系统 DOP PafA PUP 蛋白酶体 结核分枝杆菌 

分 类 号：Q5[生物学—生物化学] Q7Q81