ARIH2抑制LUBAC的线性泛素化连接酶活性  

ARIH2 Inhibits the Linear Ubiquitination Ligase Activity of LUBAC

作　　者：陈文哲 李磊 张令强[1,2] CHEN Wen-Zhe;LI Lei;ZHANG Ling-Qiang(Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Anhui Medical University,Beijing 102200,China;Institute of Biomics,Academy of Military Medicine,Academy of Military Sciences,National Center for Protein Science(Beijing),Beijing 102200,China)

机构地区：[1]安徽医科大学基础医学院病理生理教研室,合肥230032 [2]军事科学院军事医学研究院生命组学研究所国家蛋白质科学中心(北京),北京102200

出　　处：《中国生物化学与分子生物学报》2022年第10期1343-1350,共8页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家重点研发计划(No.2021YFA1300200)资助。

摘　　要：线性泛素化修饰在肿瘤及免疫系统中均发挥着重要作用。线性泛素链组装复合体(linear ubiquitin chain assembly complex,LUBAC)是目前已知的唯一能够催化合成线性泛素链的泛素连接酶。本研究发现,泛素连接酶2(ariadne homolog 2,ARIH2)作为LUBAC新的相互作用蛋白质,能够抑制LUBAC对底物的线性泛素化修饰水平。通过免疫共沉淀实验发现,ARIH2与HOIP存在相互作用,且GST pull-down结果说明,HOIP通过ZF-NZF结构域与ARIH2发生相互作用。进一步的免疫沉淀结果证明,LUBAC并不能线性泛素化修饰ARIH2。反之,ARIH2能够抑制LUBAC对底物的线性泛素化修饰水平,其机制可能是ARIH2影响了SHARPIN的泛素化水平,从而影响LUBAC酶活性,进而导致LUBAC对底物的线性泛素化水平减弱。Linear ubiquitination plays an important role in tumor and the immune system.Linear ubiquitin chain assembly complex(LUBAC) is the only known ubiquitin ligase that can catalyze the synthesis of linear ubiquitin chains.We found that ubiquitin ligase ariadne homolog 2(ARIH2) was a new interacting protein of LUBAC,and ARIH2 inhibited the level of linear ubiquitination of substrates by LUBAC.We further demonstrated that ARIH2 interacted with HOIP by Co-IP experiment,and that HOIP interacted with ARIH2 through the ZF-NZF(zinc finger-Npl4-Zinc finger) domain by GST pull-down experiments.Moreover,we showed that LUBAC could not modify ARIH2 by linear ubiquitination;On the contrary,ARIH2 inhibited the linear ubiquitination level of LUBAC substrates.The mechanism may be that ARIH2 affects the ubiquitination level of SHANK-associated RH domain interacting protein(SHARPIN),thereby affecting the enzyme activity of LUBAC,which leads to the weakening of the linear ubiquitination level of LUBAC to the substrate.

关 键 词：泛素连接酶 线性泛素化修饰 线性泛素链组装复合体 

分 类 号：Q7[生物学—分子生物学]