Yu Zhongxia, Song Hui, Jia Mutian, Zhang Jintao, Wang Wenwen, Li Qi, Zhang Lining, Zhao Wei
Department of Immunology, Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Shandong University, Jinan, China.
State Key Laboratory of Microbial Technology, Shandong University, Jinan, China.
J Exp Med. 2017 Dec 4;214(12):3553-3563. doi: 10.1084/jem.20170180. Epub 2017 Nov 14.
Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection-induced physiological enhancer of TBK1 expression. USP1-UAF1 complex enhanced TLR3/4 and RIG-I-induced IFN regulatory factor 3 (IRF3) activation and subsequent IFN-β secretion. Mechanistically, USP1 and UAF1 bound to TBK1, removed its K48-linked polyubiquitination, and then reversed the degradation process of TBK1. Furthermore, we found that ML323, a specific USP1-UAF1 inhibitor, attenuated IFN-β expression and enhanced viral replication both in vitro and in vivo Therefore, our results outline a novel mechanism for the control of TBK1 activity and suggest USP1-UAF1 complex as a potential target for the prevention of viral diseases.
TANK结合激酶1（TBK1）的最佳激活对于启动先天性抗病毒免疫和维持免疫稳态至关重要。尽管已有报道称几种E3泛素连接酶通过介导TBK1的多聚泛素化来调节其激活，但去泛素化酶对TBK1活性的作用仍不清楚。在此，我们鉴定了一种由泛素特异性肽酶1（USP1）和USP1相关因子1（UAF1）形成的去泛素化酶复合物，作为病毒感染诱导的TBK1表达的生理增强剂。USP1-UAF1复合物增强了TLR3/4和RIG-I诱导的干扰素调节因子3（IRF3）激活以及随后的干扰素-β分泌。从机制上讲，USP1和UAF1与TBK1结合，去除其K48连接的多聚泛素化，然后逆转TBK1的降解过程。此外，我们发现ML323，一种特异性USP1-UAF1抑制剂，在体外和体内均减弱了干扰素-β的表达并增强了病毒复制。因此，我们的结果概述了一种控制TBK1活性的新机制，并表明USP1-UAF1复合物是预防病毒性疾病的潜在靶点。
