EV713C protease cleaves host anti-viral factor OAS3 and enhances virus replication

作     者：Xiaolei Zhou Li Tian Jian Wang Baisong Zheng Wenyan Zhang Xiaolei Zhou;Li Tian;Jian Wang;Baisong Zheng;Wenyan Zhang

作者机构：Center for Infectious Diseases and Pathogen BiologyInstitute of Virology and AIDS ResearchKey Laboratory of Organ Regeneration and Transplantation of the Ministry of EducationThe First Hospital of Jilin UniversityJilin130021China 

出 版 物：《Virologica Sinica》 (中国病毒学（英文版）)

年 卷 期：2022年第37卷第3期

页      面：418-426页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 100103[医学-病原生物学] 10[医学] 

基　　金：supported by funding from the National Key R&D Program of China(2021YFC2301900 and 2301904) National Natural Science Foundation of China(81930062) Health Commission of Jilin Province(2020J059) the Key Laboratory of Molecular Virology,Jilin Province(20102209)。 

主　　题：Enteroviruses EV71 3C protease Cleavage Anti-viral factor OAS3 

摘      要：The global spread of enteroviruses(EVs)has become more frequent,severe and life-threatening.Intereron(IFN)I has been proved to control EVs by regulating IFN-stimulated genes(ISG)expression.20-50-oligoadenylate synthetases 3(OAS3)is an important ISG in the OAS/RNase L antiviral system.The relationship between OAS3 and EVs is still unclear.Here,we reveal that OAS3,superior to OAS1 and OAS2,significantly inhibited EV71 replication in vitro.However,EV71 utilized autologous 3C protease(3C^(pro))to cleave intracellular OAS3 and enhance viral replication.Rupintrivir,a human rhinovirus 3C protease inhibitor,completely abolished the cleavage of EV713C^(pro)on OAS3.And the proteolytically deficient mutants H40G,E71A,and C147G of EV713C^(pro)also lost the ability of OAS3 cleavage.Mechanistically,the Q982-G983 motif in C-terminal of OAS3 was identified as a crucial 3C^(pro)cutting site.Further investigation indicated that OAS3 inhibited not only EV71 but also Coxsackievirus B3(CVB3),Coxsackievirus A16(CA16),Enterovirus D68(EVD68),and Coxsackievirus A6(CA6)subtypes.Notably,unlike other four subtypes,CA163C^(pro)could not cleave OAS3.Two key amino acids variation Ile36 and Val86 in CA163C^(pro)might result in weak and delayed virus replication of CA16 because of failure of OAS and 3AB cleavage.Our works elucidate the broad anti-EVs function of OAS3,and illuminate a novel mechanism by which EV71 use 3C^(pro)to escape the antiviral effect of OAS3.These findings can be an important entry point for developing novel therapeutic strategies for multiple EVs infection.