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.2'-5'-oligoadenylate syn-thetases 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 repli-cation in vitro.However,EV71 utilized autologous 3C protease(3Cpro)to cleave intracellular OAS3 and enhance viral replication.Rupintrivir,a human rhinovirus 3C protease inhibitor,completely abolished the cleavage of EV71 3Cpro on OAS3.And the proteolytically deficient mutants H40G,E71A,and C147G of EV71 3Cpro also lost the ability of OAS3 cleavage.Mechanistically,the Q982-G983 motif in C-terminal of OAS3 was identified as a crucial 3Cpro cutting site.Further investigation indicated that OAS3 inhibited not only EV71 but also Coxsack-ievirus B3(CVB3),Coxsackievirus A1 6(CA1 6),Enterovirus D68(EVD68),and Coxsackievirus A6(CA6)subtypes.Notably,unlike other four subtypes,CA1 6 3Cpro could not cleave OAS3.Two key amino acids variation Ile36 and Va186 in CA16 3Cpro 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 3Cpro to escape the antiviral effect of OAS3.These findings can be an important entry point for developing novel therapeutic strategies for multiple EVs infection.

Xiaolei Zhou;Li Tian;Jian Wang;Baisong Zheng;Wenyan Zhang

Center for Infectious Diseases and Pathogen Biology,Institute of Virology and AIDS Research,Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education,The First Hospital of Jilin University,Jilin,130021,China

中国病毒学

[1]Xiaolei Zhou;Li Tian;Jian Wang;Baisong Zheng;Wenyan Zhang-.EV71 3C protease cleaves host anti-viral factor OAS3 and enhances virus replication)[J].中国病毒学,2022(03):418-426

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