Human enterovirus A71(EV-A71)is a major causative agent of hand,foot and mouth disease(HFMD),which poses a significant public health threat,particularly among young children.Mitochondrial antiviral signaling protein(M...Human enterovirus A71(EV-A71)is a major causative agent of hand,foot and mouth disease(HFMD),which poses a significant public health threat,particularly among young children.Mitochondrial antiviral signaling protein(MAVS)and interferon regulatory factor 3(IRF3)are vital proteins for the induction of type I interferons(IFN-I)and downstream interferon-stimulated genes(ISGs)during EVA71 infection.While posttranslational modifications are known to critically influence viral infection processes,the mechanisms by which EV-A71 exploits host deubiquitinases(DUBs)for immune evasion remain poorly understood.In this study,we demonstrated that EV-A71 infection upregulated ubiquitinspecific protease 5(USP5)expression.Knockdown of USP5 not only inhibited EV-A71 replication but also observably increased the production of IFN-I and ISGs.Furthermore,USP5 also regulated the replication of EV-D68 and CVA16 and the production of IFN-I and ISGs.Mechanistically,USP5 physically interacted with MAVS and IRF3 and reduced the K63-linked polyubiquitination of MAVS and IRF3.Conversely,USP5 knockdown increased the K63-linked polyubiquitination of MAVS and IRF3,thereby accelerating the phosphorylation of IRF3 and increasing IFN-I production during EV-A71 infection.Furthermore,pharmacological inhibition of USP5 with the small-molecule inhibitor PR-619 significantly potentiated the antiviral effects of IFN against EV-A71.Collectively,our findings reveal a previously unrecognized role of USP5 in facilitating EV-A71 immune evasion by dampening MAVSand IRF3-mediated antiviral signaling.These insights provide a novel therapeutic avenue for combating EV-A71 infection through targeted modulation of the USP5-IRF3 axis.展开更多
基金supported by the National Natural Science Foundation of China(32300133 to SZ.and 32100106 to YR)the China Postdoctoral Science Foundation(2023M730965 to SZ.)+3 种基金the Science and Technology Department of Henan Province(232102311103 to SZ.)the Chinese Academy of Sciences(CAS)Youth Innovation Promotion Association(2023351 to YR)the Hubei Province Natural Science Funds(2023AFA008 and 2023AFB582 to YR)the Open project of the State Key Laboratory of Antiviral Drugs,Henan University(FX3020A030002).
文摘Human enterovirus A71(EV-A71)is a major causative agent of hand,foot and mouth disease(HFMD),which poses a significant public health threat,particularly among young children.Mitochondrial antiviral signaling protein(MAVS)and interferon regulatory factor 3(IRF3)are vital proteins for the induction of type I interferons(IFN-I)and downstream interferon-stimulated genes(ISGs)during EVA71 infection.While posttranslational modifications are known to critically influence viral infection processes,the mechanisms by which EV-A71 exploits host deubiquitinases(DUBs)for immune evasion remain poorly understood.In this study,we demonstrated that EV-A71 infection upregulated ubiquitinspecific protease 5(USP5)expression.Knockdown of USP5 not only inhibited EV-A71 replication but also observably increased the production of IFN-I and ISGs.Furthermore,USP5 also regulated the replication of EV-D68 and CVA16 and the production of IFN-I and ISGs.Mechanistically,USP5 physically interacted with MAVS and IRF3 and reduced the K63-linked polyubiquitination of MAVS and IRF3.Conversely,USP5 knockdown increased the K63-linked polyubiquitination of MAVS and IRF3,thereby accelerating the phosphorylation of IRF3 and increasing IFN-I production during EV-A71 infection.Furthermore,pharmacological inhibition of USP5 with the small-molecule inhibitor PR-619 significantly potentiated the antiviral effects of IFN against EV-A71.Collectively,our findings reveal a previously unrecognized role of USP5 in facilitating EV-A71 immune evasion by dampening MAVSand IRF3-mediated antiviral signaling.These insights provide a novel therapeutic avenue for combating EV-A71 infection through targeted modulation of the USP5-IRF3 axis.
