title: 3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7.
abstract: Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family. Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C(pro), an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C(pro) targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C(pro). Together, these results suggest that a dynamic interplay between 3C(pro) and IRF7 may determine the outcome of EV-D68 infection.
  
  
  OBJECTIVE
  EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C(pro)-IRF7 interaction may represent an interface that dictates EV-D68 infection.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Zichun
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Liu
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lei
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA tshuo@uic.edu wangjw28@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China tshuo@uic.edu wangjw28@163.com.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
mesh_terms: D000086042:3C Viral Proteases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D030016:Enterovirus D, Human / Q000201:enzymology* / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D059748:Proteolysis; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases