title: Enterovirus 68 3C protease cleaves TRIF to attenuate antiviral responses mediated by Toll-like receptor 3.
abstract: Human enterovirus 68 (EV68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family. Over the past several years, there have been increasingly documented outbreaks of respiratory disease associated with EV68. As a globally emerging pathogen, EV68 infects both adults and children. However, the molecular basis of EV68 pathogenesis is unknown. Here we report that EV68 inhibits Toll-like receptor 3 (TLR3)-mediated innate immune responses by targeting the TIR domain-containing adaptor inducing beta interferon (TRIF). In infected HeLa cells, EV68 inhibits poly(I·C)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression. Further investigations revealed that TRIF, a critical adaptor downstream of TLR3, is targeted by EV68. When expressed alone, 3C(pro), an EV68-encoded protease, cleaves TRIF. 3C(pro) mediates TRIF cleavage at Q312 and Q653, which are sites in the amino- and carboxyl-terminal domains, respectively. This cleavage relies on 3C(pro)'s cysteine protease activity. Cleavage of TRIF abolishes the capacity of TRIF to activate NF-κB and IFN-β signaling. These results suggest that control of TRIF by 3C(pro) may be a mechanism by which EV68 subverts host innate immune responses.
  
  
  OBJECTIVE
  EV68 is a globally emerging pathogen, but the molecular basis of EV68 pathogenesis is unclear. Here we report that EV68 inhibits TLR3-mediated innate immune responses by targeting TRIF. Further investigations revealed that TRIF is cleaved by 3C(pro). These results suggest that control of TRIF by 3C(pro) may be a mechanism by which EV68 impairs type I IFN production in response to TLR3 activation.
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: 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: Linlin
authors.initials: L
authors.lastname: Li
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: 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.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhou
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: Zhuo
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA wangjw28@163.com tshuo@uic.edu.
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 wangjw28@163.com tshuo@uic.edu.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
mesh_terms: D000086042:3C Viral Proteases; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D030016:Enterovirus D, Human / Q000201:enzymology* / Q000235:genetics; D004769:Enterovirus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D059748:Proteolysis; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016328:NF-kappa B; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014764:Viral Proteins; D016899:Interferon-beta; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases