title: Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3.
abstract: Enterovirus 71 (EV71) causes hand-foot-and-mouth disease and neurological complications in young children. Although the underlying mechanisms remain obscure, impaired or aberrant immunity is thought to play a role. In infected cells, EV71 suppresses type I interferon responses mediated by retinoid acid-inducible gene I (RIG-I). This involves the EV71 3C protein, which disrupts the formation of a functional RIG-I complex. In the present study, we report that EV71 inhibits the induction of innate immunity by Toll-like receptor 3 (TLR3) via a distinct mechanism. In HeLa cells stimulated with poly(I · C), EV71 inactivates interferon regulatory factor 3 and drastically suppresses interferon-stimulated gene expression. Notably, EV71 specifically downregulates a TRIF, TIR domain-containing adaptor inducing beta interferon (IFN-β). When expressed alone in mammalian cells, EV71 3C is capable of exhibiting these activities. EV71 3C associates with and induces TRIF cleavage in the presence of Z-VAD-FMK, a caspase inhibitor. TRIF cleavage depends on its amino acid pair Q312-S313, which resembles a proteolytic site of picornavirus 3C proteases. Further, site-specific 3C mutants with a defective protease activity bind TRIF but fail to mediate TRIF cleavage. Consequently, these 3C mutants are unable to inhibit NF-κB and IFN-β promoter activation. TRIF cleavage mediated by EV71 may be a mechanism to impair type I IFN production in response to Toll-like receptor 3 (TLR3) activation.
authors.affiliation: State Key Laboratory of Molecular Virology and Genetic Engineering, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Lei
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Sun
authors.forename: Xinlei
authors.initials: X
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
mesh_terms: D000086042:3C Viral Proteases; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D029821:Enterovirus A, Human / Q000276:immunology* / Q000472:pathogenicity*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050505:Mutant Proteins; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases