The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses.
Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease and fatal neurological diseases. Immature or impaired immunity is thought to associate with increased morbidity and mortality. In a murine model, EV71 does not facilitate the production of type I interferon (IFN) that plays a critical role in the first-line defense against viral infection. Administration of a neutralizing antibody to IFN-alpha/beta exacerbates the virus-induced disease. However, the molecular events governing this process remain elusive. Here, we report that EV71 suppresses the induction of antiviral immunity by targeting the cytosolic receptor retinoid acid-inducible gene I (RIG-I). In infected cells, EV71 inhibits the expression of IFN-beta, IFN-stimulated gene 54 (ISG54), ISG56, and tumor necrosis factor alpha. Among structural and nonstructural proteins encoded by EV71, the 3C protein is capable of inhibiting IFN-beta activation by virus and RIG-I. Nevertheless, EV71 3C exhibits no inhibitory activity on MDA5. Remarkably, when expressed in mammalian cells, EV71 3C associates with RIG-I via the caspase recruitment domain. This precludes the recruitment of an adaptor IPS-1 by RIG-I and subsequent nuclear translocation of interferon regulatory factor 3. An R84Q or V154S substitution in the RNA binding motifs has no effect. An H40D substitution is detrimental, but the protease activity associated with 3C is dispensable. Together, these results suggest that inhibition of RIG-I-mediated type I IFN responses by the 3C protein may contribute to the pathogenesis of EV71 infection.
Lei
Xiaobo
X
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.
Liu
Xinlei
X
Ma
Yijie
Y
Sun
Zhenmin
Z
Yang
Yaowu
Y
Jin
Qi
Q
He
Bin
B
Wang
Jianwei
J
D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D051017:Apoptosis Regulatory Proteins; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D029821:Enterovirus A, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D007108:Immune Tolerance; D050838:Interferon Regulatory Factor-3 / Q000096:biosynthesis* / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D020125:Mutation, Missense; D011485:Protein Binding; D025941:Protein Interaction Mapping; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D014157:Transcription Factors / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C484290:IFIT1 protein, human; C484289:IFIT2 protein, human; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D037521:Virulence Factors; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases