title: Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets.
abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel and highly pathogenic human coronavirus and has quickly spread to other countries in the Middle East, Europe, North Africa and Asia since 2012. Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. Further analysis showed that ORF4b could also inhibit IRF3 and IRF7-induced production of IFN-β, whereas deletion of the nuclear localization signal of ORF4b abrogated its ability to inhibit IRF3 and IRF7-induced production of IFN-β, but not IFN-β production induced by RIG-I, MDA5, MAVS, IKKε, and TBK-1, suggesting that ORF4b could inhibit the induction of IFN-β in both the cytoplasm and nucleus. Collectively, these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. Viruses have evolved multiple strategies to evade or thwart a host's antiviral responses. A novel human coronavirus (HCoV), Middle East respiratory syndrome coronavirus (MERS-CoV), is distinguished from other coronaviruses by its high pathogenicity and mortality. However, virulence determinants that distinguish MERS-CoV from other HCoVs have yet to be identified. MERS-CoV ORF4b antagonizes the early antiviral response, which may contribute to MERS-CoV pathogenesis. Here, we report the identification of the interferon (IFN) antagonism mechanism of MERS-CoV ORF4b. MERS-CoV ORF4b inhibits the production of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. These findings provide a rationale for the novel pathogenesis of MERS-CoV as well as a basis for developing a candidate therapeutic against this virus.
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.|Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
authors.forename: Wenling
authors.initials: W
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Key Laboratory of Pathogen System Biology, Ministry of Health; Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, 100176, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Tan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology*; D003593:Cytoplasm / Q000378:metabolism / Q000821:virology*; D000071457:DEAD Box Protein 58 / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D065207:Middle East Respiratory Syndrome Coronavirus / Q000472:pathogenicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D014764:Viral Proteins; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1