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FEBS Lett . Middle East respiratory syndrome coronavirus ORF4b protein inhibits TLR7- and TLR9-dependent alpha interferon induction

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  • FEBS Lett . Middle East respiratory syndrome coronavirus ORF4b protein inhibits TLR7- and TLR9-dependent alpha interferon induction


    FEBS Lett


    . 2022 Aug 27.
    doi: 10.1002/1873-3468.14486. Online ahead of print.
    Middle East respiratory syndrome coronavirus ORF4b protein inhibits TLR7- and TLR9-dependent alpha interferon induction


    Yoshinori Kitagawa 1 , Takumi Tsukamoto 2 , Masae Itoh 2 , Bin Gotoh 1



    Affiliations

    Abstract

    The Toll-like receptor (TLR)7- and TLR9-dependent signaling cascade is responsible for production of a large amount of alpha interferon by plasmacytoid dendritic cells upon viral infection. Here, we show that Middle East respiratory syndrome coronavirus (MERS-CoV) accessory protein ORF4b has the most potential among the MERS-CoV accessory proteins to inhibit the TLR7/9-signaling-dependent alpha interferon production. ORF4b protein, which has a bipartite nuclear localization signal, was found to bind to IKKα, a kinase responsible for phosphorylation of interferon regulatory factor (IRF)7. This interaction caused relocation of a large proportion of IKKα from the cytoplasm to the nucleus. Studies using ORF4b and IKKα mutants demonstrated that ORF4b protein inhibited IKKα-mediated IRF7 phosphorylation by sequestering IKKα in the nucleus and by impeding the phosphorylation process of cytoplasmic IKKα.

    Keywords: IKKα; Middle East respiratory syndrome coronavirus; ORF4b protein; TLR7/9-dependent signaling cascade; accessory proteins; interferon; plasmacytoid dendritic cells.

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