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. 2022 Oct;596(19):2538-2554.
doi: 10.1002/1873-3468.14486. Epub 2022 Sep 8.

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
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Free article

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

Yoshinori Kitagawa et al. FEBS Lett. 2022 Oct.
Free article

Abstract

The Toll-like receptor (TLR)7- and TLR9-dependent signalling 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 signalling cascade; accessory proteins; interferon.

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References

    1. Yang Y, Zhang L, Geng H, Deng Y, Huang B, Guo Y, et al. The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists. Protein Cell. 2013;4:951-61.
    1. Matthews KL, Coleman CM, van der Meer Y, Snijder EJ, Frieman MB. The ORF4b-encoded accessory proteins of Middle East respiratory syndrome coronavirus and two related bat coronaviruses localize to the nucleus and inhibit innate immune signalling. J Gen Virol. 2014;95:874-82.
    1. Kehrer T, Garcia-Sastre A, Miorin L. Control of innate immune activation by severe acute respiratory syndrome coronavirus 2 and other coronaviruses. J Interferon Cytokine Res. 2021;41:205-19.
    1. Li JY, Zhou ZJ, Wang Q, He QN, Zhao MY, Qiu Y, et al. Innate immunity evasion strategies of highly pathogenic coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2. Front Microbiol. 2021;12:770656.
    1. Menachery VD, Mitchell HD, Cockrell AS, Gralinski LE, Yount BL Jr, Graham RL, et al. MERS-CoV accessory ORFs play key role for infection and pathogenesis. mBio. 2017;8:e00665-17.

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