tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Takumi Tsukamoto[SUP] 2 [/SUP], Masae Itoh[SUP] 2 [/SUP], Bin Gotoh[SUP] 1 [/SUP]
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.
. 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[SUP] 1 [/SUP], Takumi Tsukamoto[SUP] 2 [/SUP], Masae Itoh[SUP] 2 [/SUP], Bin Gotoh[SUP] 1 [/SUP]
Affiliations
- PMID: 36053897
- DOI: 10.1002/1873-3468.14486
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.