Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling.
Classical swine fever virus NS5A protein antagonizes innate immune response by inhibiting the NF-κB signaling.
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DOI：
10.1016/j.virs.2023.09.002
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发表时间：
2023-12
影响因子：
5.5
通讯作者：
Tu, Changchun
中科院分区：
文献类型：
--
作者：
Sun, Jinfu;Li, Jiaying;Li, Liming;Yu, Haixiao;Ma, Ping;Wang, Yingnan;Zhu, Jinqi;Feng, Zezhong;Tu, Changchun
关键词：
猪瘟病毒(CSFV)NS5A非结构蛋白是一种多功能蛋白，参与病毒基因组复制、蛋白翻译、病毒颗粒组装和细胞信号通路的调节。已有报道表明，NS5A可抑制Poly(I：C)诱导的核因子-κB信号转导，但其作用机制尚不清楚。在这里，我们报道了NS5A直接与IκB激酶(IKK)复合体的调节亚单位--NF-κB基本调节子(NEMO)相互作用，从而抑制了NF-κB信号通路。进一步的研究表明，Nemo的锌指结构域和NS5A的AA126-250片段是Nemo与NS5A相互作用所必需的。机制分析表明，NS5A介导了NEMO蛋白酶体的降解。泛素化实验表明，NS5A诱导NEMO蛋白酶体降解的K27连接而不是K48连接的多泛素化。此外，NS5A阻断了K63连接的NEMO的多泛素化，从而抑制了IKK的磷酸化、IκBα的降解和NF-κB的激活。这些发现揭示了猪瘟病毒抑制宿主先天免疫的新机制，这可能指导未来针对猪瘟病毒的药物设计。猪瘟病毒NS5A蛋白直接与核因子-κB必需调节物(NEMO)相互作用。CSFV NS5A介导NEMO蛋白酶体降解。NS5A阻断K63连接的NEMO的多泛素化。NS5A通过抑制IKK的磷酸化、IκB的α降解和NF-κB的激活来逃避宿主的天然免疫反应。
The NS5A non-structural protein of classical swine fever virus (CSFV) is a multifunctional protein involved in viral genomic replication, protein translation, assembly of infectious virus particles, and regulation of cellular signaling pathways. Previous report showed that NS5A inhibited nuclear factor kappa B (NF-κB) signaling induced by poly(I:C); however, the mechanism involved has not been elucidated. Here, we reported that NS5A directly interacted with NF-κB essential modulator (NEMO), a regulatory subunit of the IκB kinase (IKK) complex, to inhibit the NF-κB signaling pathway. Further investigations showed that the zinc finger domain of NEMO and the aa 126–250 segment of NS5A are essential for the interaction between NEMO and NS5A. Mechanistic analysis revealed that NS5A mediated the proteasomal degradation of NEMO. Ubiquitination assay showed that NS5A induced the K27-linked but not the K48-linked polyubiquitination of NEMO for proteasomal degradation. In addition, NS5A blocked the K63-linked polyubiquitination of NEMO, thus inhibiting IKK phosphorylation, IκBα degradation, and NF-κB activation. These findings revealed a novel mechanism by which CSFV inhibits host innate immunity, which might guide the drug design against CSFV in the future. Classical swine fever virus NS5A protein directly interacts with NF-κB essential modulator (NEMO). CSFV NS5A mediates proteasomal degradation of NEMO. NS5A blocks k63-linked polyubiquitination of NEMO. NS5A inhibits IKK phosphorylation, IκBα degradation, and NF-κB activation to evade host innate immune response.
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影响因子：
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