Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK
Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK
复制标题
甲型流感病毒编码的 NS1 毒力因子蛋白通过靶向 IKK 抑制先天免疫反应
DOI：
10.1111/cmi.12005
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发表时间：
2012-12-01
影响因子：
3.4
通讯作者：
Huang, Wenlin
中科院分区：
文献类型：
--
作者：
Gao, Shijuan;Song, Liping;Huang, Wenlin
IKK/NF-kappa B通路是细胞为防御流感病毒等病毒感染而启动的重要信号传递过程。因此，这条途径是病毒试图对抗宿主对感染的反应的主要目标。在这里，我们报道了甲型流感病毒NS1蛋白通过C端效应域与IKK物理相互作用，特异性地抑制了IKK介导的NF-kappa B的激活和NF-kappa B诱导的抗病毒基因的产生。NS1与IKKα/IKKβ的相互作用影响其在胞浆和胞核的磷酸化功能。在细胞质中，NS1不仅在经典途径中阻断了ikkβ介导的I kappaB的磷酸化和降解，而且在另一条途径中抑制了IKKA介导的P100到P52的加工，从而抑制了核转录因子-kappa B的核转位，从而抑制了下游的核转录因子-kappaB基因的表达。在细胞核中，NS1损害了IKK介导的组蛋白H3Ser10的磷酸化，而组蛋白H3Ser10是诱导核因子-kappa B靶基因快速表达的关键因素。这些结果揭示了甲型流感病毒NS1蛋白通过破坏IKK功能来中和宿主核因子-kappaB介导的抗病毒反应的新机制。通过这种方式，NS1减弱了对感染的抗病毒反应，并反过来加强了病毒的致病作用。
The IKK/NF-kappa B pathway is an essential signalling process initiated by the cell as a defence against viral infection like influenza virus. This pathway is therefore a prime target for viruses attempting to counteract the host response to infection. Here, we report that the influenza A virus NS1 protein specifically inhibits IKK-mediated NF-kappa B activation and production of the NF-kappa B induced antiviral genes by physically interacting with IKK through the C-terminal effector domain. The interaction between NS1 and IKK alpha/IKK beta affects their phosphorylation function in both the cytoplasm and nucleus. In the cytoplasm, NS1 not only blocks IKK beta-mediated phosphorylation and degradation of I kappa Ba in the classical pathway but also suppresses IKKa-mediated processing of p100 to p52 in the alternative pathway, which leads to the inhibition of nuclear translocation of NF-kappa B and the subsequent expression of downstream NF-kappa B target genes. In the nucleus, NS1 impairs IKK-mediated phosphorylation of histone H3 Ser 10 that is critical to induce rapid expression of NF-kappa B target genes. These results reveal a new mechanism by which influenza A virus NS1 protein counteracts host NF-kappa B-mediated antiviral response through the disruption of IKK function. In this way, NS1 diminishes antiviral responses to infection and, in turn, enhances viral pathogenesis.