Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK

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.