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

The IKK/NF‐κB 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‐κB activation and production of the NF‐κB induced antiviral genes by physically interacting with IKK through the C‐terminal effector domain. The interaction between NS1 and IKKα/IKKβ affects their phosphorylation function in both the cytoplasm and nucleus. In the cytoplasm, NS1 not only blocks IKKβ‐mediated phosphorylation and degradation of IκBα in the classical pathway but also suppresses IKKα‐mediated processing of p100 to p52 in the alternative pathway, which leads to the inhibition of nuclear translocation of NF‐κB and the subsequent expression of downstream NF‐κB target genes. In the nucleus, NS1 impairs IKK‐mediated phosphorylation of histone H3 Ser 10 that is critical to induce rapid expression of NF‐κB target genes. These results reveal a new mechanism by which influenza A virus NS1 protein counteracts host NF‐κB‐mediated antiviral response through the disruption of IKK function. In this way, NS1 diminishes antiviral responses to infection and, in turn, enhances viral pathogenesis.