Hepatitis C Virus Nonstructural Protein 5A Interacts with Immunomodulatory Kinase IKKε to Negatively Regulate Innate Antiviral Immunity

초록

Hepatitis C virus (HCV) infection can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV employs diverse strategies to evade host antiviral innate immune responses to mediate a persistent infection. In the present study, we show that nonstructural protein 5A (NS5A) interacts with an NF-kappa B inhibitor immunomodulatory kinase, IKK epsilon, and subsequently downregulates beta interferon (IFN-ss) promoter activity. We further demonstrate that NS5A inhibits DDX3-mediated IKKe and interferon regulatory factor 3 (IRF3) phosphorylation. We also note that hyperphosphorylation of NS5A mediates protein interplay between NS5A and IKK epsilon, thereby contributing to NS5A mediated modulation of IFN-ss signaling. Lastly, NS5A inhibits IKKe-dependent p65 phosphorylation and NF-kappa B activation. Based on these findings, we propose NS5A as a novel regulator of IFN signaling events, specifically by inhibiting IKKe downstream signaling cascades through its interaction with IKKe. Taken together, these data suggest an additional mechanistic means by which HCV modulates host antiviral innate immune responses to promote persistent viral infection.

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