KMID : 0578320220450100702
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Molecules and Cells 2022 Volume.45 No. 10 p.702 ~ p.717
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Hepatitis C Virus Nonstructural Protein 5A Interacts with Immunomodulatory Kinase IKK¥å to Negatively Regulate Innate Antiviral Immunity
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Kang Sang-Min
Park Ji-Young Han Hee-Jeong Song Byeong-Min Tark Dong-Seob Choi Byeong-Sun Hwang Soon-B
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Abstract
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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-¥êB inhibitor immunomodulatory kinase, IKK¥å, and subsequently downregulats beta interferon (IFN-¥â) promoter activity. We further demonstrate that NS5A inhibits DDX3-mediated IKK¥å and interferon regulatory factor 3 (IRF3) phosphorylation. We also note that hyperphosphorylation of NS5A mediats protein interplay between NS5A and IKK¥å, thereby contributing to NS5A-mediated modulation of IFN-¥â signaling. Lastly, NS5A inhibits IKK¥å-dependent p65 phosphorylation and NF-¥êB activation. Based on these findings, we propose NS5A as a novel regulator of IFN signaling events, specifically by inhibiting IKK¥å downstream signaling cascades through its interaction with IKK¥å. 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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KEYWORD
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DDX3, IFN-¥â, IKK¥å, IRF3, NS5A, hepatitis C virus.
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