NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling

• Published in: Frontiers in immunology Vol. 11; p. 51
• Main Authors: Li, Aixin, Wang, Wenbiao, Wang, Yingchong, Chen, Keli, Xiao, Feng, Hu, Dingwen, Hui, Lixia, Liu, Weiyong, Feng, Yuqian, Li, Geng, Tan, Qiuping, Liu, Yingle, Wu, Kailang, Wu, Jianguo
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 14.02.2020
• Subjects: Active Transport, Cell Nucleus; Binding Sites; Cell Nucleus - metabolism; DEAD Box Protein 58 - metabolism; Host-Pathogen Interactions; Humans; IFN-β; Immunology; Interferon Regulatory Factor-3 - metabolism; Interferon-beta - metabolism; IRF3; methyltransferase; NS5; Phosphorylation; Protein Binding; Receptors, Immunologic - metabolism; RIG-I; Signal Transduction; Ubiquitination; Viral Nonstructural Proteins - metabolism; Zika Virus - metabolism; Zika Virus - physiology; Zika Virus Infection - metabolism; Zika Virus Infection - virology; ZIKV; NS5; IFN-β; methyltransferase; IRF3; ubiquitination; RIG-I
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.00051

During host-virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, restricts host immune responses through a distinct mechanism. ZIKV nonstructural protein 5 (NS5) interacts with the host retinoic acid-inducible gene I (RIG-I), an essential signaling molecule for defending pathogen infections. NS5 subsequently represses K63-linked polyubiquitination of RIG-I, attenuates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), and inhibits the expression and production of interferon-β (IFN-β), thereby restricting the RIG-I signaling pathway. Interestingly, we demonstrate that the methyltransferase (MTase) domain of NS5 is required for the repression of RIG-I ubiquitination, IRF3 activation, and IFN-β production. Detailed studies further reveal that the conservative active site D146 of NS5 is critical for the suppression of the RIG-I signaling. Therefore, we uncover an essential role of NS5 conservative site D146 in ZIKV-mediated repression of innate immune system, illustrate a distinct mechanism by which ZIKV evades host immune responses, and discover a potential target for anti-viral infection.