title: The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein.
abstract: Previous studies have shown that both hepatitis A virus and hepatitis C virus inhibit innate immunity by cleaving the mitochondrial antiviral signaling (MAVS) protein, an essential component of the virus-activated signaling pathway that activates NF-kappaB and IFN regulatory factor-3 to induce the production of type I IFN. For human hepatitis B virus (HBV), hepatitis B s-Ag, hepatitis B e-Ag, or HBV virions have been shown to suppress TLR-induced antiviral activity with reduced IFN-beta production and subsequent induction of IFN-stimulated genes. However, HBV-mediated suppression of the RIG-I-MDA5 pathway is unknown. In this study, we found that HBV suppressed poly(deoxyadenylate-thymidylate)-activated IFN-beta production in hepatocytes. Specifically, hepatitis B virus X (HBX) interacted with MAVS and promoted the degradation of MAVS through Lys(136) ubiquitin in MAVS protein, thus preventing the induction of IFN-beta. Further analysis of clinical samples revealed that MAVS protein was downregulated in hepatocellular carcinomas of HBV origin, which correlated with increased sensitivities of primary murine hepatocytes isolated from HBX knock-in transgenic mice upon vesicular stomatitis virus infections. By establishing a link between MAVS and HBX, this study suggests that HBV can target the RIG-I signaling by HBX-mediated MAVS downregulation, thereby attenuating the antiviral response of the innate immune system.
authors.affiliation: Beijing Institute of Biotechnology, China.
authors.forename: Congwen
authors.initials: C
authors.lastname: Wei
authors.forename: Caifei
authors.initials: C
authors.lastname: Ni
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: XiaoLi
authors.initials: X
authors.lastname: Yang
authors.forename: Zirui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Jia
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Kai
authors.initials: K
authors.lastname: Guan
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Cheng
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Youliang
authors.initials: Y
authors.lastname: Wang
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Wen
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D056945:Hep G2 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011067:Poly dA-dT / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014709:Vero Cells; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D024101:Mitochondrial Proteins; D011971:Receptors, Immunologic; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D011067:Poly dA-dT; D007371:Interferon-gamma; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases