The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein.
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.
Wei
Congwen
C
Beijing Institute of Biotechnology, China.
Ni
Caifei
C
Song
Ting
T
Liu
Yu
Y
Yang
XiaoLi
X
Zheng
Zirui
Z
Jia
Yongxia
Y
Yuan
Yuan
Y
Guan
Kai
K
Xu
Yang
Y
Cheng
Xiaozhong
X
Zhang
Yanhong
Y
Yang
Xiao
X
Wang
Youliang
Y
Wen
Chaoyang
C
Wu
Qing
Q
Shi
Wei
W
Zhong
Hui
H
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
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