The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein

J Immunol. 2010 Jul 15;185(2):1158-68. doi: 10.4049/jimmunol.0903874. Epub 2010 Jun 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology
  • DEAD-box RNA Helicases / metabolism
  • Down-Regulation
  • Hep G2 Cells
  • Humans
  • Immunity, Innate / immunology*
  • Immunoblotting
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Kinetics
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / immunology*
  • Mitochondrial Proteins / metabolism
  • Poly dA-dT / genetics
  • Poly dA-dT / immunology
  • Poly dA-dT / metabolism
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Trans-Activators / genetics
  • Trans-Activators / immunology*
  • Trans-Activators / metabolism
  • Transfection
  • Vero Cells

Substances

  • Adaptor Proteins, Signal Transducing
  • Mitochondrial Proteins
  • Trans-Activators
  • VISA protein, human
  • hepatitis B virus X protein
  • Poly dA-dT
  • Interferon-gamma
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases