The Hepatitis B Virus X Protein Disrupts Innate Immunity by Downregulating Mitochondrial Antiviral Signaling Protein

Previous studies have shown that both hepatitis Avirus 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- k B 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- b 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- b 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- b . 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. The Journal of Immunology , 2010, 185: 1158–1168.

[1]  Virgil L. Woods,et al.  Ebolavirus VP35 uses a bimodal strategy to bind dsRNA for innate immune suppression , 2009, Proceedings of the National Academy of Sciences.

[2]  Yanhong Zhang,et al.  Negative Regulation of MAVS-Mediated Innate Immune Response by PSMA71 , 2009, The Journal of Immunology.

[3]  Dongliang Yang,et al.  Hepatitis B virus suppresses toll‐like receptor–mediated innate immune responses in murine parenchymal and nonparenchymal liver cells , 2009, Hepatology.

[4]  K. Tran,et al.  Human Respiratory Syncytial Virus Nonstructural Protein NS2 Antagonizes the Activation of Beta Interferon Transcription by Interacting with RIG-I , 2009, Journal of Virology.

[5]  K. Fung,et al.  Identification of functionally important amino acid residues in the mitochondria targeting sequence of hepatitis B virus X protein. , 2008, Virology.

[6]  G. Gerken,et al.  Toll‐like receptor‐mediated control of HBV replication by nonparenchymal liver cells in mice , 2007, Hepatology.

[7]  Fu-Sheng Wang,et al.  Clinical immune characterization of hepatitis B virus infection and implications for immune intervention: Progress and challenges , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[8]  K. Honda,et al.  DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response , 2007, Nature.

[9]  F. Chisari,et al.  Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells , 2007, Proceedings of the National Academy of Sciences.

[10]  Hideyuki Konishi,et al.  Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125 , 2007, Proceedings of the National Academy of Sciences.

[11]  Yuqiong Liang,et al.  Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor , 2007, Proceedings of the National Academy of Sciences.

[12]  B. Shen,et al.  CUE domain containing 2 regulates degradation of progesterone receptor by ubiquitin–proteasome , 2007, The EMBO journal.

[13]  S. Lewin,et al.  Regulation of Toll‐like receptor‐2 expression in chronic hepatitis B by the precore protein , 2007, Hepatology.

[14]  G. Halliday,et al.  VISA--a pass to innate immunity. , 2007, The international journal of biochemistry & cell biology.

[15]  D. Philpott,et al.  Nod-like proteins in immunity, inflammation and disease , 2006, Nature Immunology.

[16]  M. Nassal,et al.  Stable HepG2- and Huh7-based human hepatoma cell lines for efficient regulated expression of infectious hepatitis B virus. , 2006, Journal of hepatology.

[17]  S. Riordan,et al.  Reduced Expression of Toll-Like Receptor 2 on Peripheral Monocytes in Patients with Chronic Hepatitis B , 2006, Clinical and Vaccine Immunology.

[18]  J. Tschopp,et al.  Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. , 2006, Molecular cell.

[19]  Antonio Bertoletti,et al.  The immune response during hepatitis B virus infection. , 2006, The Journal of general virology.

[20]  Hong-Hsing Liu,et al.  The specific and essential role of MAVS in antiviral innate immune responses. , 2006, Immunity.

[21]  J. Hiscott,et al.  MasterCARD: a priceless link to innate immunity. , 2006, Trends in molecular medicine.

[22]  Q. Ye,et al.  Stimulatory Cross-talk between NFAT3 and Estrogen Receptor in Breast Cancer Cells* , 2005, Journal of Biological Chemistry.

[23]  Zhijian J. Chen,et al.  Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Osamu Takeuchi,et al.  IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction , 2005, Nature Immunology.

[25]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[26]  Zhijian J. Chen,et al.  Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 , 2005, Cell.

[27]  Jidong Cheng,et al.  Recombinant HBsAg inhibits LPS-induced COX-2 expression and IL-18 production by interfering with the NFkappaB pathway in a human monocytic cell line, THP-1. , 2005, Journal of hepatology.

[28]  M. Gale,et al.  Evasion of intracellular host defence by hepatitis C virus , 2005, Nature.

[29]  E. Wanker,et al.  Parkin interacts with the proteasome subunit α4 , 2005 .

[30]  S. Lemon,et al.  Distinct Poly(I-C) and Virus-activated Signaling Pathways Leading to Interferon-β Production in Hepatocytes* , 2005, Journal of Biological Chemistry.

[31]  Tak W. Mak,et al.  Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors , 2005, Nature.

[32]  S. Lemon,et al.  Regulating Intracellular Antiviral Defense and Permissiveness to Hepatitis C Virus RNA Replication through a Cellular RNA Helicase, RIG-I , 2005, Journal of Virology.

[33]  S. Lemon,et al.  Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Stanley M Lemon,et al.  Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[35]  E. Wanker,et al.  Parkin interacts with the proteasome subunit alpha4. , 2005, FEBS letters.

[36]  Shizuo Akira,et al.  The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses , 2004, Nature Immunology.

[37]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[38]  G. Hu,et al.  HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice , 2004, Hepatology.

[39]  Stanley M. Lemon,et al.  Regulation of Interferon Regulatory Factor-3 by the Hepatitis C Virus Serine Protease , 2003, Science.

[40]  S. Murakami.  Hepatitis B virus X protein: a multifunctional viral regulator , 2001, Journal of Gastroenterology.

[41]  C. Yeh.  Hepatitis B virus X protein: Searching for a role in hepatocarcinogenesis , 2000 .

[42]  R. De Francesco,et al.  Structure and function of the hepatitis C virus NS3-NS4A serine proteinase. , 2000, Current topics in microbiology and immunology.

[43]  S. Murakami.  Hepatitis B Virus X Protein: Structure, Function and Biology , 1999, Intervirology.

[44]  G. Perini,et al.  The Hepatitis B pX Protein Promotes Dimerization and DNA Binding of Cellular Basic Region/Leucine Zipper Proteins by Targeting the Conserved Basic Region* , 1999, The Journal of Biological Chemistry.

[45]  M. Kew.  Increasing evidence that hepatitis B virus X gene protein and p53 protein may interact in the pathogenesis of hepatocellular carcinoma , 1997, Hepatology.

[46]  T. Liang,et al.  Proteasome complex as a potential cellular target of hepatitis B virus X protein , 1996, Journal of virology.

[47]  A. Siddiqui,et al.  Hepatitis B virus transactivator protein X interacts with the TATA-binding protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Elledge,et al.  Hepatitis B virus X protein interacts with a probable cellular DNA repair protein , 1995, Journal of virology.

[49]  C. Harris,et al.  Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  K. Koike,et al.  Interaction of hepatitis B virus X protein with a serine protease, tryptase TL2 as an inhibitor. , 1994, Oncogene.