Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon.
Hepatitis B virus (HBV) encodes the regulatory HBx protein, which is required for virus replication, although its specific role(s) in the replication cycle remains under investigation. An immunoprecipitation/mass spectrometry approach was used to identify four novel HBx binding proteins from the cytoplasmic fraction of HBx transgenic mouse livers. One of these HBx binding partners is beta interferon promoter stimulator 1 (IPS-1), an adaptor protein that plays a critical role in mediating retinoic acid-inducible gene I (RIG-I) signaling, which leads to the activation of beta interferon (IFN-β). The HBx-IPS-1 protein interaction was confirmed in plasmid-transfected HepG2 cells by reciprocal coimmunoprecipitation and Western blotting. We hypothesized that HBx might alter IPS-1 function since proteins of hepatitis C virus and hepatitis A virus similarly bind IPS-1 and target it for inactivation. The effect of HBx on IPS-1-mediated IFN-β signaling was tested in transfected 293T and HepG2 cells, and we show that HBx inhibits double-stranded DNA (dsDNA)-mediated IFN-β activation in a dose-dependent manner when expressed either alone or within the context of HBV replication. However, HBx does not inhibit poly(I:C)-activated IFN-β signaling. These results demonstrate that HBx interferes with the RIG-I pathway of innate immunity. Hepatitis B virus now joins hepatitis C virus and hepatitis A virus in targeting the same innate immune response pathway, presumably as a shared strategy to benefit replication of these viruses in the liver.
Department of Molecular Virology, Baylor College of Medicine, Houston, Texas 77030, USA.
Manish
M
Kumar
Sung Yun
SY
Jung
Amanda J
AJ
Hodgson
Charles R
CR
Madden
Jun
J
Qin
Betty L
BL
Slagle
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006515:Hepatitis B virus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D047468:Immunoprecipitation; D016899:Interferon-beta / Q000037:antagonists & inhibitors*; D008099:Liver / Q000821:virology; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D048868:Adaptor Proteins, Signal Transducing; D016899:Interferon-beta; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C057628:hepatitis B virus X protein