Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta Interferon

January 10, 2011

Journal of Virology, January 2011, p. 987-995, Vol. 85, No. 2

0022-538X/11/$012.00+0 doi:10.1128/JVI.01825-10

Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and

Inhibits the Activation of Beta Interferon

Manish Kumar,1, Sung Yun Jung,2, J. Hodgson,1 R. Madden,1, Jun

Qin,2 and Betty L. Slagle1*

Departments of Molecular Virology and Microbiology,1 Verna and Marrs McLean

Department of Biochemistry and Molecular Biology, Baylor College of Medicine,

Houston, Texas 770302

Received 27 August 2010/ Accepted 3 November 2010

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-â). 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-â signaling was tested in transfected 293T and HepG2 cells,

and we show that HBx inhibits double-stranded DNA (dsDNA)-mediated IFN-â

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-â 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.

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* Corresponding author. Mailing address: One Baylor Plaza, MS-385, Houston, TX

77030. Phone: (713) 798-3006. Fax: (713) 798-5075. E-mail: bslagle@...

Published ahead of print on 10 November 2010.

M.K. and S.Y.J. contributed equally to this report.

Present address: Department of Biology, Mason University, Fairfax, VA.

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