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J. Biol. Chem., Vol. 280, Issue 30, 27742-27754, July 29, 2005

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Novel Autoregulatory Function of Hepatitis B Virus M Protein on Surface Gene Expression^*

Tsurng-Juhn Huang, Cheng-Chan Lu¶||, Jui-Chen Tsai****, Wei-Jen Yao, Xuanyong Lu****, Ming-Derg Lai¶¶, Hsiao-Sheng Liu||||, and Ai-Li Shiau||||

From the Institute of Basic Medical Sciences, the Departments of Pathology, Nuclear Medicine, ^¶¶Biochemistry and Molecular Biology, and ^||||Microbiology and Immunology, the ^¶Center for Biosciences and Biotechnology, and the ^**Institute of Clinical Pharmacy, Medical College, National Cheng Kung University, Tainan 70428, Taiwan and the Viral Hepatitis Groups, Department of Microbiology and Immunology, Jefferson Medical College, Philadelphia, Pennsylvania 19107

The hepatitis B virus surface gene consists of a single open reading frame divided into three coding regions: pre-S1, pre-S2, and S. By alternate translation at each of the three initiation codons, L, M, and S proteins can be synthesized. Studies have shown that M protein is not essential for viral replication, virion morphogenesis, or in vitro infectivity. In this study, we show that native M protein can regulate surface gene expression at the transcriptional level. The regulatory effect of M protein is mediated through the CCAAT box within the S promoter. Deletion mapping analysis indicated that the transactivating effect of M protein is mediated through amino acids 1–57 of M protein (the MHBs^au domain), although its maximal transactivation activity coincides with that of the pre-S2 domain. This conclusion is supported by the fact that disruption of the putative V8 protease site at the pre-S2/S domain junction not only rendered M protein incapable of transactivating the S promoter but also inactivated its nuclear translocation potential. Immunoprecipitation and immunoblot experiments demonstrated that pre-S2 interacts with the three subunits of the CCAAT box-binding factor/nuclear factor Y, the cognate binding protein of the CCAAT box. These results demonstrate and define a novel regulatory role of M protein, which, under natural conditions, may undergo a proteolytic process to generate an MHBs^au species that will be translocated inside the nucleus, where it will interact with the CCAAT box-binding factor to regulate surface gene expression. Because the CCAAT box is located at a fixed position within numerous promoters, these observations might provide a plausible explanation for hepatitis B virus-associated hepatocarcinogenesis.

Received for publication, February 28, 2005 , and in revised form, May 16, 2005.

^* This work was supported by Grants 93-B-FA09-1-4 and NSC93-2320-B-006-078 from the Taiwan Ministry of Education Program for Promoting Academic Excellence in Universities (to C.-C. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Present address: Dept. of Microbiology and Immunology, School of Medicine, Drexel University, Doylestown, PA 18901.

^|| To whom correspondence should be addressed: Dept. of Pathology, Medical College, National Cheng Kung University, 138 Sheng-Li Rd., Tainan 70428, Taiwan. Tel.: 886-6-235-3535 (ext. 2641); Fax: 886-6-276-6195; E-mail: cclu{at}mail.ncku.edu.tw.

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