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Journal of Virology, August 2005, p. 9810-9820, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9810-9820.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis B Virus DNA Replication Is Coordinated by Core Protein Serine Phosphorylation and HBx Expression

Margherita Melegari,{dagger} Sarah K. Wolf, and Robert J. Schneider*

Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, New York 10016

Received 9 December 2004/ Accepted 4 April 2005

The hepatitis B virus (HBV) core protein forms the capsid of viral particles and is essential for viral genome DNA replication and maturation. The C terminus of core protein contains three serines at positions 155, 162, and 170, phosphorylation of which is important for viral DNA replication. We demonstrate that the phosphorylation of these serines is stimulated by the viral HBx protein, a regulatory protein that activates signal transduction pathways and viral replication. HBx is therefore shown to stimulate HBV replication by increasing core serine phosphorylation. Mutational, biochemical, and mixing studies of C-terminal core serine mutants demonstrate that multiple serine phosphorylations occur on the same core protein. Mutation of individual core protein serines is shown to inhibit HBV replication at distinct stages corresponding to encapsidation of viral pregenomic RNA, reverse transcription, and restriction to synthesis of specific DNA replicative intermediates. We therefore demonstrate that a primary target of HBV replication that is regulated by HBx protein corresponds to increased phosphorylation of the viral core protein. We also demonstrate that core phosphorylation mediated by HBx promotes sequential progression of viral replication through the assembly of capsids primed for different stages of DNA synthesis.

* Corresponding author. Mailing address: Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: (212) 263-6006. Fax: (212) 263-8276. E-mail: schner01{at}med.nyu.edu.

{dagger} Present address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.

Journal of Virology, August 2005, p. 9810-9820, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9810-9820.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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