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Journal of Virology, August 2002, p. 8124-8137, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8124-8137.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of SRPK1 and SRPK2 as the Major Cellular Protein Kinases Phosphorylating Hepatitis B Virus Core Protein

Henrik Daub,1* Stephanie Blencke,1 Peter Habenberger,1 Alexander Kurtenbach,1 Julia Dennenmoser,1 Josef Wissing,2 Axel Ullrich,3 and Matt Cotten1

Axxima Pharmaceuticals AG,1 Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried,3 Department of Biochemistry, Technical University of Braunschweig, 38124 Braunschweig, Germany2

Received 1 February 2002/ Accepted 3 May 2002

Phosphorylation of hepatitis B virus (HBV) core protein has recently been shown to be a prerequisite for pregenomic RNA encapsidation into viral capsids, but the host cell kinases mediating this essential step of the HBV replication cycle have not been identified. We detected two kinases of 95 and 115 kDa in HuH-7 total cell lysates which interacted specifically with the HBV core protein and phosphorylated its arginine-rich C-terminal domain. The 95-kDa kinase was purified and characterized as SR protein-specific kinase 1 (SRPK1) by mass spectrometry. Based on this finding, the 115-kDa kinase could be identified as the related kinase SRPK2 by immunoblot analysis. In vitro, both SRPKs phosphorylated HBV core protein on the same serine residues which are found to be phosphorylated in vivo. Moreover, the major cellular HBV core kinase activity detected in the total cell lysate showed biochemical properties identical to those of SRPK1 and SRPK2, as examined by measuring binding to a panel of chromatography media. We also clearly demonstrate that neither the cyclin-dependent kinases Cdc2 and Cdk2 nor protein kinase C, previously implicated in HBV core protein phosphorylation, can account for the HBV core protein kinase activity. We conclude that both SRPK1 and SRPK2 are most likely the cellular protein kinases mediating HBV core protein phosphorylation during viral infection and therefore represent important host cell targets for therapeutic intervention in HBV infection.

* Corresponding author. Mailing address: Axxima Pharmaceuticals AG, Am Klopferspitz 19, 82152 Martinsried, Germany. Phone: 49 89 740 165 61. Fax: 49 89 740 165 425. E-mail: daub{at}axxima.com.

Journal of Virology, August 2002, p. 8124-8137, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8124-8137.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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