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Journal of Virology, May 2009, p. 5219-5231, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02378-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Protein Array Identification of Substrates of the Epstein-Barr Virus Protein Kinase BGLF4{triangledown} ,{dagger}

Jian Zhu,1 Gangling Liao,3,4 Liang Shan,1 Jun Zhang,2 Mei-Ru Chen,5 Gary S. Hayward,1,3,4 S. Diane Hayward,1,3,4* Prashant Desai,3,4 and Heng Zhu1,2,4*

Department of Pharmacology and Molecular Sciences,1 High Throughput Biology Center,2 Department of Oncology, Johns Hopkins School of Medicine,3 Kimmel Cancer Center, Baltimore, Maryland 21231,4 Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan5

Received 17 November 2008/ Accepted 16 February 2009

A conserved family of herpesvirus protein kinases plays a crucial role in herpesvirus DNA replication and virion production. However, despite the fact that these kinases are potential therapeutic targets, no systematic studies have been performed to identify their substrates. We generated an Epstein-Barr virus (EBV) protein array to evaluate the targets of the EBV protein kinase BGLF4. Multiple proteins involved in EBV lytic DNA replication and virion assembly were identified as previously unrecognized substrates for BGLF4, illustrating the broad role played by this protein kinase. Approximately half of the BGLF4 targets were also in vitro substrates for the cellular kinase CDK1/cyclin B. Unexpectedly, EBNA1 was identified as a substrate and binding partner of BGLF4. EBNA1 is essential for replication and maintenance of the episomal EBV genome during latency. BGLF4 did not prevent EBNA1 binding to sites in the EBV latency origin of replication, oriP. Rather, we found that BGLF4 was recruited by EBNA1 to oriP in cells transfected with an oriP vector and BGLF4 and in lytically induced EBV-positive Akata cells. In cells transfected with an oriP vector, the presence of BGLF4 led to more rapid loss of the episomal DNA, and this was dependent on BGLF4 kinase activity. Similarly, expression of doxycycline-inducible BGLF4 in Akata cells led to a reduction in episomal EBV genomes. We propose that BGLF4 contributes to effective EBV lytic cycle progression, not only through phosphorylation of EBV lytic DNA replication and virion proteins, but also by interfering with the EBNA1 replication function.

* Corresponding author. Mailing address for H. Zhu: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, BRB 333, 733 N. Broadway Ave., Baltimore, MD 21205. Phone: (410) 502-0878. Fax: (410) 502-1872. E-mail: heng.zhu{at}jhmi.edu. Mailing address for S. D. Hayward: Department of Oncology, Johns Hopkins University School of Medicine, Bunting- Blaustein Building CRB308, 1650 Orleans Street, Baltimore, MD 21231-1000. Phone: (410) 955-2548. Fax: (410) 502-6802. E-mail: dhayward{at}jhmi.edu

{triangledown} Published ahead of print on 25 February 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, May 2009, p. 5219-5231, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02378-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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