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Journal of Virology, July 2004, p. 7634-7644, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7634-7644.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Epstein-Barr Virus ZEBRA Protein at Its Casein Kinase 2 Sites Mediates Its Ability To Repress Activation of a Viral Lytic Cycle Late Gene by Rta

Ayman S. El-Guindy1 and George Miller1,2,3*

Departments of Molecular Biophysics and Biochemistry,1 Pediatrics,2 Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 065203

Received 2 February 2004/ Accepted 16 March 2004

ZEBRA, a member of the bZIP family, serves as a master switch between latent and lytic cycle Epstein-Barr virus (EBV) gene expression. ZEBRA influences the activity of another viral transactivator, Rta, in a gene-specific manner. Some early lytic cycle genes, such as BMRF1, are activated in synergy by ZEBRA and Rta. However, ZEBRA suppresses Rta's ability to activate a late gene, BLRF2. Here we show that this repressive activity is dependent on the phosphorylation state of ZEBRA. We find that two residues of ZEBRA, S167 and S173, that are phosphorylated by casein kinase 2 (CK2) in vitro are also phosphorylated in vivo. Inhibition of ZEBRA phosphorylation at the CK2 substrate motif, either by serine-to-alanine substitutions or by use of a specific inhibitor of CK2, abolished ZEBRA's capacity to repress Rta activation of the BLRF2 gene, but did not alter its ability to initiate the lytic cycle or to synergize with Rta in activation of the BMRF1 early-lytic-cycle gene. These studies illustrate how the phosphorylation state of a transcriptional activator can modulate its behavior as an activator or repressor of gene expression. Phosphorylation of ZEBRA at its CK2 sites is likely to play an essential role in proper temporal control of the EBV lytic life cycle.

* Corresponding author. Mailing address: Yale University School of Medicine, Department of Pediatrics, Room 420, LSOG, 333 Cedar St., P.O. Box 208064, New Haven, CT 06520-8064. Phone: (203) 785-4758. Fax: (203) 785-6961. E-mail: George.Miller{at}yale.edu.

Journal of Virology, July 2004, p. 7634-7644, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7634-7644.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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