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Journal of Virology, November 2007, p. 11850-11860, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.01421-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Protein Kinase CK2 Phosphorylation of EB2 Regulates Its Function in the Production of Epstein-Barr Virus Infectious Viral Particles

INSERM U758, 46 allée d'Italie, 69364 Lyon Cedex 07, France,¹ ENSLyon, 46 allée d'Italie, 69364 Lyon Cedex 07, France,² IFR 128 BioSciences Gerland-Lyon Sud, 21 avenue Tony Garnier, 69365 Lyon Cedex 07, France,³ INSERM U873, IRTSV, CEA, 38054 Grenoble, France,⁴ INSERM U837, Centre Jean Pierre Aubert, 1 Place de Verdun, 59045 Lille Cedex, France,⁵ Université Lille 2, Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Centre Jean-Pierre Aubert, 1 Place de Verdun, 59045 Lille, France,⁶ CNRS UMR 8161, Institut Pasteur, 1 rue du Professeur Calmette, 59031 Lille Cedex, France⁷

Received 29 June 2007/ Accepted 7 August 2007

The Epstein-Barr Virus (EBV) early protein EB2 (also called BMLF1, Mta, or SM) promotes the nuclear export of a subset of early and late viral mRNAs and is essential for the production of infectious virions. We show here that in vitro, protein kinase CK2 and -ß subunits bind both individually and, more efficiently, as a complex to the EB2 N terminus and that the CK2ß regulatory subunit also interacts with the EB2 C terminus. Immunoprecipitated EB2 has CK2 activity that phosphorylates several sites within the 80 N-terminal amino acids of EB2, including Ser-55, -56, and -57, which are localized next to the nuclear export signal. EB2S3E, the phosphorylation-mimicking mutant of EB2 at these three serines, but not the phosphorylation ablation mutant EB2S3A, efficiently rescued the production of infectious EBV particles by HEK293_BMLF1-KO cells harboring an EB2-defective EBV genome. The defect of EB2S3A in transcomplementing 293_BMLF1-KO cells was not due to impaired nucleocytoplasmic shuttling of the mutated protein but was associated with a decrease in the cytoplasmic accumulation of several late viral mRNAs. Thus, EB2-mediated production of infectious EBV virions is regulated by CK2 phosphorylation at one or more of the serine residues Ser-55, -56, and -57.

Published ahead of print on 15 August 2007.