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J. Biol. Chem., Vol. 280, Issue 32, 29135-29143, August 12, 2005

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Varicella-Zoster Virus IE63 Protein Phosphorylation by Roscovitine-sensitive Cyclin-dependent Kinases Modulates Its Cellular Localization and Activity^*

Lionel Habran, Sébastien Bontems, Emmanuel Di Valentin, Catherine Sadzot-Delvaux, and Jacques Piette, Research Director for the National Fund for Scientific Research¶

From the Laboratory of Virology and Immunology, Center for Biomedical Genoproteomics, Institute of Pathology B23, University of Liège, B-4000, Liège, Belgium

During the first stage of Varicella-Zoster virus (VZV) infection, IE63 (immediate early 63 protein) is mostly expressed in the nucleus and also slightly in the cytoplasm, and during latency, IE63 localizes in the cytoplasm quite exclusively. Because phosphorylation is known to regulate various cellular mechanisms, we investigated the impact of phosphorylation by roscovitine-sensitive cyclin-dependent kinase (RSC) on the localization and functional properties of IE63. We demonstrated first that IE63 was phosphorylated on Ser-224 in vitro by CDK1 and CDK5 but not by CDK2, CDK7, or CDK9. Furthermore, by using roscovitine and CDK1 inhibitor III (CiIII), we showed that CDK1 phosphorylated IE63 on Ser-224 in vivo. By mutagenesis and the use of inhibitors, we demonstrated that phosphorylation on Ser-224 was important for the correct localization of the protein. Indeed, the substitution of these residues by alanine led to an exclusive nuclear localization of the protein, whereas mutations into glutamic acid did not modify its subcellular distribution. When transfected or VZV-infected cells were treated with roscovitine or CiIII, an exclusive nuclear localization of IE63 was also observed. By using a transfection assay, we also showed that phosphorylation on Ser-224 and Thr-222 was essential for the down-regulation of the basal activity of the VZV DNA polymerase gene promoter. Similarly, roscovitine and CiIII impaired these properties of the wild-type form of IE63. These observations clearly demonstrated the importance of CDK1-mediated IE63 phosphorylation for a correct distribution of IE63 between both cellular compartments and for its repressive activity toward the promoter tested.

Received for publication, March 25, 2005 , and in revised form, June 2, 2005.

^* This work was supported in part by a research grant from the Belgian National Fund for Scientific Research (Brussels, Belgium). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the National Fund for Scientific Research (Brussels, Belgium).

Supported by a Télévie Grant.

^¶ To whom correspondence should be addressed: Laboratory of Virology and Immunology, Institute of Pathology B23, University of Liège, B-4000 Liège, Belgium. Tel.: 32-4-366-2442; Fax: 32-4-366-9933; E-mail: jpiette{at}ulg.ac.be.

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