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Journal of Virology, February 2003, p. 2359-2368, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2359-2368.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Conserved Protein Kinases Encoded by Herpesviruses and Cellular Protein Kinase cdc2 Target the Same Phosphorylation Site in Eukaryotic Elongation Factor 1{delta}

Yasushi Kawaguchi,1,2,3* Kentaro Kato,1 Michiko Tanaka,1 Mikiko Kanamori,1 Yukihiro Nishiyama,2 and Yuji Yamanashi1

Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510,1 Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya, 466-8550,2 PRESTO, Japan Science and Technology Corporation, Tachikawa, Tokyo 190-0012, Japan3

Received 7 August 2002/ Accepted 15 November 2002

Earlier studies have shown that translation elongation factor 1{delta} (EF-1{delta}) is hyperphosphorylated in various mammalian cells infected with representative alpha-, beta-, and gammaherpesviruses and that the modification is mediated by conserved viral protein kinases encoded by herpesviruses, including UL13 of herpes simplex virus type 1 (HSV-1), UL97 of human cytomegalovirus, and BGLF4 of Epstein-Barr virus (EBV). In the present study, we attempted to identify the site in EF-1{delta} associated with the hyperphosphorylation by the herpesvirus protein kinases. Our results are as follows: (i) not only in infected cells but also in uninfected cells, replacement of the serine residue at position 133 (Ser-133) of EF-1{delta} by alanine precluded the posttranslational processing of EF-1{delta}, which corresponds to the hyperphosphorylation. (ii) A purified chimeric protein consisting of maltose binding protein (MBP) fused to a domain of EF-1{delta} containing Ser-133 (MBP-EFWt) is specifically phosphorylated in in vitro kinase assays by purified recombinant UL13 fused to glutathione S-transferase (GST) expressed in the baculovirus system. In contrast, the level of phosphorylation by the recombinant UL13 of MBP-EFWt carrying an alanine replacement of Ser-133 (MBP-EFS133A) was greatly impaired. (iii) MBP-EFWt is also specifically phosphorylated in vitro by purified recombinant BGLF4 fused to GST expressed in the baculovirus system, and the level of phosphorylation of MBP-EFS133A by the recombinant BGLF4 was greatly reduced. (iv) The sequence flanking Ser-133 of EF-1{delta} completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates Ser-133 of EF-1{delta}. (v) As observed with EF-1{delta}, the casein kinase II ß subunit (CKIIß) was specifically phosphorylated by UL13 in vitro, while the level of phosphorylation of CKIIß by UL13 was greatly diminished when a serine residue at position 209, which has been reported to be phosphorylated by cdc2, was replaced with alanine. These results indicate that the conserved protein kinases encoded by herpesviruses and a cellular protein kinase, cdc2, have the ability to target the same amino acid residues for phosphorylation. Our results raise the possibility that the viral protein kinases mimic cdc2 in infected cells.

* Corresponding author. Mailing address: Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2451. Fax: 81-52-722-2452. E-mail: ykawagu{at}med.nagoya-u.ac.jp.

Journal of Virology, February 2003, p. 2359-2368, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2359-2368.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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