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Journal of Virology, June 2001, p. 5119-5128, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5119-5128.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of Major Phosphorylation Sites of Epstein-Barr Virus Nuclear Antigen Leader Protein (EBNA-LP): Ability of EBNA-LP To Induce Latent Membrane Protein 1 Cooperatively with EBNA-2 Is Regulated by Phosphorylation†

Akihiko Yokoyama,1 Michiko Tanaka,1 Go Matsuda,1 Kentaro Kato,1 Mikiko Kanamori,1 Hiroshi Kawasaki,2 Hisashi Hirano,2 Issay Kitabayashi,3 Misao Ohki,3 Kanji Hirai,1,Dagger and Yasushi Kawaguchi1,*

Department of Tumor Virology, Division of Virology and Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510,1 Division of Plant Engineering, Kihara Institute for Biological Research, Yokohama City University, Totsuka-ku, Yokoyama 244,2 and Cancer Genomics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045,3 Japan

Received 27 November 2000/Accepted 1 March 2001

Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is a phosphoprotein suggested to play important roles in EBV-induced immortalization of B cells. One of the potential functions of EBNA-LP is a cooperative induction with EBNA-2 of viral and cellular gene expression, including that of the genes for viral latent membrane protein 1 (LMP-1) and cellular cyclin D2. We report here that the phosphorylation of EBNA-LP by cellular kinase(s) is critical to its ability to cooperate with EBNA-2 in up-regulating the expression of LMP-1 in a B-lymphoma cell line. Our conclusion is based on the following observations. (i) Mass-spectrometric analysis of purified EBNA-LP and mutational analyses of EBNA-LP revealed that the serine residue at position 35 in the W2 repeat domain is the major phosphorylation site of EBNA-LP in vivo. (ii) Substitutions of this site in each W2 repeat domain with alanine markedly reduced the ability of the protein to induce LMP-1 expression in combination with EBNA-2 in Akata cells. (iii) Replacement at the major phosphorylation sites with glutamic acids restored the wild-type phenotype. It is well established that this substitution mimics constitutive phosphorylation. These results indicated that the coactivator function of EBNA-LP is regulated by phosphorylation.

* Corresponding author. Mailing address: Department of Tumor Virology, Division of Virology and Immunology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Phone: 81-3-5803-5816. Fax: 81-3-5803-0241. E-mail: kawaguchi.creg{at}mri.tmd.ac.jp.

dagger This article is dedicated to the memory of Kanji Hirai.

Dagger Deceased.

Journal of Virology, June 2001, p. 5119-5128, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5119-5128.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.