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Journal of Virology, July 2003, p. 8019-8030, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.8019-8030.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Manipulates the Activity of Glycogen Synthase Kinase-3ß

Masahiro Fujimuro and S. Diane Hayward*

Viral Oncology Program, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21231

Received 28 January 2003/ Accepted 22 April 2003

The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is expressed in all KSHV-associated malignancies. LANA is essential for replication and maintenance of the viral episomes during latent infection. However, LANA also has a transcriptional regulatory role and can affect gene expression both positively and negatively. A previously performed yeast two-hybrid screen identified glycogen synthase kinase 3 (GSK-3) as a LANA-interacting protein. Interaction with both GSK-3{alpha} and GSK-3ß was confirmed in transfected cells with coprecipitation assays. GSK-3ß also interacted with the herpesvirus saimiri homolog ORF73. GSK-3ß is an intermediate in the Wnt signaling pathway and a negative regulator of ß-catenin. In transfected cells, LANA was shown to overcome GSK-3ß-mediated degradation of ß-catenin. Examination of primary effusion lymphoma (PEL) cells found increased levels of ß-catenin relative to KSHV-negative B cells, and this translated into increased activity of a ß-catenin-responsive reporter containing Tcf/Lef binding sites. In tetradecanoyl phorbol acetate-treated PEL cells, loss of LANA expression correlated temporally with loss of detectable ß-catenin. LANA was found to alter the intracellular distribution of GSK-3ß so that nuclear GSK-3ß was more readily detectable in the presence of LANA. Mapping experiments with coimmunoprecipitation assays revealed that both N-terminal and C-terminal LANA sequences were required for efficient GSK-3ß interaction. LANA mutants that were defective for GSK-3ß interaction were unable to mediate GSK-3ß relocalization or activate a ß-catenin-responsive Tcf-luciferase reporter. This study identified manipulation of GSK-3ß activity as a mechanism by which LANA may modify transcriptional activity and contribute to the phenotype of primary effusion lymphoma.

* Corresponding author. Mailing address: Viral Oncology Program, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 614-0592. Fax: (410) 502-6802. E-mail: dhayward{at}jhmi.edu.

Journal of Virology, July 2003, p. 8019-8030, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.8019-8030.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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