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Journal of Virology, September 2000, p. 8532-8540, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Carboxy Terminus of Human Herpesvirus 8 Latency-Associated Nuclear Antigen Mediates Dimerization, Transcriptional Repression, and Targeting to Nuclear Bodies

David R. Schwam, Randy L. Luciano, Shahana S. Mahajan, LaiYee Wong, and Angus C. Wilson*

Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016

Received 14 February 2000/Accepted 21 June 2000

Human herpesvirus 8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) is the causative agent of Kaposi's sarcoma and certain B-cell lymphomas. In most infected cells, HHV-8 establishes a latent infection characterized by the expression of latency-associated nuclear antigen (LANA) encoded by open reading frame 73. Although unrelated by sequence, there are functional similarities between LANA and the EBNA-1 protein of Epstein-Barr virus. Both accumulate as subnuclear speckles and are required for maintenance of the viral episome. EBNA-1 also regulates viral gene expression and is required for cell immortalization, suggesting that LANA performs similar functions in the context of HHV-8 infection. Here we show that LANA forms stable dimers, or possibly higher-order multimers, and that this is mediated by a conserved region in the C terminus. By expressing a series of truncations, we show that both the N- and C-terminal regions localize to the nucleus, although only the C terminus accumulates as nuclear speckles characteristic of the intact protein. Lastly, we show that LANA can function as a potent transcriptional repressor when tethered to constitutively active promoters via a heterologous DNA-binding domain. Domains in both the N and C termini mediate repression. This suggests that one function of LANA is to suppress the expression of the viral lytic genes or cellular genes involved in the antiviral response.

* Corresponding author. Mailing address: NYU School of Medicine, Department of Microbiology, 550 First Ave., New York, NY 10016. Phone: (212) 263-0206. Fax: (212) 263-8276. E-mail: wilsoa02{at}med.nyu.edu.

Journal of Virology, September 2000, p. 8532-8540, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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