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Journal of Virology, June 2006, p. 5273-5282, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02541-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acetylation of the Latency-Associated Nuclear Antigen Regulates Repression of Kaposi's Sarcoma-Associated Herpesvirus Lytic Transcription

Fang Lu,1 Latasha Day,1 S.-J. Gao,2 and Paul M. Lieberman*

The Wistar Institute, Philadelphia, Pennsylvania 19104,1 University of Texas Health Science Center at San Antonio, San Antonio, Texas 782292

Received 5 December 2005/ Accepted 15 March 2006

Reactivation of the Kaposi's sarcoma-associated herpesvirus (KSHV) lytic cycle can be initiated by transcription activation of the ORF50 immediate early gene (Rta). We show that ORF50 transcription is actively repressed by the KSHV latency-associated nuclear antigen (LANA) during latency. Depletion of LANA by small interfering RNA derepressed ORF50 transcription in the latently infected BCBL1 pleural effusion lymphoma-derived cell line. In contrast, overexpression of LANA suppressed ORF50 mRNA levels in BCBL1 cells. ORF50 transcription was significantly elevated during primary infection with recombinant virus lacking LANA, further indicating that LANA plays a role in lytic gene silencing during the establishment of latency. Chromatin immunoprecipitation assays indicated that LANA interacts with the ORF50 promoter region in latently infected cells. Histone deacetylase inhibitors, including sodium butyrate (NaB) and trichostatin A, caused the rapid dissociation of LANA from the ORF50 promoter. NaB treatment of latently infected BCBL1 cells disrupted a stable interaction between LANA and the cellular proteins Sp1 and histone H2B. We also found immunological and radiochemical evidence that LANA is subject to lysine acetylation after NaB treatment. These findings support the role of LANA as a transcriptional repressor of lytic reactivation and provide evidence that lysine acetylation regulates LANA interactions with chromatin, Sp1, and ORF50 promoter DNA.

* Corresponding author. Mailing address: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104. Phone: (215) 898-9491. Fax: (215) 898-0663. E-mail: lieberman{at}wistar.org.

Journal of Virology, June 2006, p. 5273-5282, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02541-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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