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Molecular and Cellular Biology, November 2000, p. 8254-8263, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Inhibition of p300 Histone Acetyltransferase by Viral Interferon Regulatory Factor

M. Li,1 B. Damania,1 X. Alvarez,2 V. Ogryzko,3 K. Ozato,3 and J. U. Jung1,*

Department of Microbiology and Molecular Genetics1 and Department of Pathology,2 New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, and Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, Bethesda, Maryland 208923

Received 14 March 2000/Returned for modification 11 May 2000/Accepted 8 August 2000

Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcomas, body cavity-based lymphomas, and some forms of Castleman's disease. The K9 open reading frame of KSHV encodes a viral interferon regulatory factor (vIRF) which functions as a repressor for cellular interferon-mediated signal transduction and as an oncogene to induce cell growth transformation. We demonstrate that KSHV vIRF directly interacts with cellular transcriptional coactivator p300 and displaces p300/CBP-associated factor from p300 complexes. This interaction inhibits the histone acetyltransferase activity of p300, resulting in drastic reduction of nucleosomal histone acetylation and alteration of chromatin structure. As a consequence, vIRF expression markedly alters cellular cytokine expression, which is regulated by acetylation of nucleosomal histones. These results demonstrate that KSHV vIRF interacts with and inhibits the p300 transcriptional coactivator to circumvent the host antiviral immune response and to induce a global alteration of cellular gene expression. These studies also illustrate how a cellular gene captured by a herpesvirus has evolved several functions that suit the needs of the virus.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, 1 Pine Hill Dr., Southborough, MA 01772. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: jae_jung{at}hms.harvard.edu.

Molecular and Cellular Biology, November 2000, p. 8254-8263, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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