Inhibition of p300 Histone Acetyltransferase by Viral Interferon Regulatory Factor

Abstract

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.

ACKNOWLEDGMENTS

We thank R. Desrosiers, K. Williams, B. Means, and L. Alexander for critical reading of the manuscript. We also thank B. Roy for manuscript preparation, K. Toohey for photography support, and M. DeMaria for flow cytometry analysis.

This work was supported by U.S. Public Health Service grants CA31363, CA82057, CA86841, AI38131, and RR00168 and ACS grant RPG001102. Jae Jung is a Leukemia and Lymphoma Society Scholar, and B. Damania is a fellow of the Cancer Research Institute.