Inhibition of p300 histone acetyltransferase by viral interferon regulatory factor

Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identi fied in Kaposi's sarcomas, body cavity-based lymphomas, and some forms of C astleman's disease. The K9 open reading frame of KSHV encodes a viral inter feron regulatory factor (vIRF) which functions as a repressor far cellular interferon-mediated signal transduction and as an oncogene to induce cell g ran th transformation. We demonstrate that KSHV vIRF directly interacts wit h cellular transcriptional coactivator p300 and displaces p300/CBP-associat ed factor from p300 complexes. This interaction inhibits the histone acetyl transferase activity of p300, resulting in drastic reduction of nucleosomal histone acetylation and alteration of chromatin structure. As a consequenc e, vIRF expression markedly alters cellular cytokine expression, which is r egulated by acetylation of nucleosomal histones. These results demonstrate that KSHV vIRF interacts with and inhibits the p300 transcriptional coactiv ator to circumvent the host antiviral immune response and to induce a globa l alteration of cellular gene expression. These studies also illustrate how a cellular gene captured by a herpesvirus has evolved several functions th at suit the needs of the virus.