Inhibition of p300 histone acetyltransferase by viral interferon regulatory factor.
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.
Li
M
M
Department of Microbiology and Molecular Genetics, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA.
Damania
B
B
Alvarez
X
X
Ogryzko
V
V
Ozato
K
K
Jung
J U
JU
D016475:3T3 Cells; D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006657:Histones / Q000378:metabolism; D007313:Insecta; D050835:Interferon Regulatory Factors; D051379:Mice; D018613:Microscopy, Confocal; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009707:Nucleosomes / Q000378:metabolism; D016366:Open Reading Frames; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014764:Viral Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D002843:Chromatin; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D050835:Interferon Regulatory Factors; D009707:Nucleosomes; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C413486:viral interferon regulatory factors