title: Kaposi's sarcoma-associated herpesvirus-encoded vIRF-3 stimulates the transcriptional activity of cellular IRF-3 and IRF-7.
abstract: Kaposi's sarcoma-associated herpesvirus has been linked to Kaposi's sarcoma, body cavity-based lymphoma, and Castleman's disease. The Kaposi's sarcoma-associated herpesvirus genome contains a cluster of open reading frames encoding proteins (vIRFs) with homology to the cellular transcription factors of the interferon regulatory factor family. vIRF-3, also called LANA2, is a latently expressed nuclear protein. Here we demonstrate that vIRF-3 directly interacts with cellular interferon regulatory factor (IRF) IRF-3, IRF-7, and the transcriptional co-activator CBP/p300. The mapping of the vIRF-3 binding domain revealed that vIRF-3 associates with both IRF-3 and IRF-7 through its C-terminal region. The p300 domain, which interacts with vIRF-3, is distinct from the previously identified IBiD domain, to which both vIRF-1 and IRF-3 bind. Thus, in contrast to vIRF-1, vIRF-3 neither blocks the interaction between IRF-3 and p300 nor inhibits the histone acetylation. Although vIRF-3 is not a DNA-binding protein, it is recruited to the IFNA promoters via its interaction with IRF-3 and IRF-7. The presence of vIRF-3 in the enhanceosome assembled on the IFNA promoters increases binding of IRF-3, IRF-7, and acetylated histone H3 to this promoter region. Consequently, vIRF-3 stimulates the IRF-3- and IRF-7-mediated activation of type I interferon (IFNA and IFNB) genes and the synthesis of biologically active type I interferons in infected B cells. These studies illustrate that vIRF-3 and vIRF-1 have clearly distinct functions. In addition to its co-repressor activity, vIRF-3 can also act as a transcriptional activator on genes controlled by cellular IRF-3 and IRF-7.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Barbora
authors.initials: B
authors.lastname: Lubyova
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Kellum
authors.forename: Augusto J
authors.initials: AJ
authors.lastname: Frisancho
authors.forename: Paula M
authors.initials: PM
authors.lastname: Pitha
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D004347:Drug Interactions; D015870:Gene Expression; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007163:Immunosorbent Techniques; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D008223:Lymphoma; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D004247:DNA