Abstract
Kaposi's sarcoma-associated herpesvirus encodes four genes with homology to the family of interferon regulatory factors (IRFs). At least one of these viral IRFs, vIRF-3, is expressed in latently Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma (PEL) cells and is essential for the survival of PEL cells. We now report that vIRF-3 interacts with cellular IRF-5, thereby inhibiting binding of IRF-5 to interferon-responsive promoter elements. Consequently, vIRF-3 blocked IRF-5-mediated promoter activation. A central double helix motif present in vIRF-3 was sufficient to abrogate both DNA binding and transcriptional transactivation by IRF-5. Upon DNA damage or activation of the interferon or Toll-like receptor pathways, cytoplasmic IRF-5 has been reported to be translocated to the nucleus, which results in induction of both p53-independent apoptosis and p21-mediated cell cycle arrest. We report here that IRF-5 is present in the nuclei of PEL cells without interferon stimulation. Silencing of vIRF-3 expression in PEL cells was accompanied by increased sensitivity to interferon-mediated apoptosis and up-regulation of IRF-5 target genes. In addition, vIRF-3 antagonized IRF-5-mediated activation of the p21 promoter. The data presented here indicate that vIRF-3 contributes to immune evasion and sustained proliferation of PEL cells by releasing IRF-5 from transcription complexes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Active Transport, Cell Nucleus / immunology
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Amino Acid Motifs / genetics
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Amino Acid Motifs / immunology
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Apoptosis / genetics
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Apoptosis / immunology
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Cell Nucleus / genetics
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Cell Nucleus / immunology
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Cell Nucleus / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / immunology
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Gene Silencing
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Herpesvirus 8, Human / genetics
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Herpesvirus 8, Human / immunology
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Herpesvirus 8, Human / metabolism*
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Humans
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / immunology
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Interferon Regulatory Factors / metabolism*
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Lymphoma, Primary Effusion / genetics
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Lymphoma, Primary Effusion / immunology
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Lymphoma, Primary Effusion / metabolism
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Protein Binding / genetics
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Protein Binding / immunology
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Receptors, Interferon / genetics
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Receptors, Interferon / immunology
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Receptors, Interferon / metabolism
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Response Elements*
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Sarcoma, Kaposi / genetics
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Sarcoma, Kaposi / immunology
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Sarcoma, Kaposi / metabolism
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Toll-Like Receptors / genetics
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism
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Transcriptional Activation / genetics
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Transcriptional Activation / immunology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / immunology
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation / genetics
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Up-Regulation / immunology
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Viral Proteins / genetics
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Viral Proteins / immunology
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Viral Proteins / metabolism*
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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IRF5 protein, human
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Interferon Regulatory Factors
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Receptors, Interferon
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TP53 protein, human
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Toll-Like Receptors
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Tumor Suppressor Protein p53
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Viral Proteins
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viral interferon regulatory factors