The Kaposi's Sarcoma-associated Herpesvirus-encoded vIRF-3 Inhibits Cellular IRF-5.
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.
Wies
Effi
E
Virologisches Institut, Universitätsklinikum Erlangen, D-91054 Erlangen, Germany.
Hahn
Alexander S
AS
Schmidt
Katharina
K
Viebahn
Cornelia
C
Rohland
Nadine
N
Lux
Anja
A
Schellhorn
Tim
T
Holzer
Angela
A
Jung
Jae U
JU
Neipel
Frank
F
D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020868:Gene Silencing; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054685:Lymphoma, Primary Effusion / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020218:Response Elements; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D017471:Receptors, Interferon; C495901:TP53 protein, human; D051193:Toll-Like Receptors; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C413486:viral interferon regulatory factors