Inhibition of nuclear factor kappaB activity by viral interferon regulatory factor 3 of Kaposi's sarcoma-associated herpesvirus.
Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays an important role in the immune system and cell death. Many viral proteins modulate NF-kappaB to escape host immune surveillance, promote cell survival, and enhance viral replication. In the present study, we show that NF-kappaB activity is downmodulated by viral interferon regulatory factor 3 (vIRF3), which is encoded by Kaposi's sarcoma-associated herpesvirus open-reading frame K10.5. vIRF3 repressed NF-kappaB-dependent transcription in a dose-dependent manner and inhibited the activation of NF-kappaB induced by tumor necrosis factor (TNF)-alpha. In vivo studies showed vIRF3 inhibited IkappaB kinase beta (IKKbeta) activity, but not IKKalpha activity, resulting in reduced IkappaB phosphorylation. Immunofluorescence assays showed that vIRF3 interfered with nuclear translocation of NF-kappaB. In addition, consistent with the inhibition of NF-kappaB activity, vIRF3 sensitized cells to TNF-alpha-induced apoptosis. While vIRF3 interacts with IKKbeta in vitro and in 293T cells, we were unable to demonstrate vIRF3-IKKbeta interaction in BCBL-1 cells. Our results indicate that vIRF3 can regulate the host immune system and apoptosis via inhibition of NF-kappaB activity.
Seo
Taegun
T
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Park
Junsoo
J
Lim
Chunghun
C
Choe
Joonho
J
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D019288:Herpesvirus 8, Human; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D050835:Interferon Regulatory Factors; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014764:Viral Proteins
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human