Inhibition of nuclear factor |[kappa]|B activity by viral interferon regulatory factor 3 of Kaposi's sarcoma-associated herpesvirus

摘要

Nuclear factor-B (NF-B) is a transcription factor that plays an important role in the immune system and cell death. Many viral proteins modulate NF-B to escape host immune surveillance, promote cell survival, and enhance viral replication. In the present study, we show that NF-B 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-B-dependent transcription in a dose-dependent manner and inhibited the activation of NF-B induced by tumor necrosis factor (TNF)-. In vivo studies showed vIRF3 inhibited IB kinase (IKK) activity, but not IKK activity, resulting in reduced IB phosphorylation. Immunofluorescence assays showed that vIRF3 interfered with nuclear translocation of NF-B. In addition, consistent with the inhibition of NF-B activity, vIRF3 sensitized cells to TNF--induced apoptosis. While vIRF3 interacts with IKK in vitro and in 293T cells, we were unable to demonstrate vIRF3–IKK interaction in BCBL-1 cells. Our results indicate that vIRF3 can regulate the host immune system and apoptosis via inhibition of NF-B activity.