Inhibition of nuclear factor κB activity by viral interferon regulatory factor 3 of Kaposi's sarcoma-associated herpesvirus

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