The biochemistry of NF-κB activation. NF-κB is sequestered in the cytoplasm by the inhibitory IκB proteins. Stimulation by a diverse array of pathogens and other inducers including viruses, cytokines, and stress-inducing agents leads to the activation of signaling cascades that culminate with the activation of the IKK complex and phosphorylation of the IκB inhibitor. NF-κB DNA binding subunits are released and translocate to the nucleus where they transactivate NF-κB responsive genes containing the decameric sequence (5′-GGGRNNYYCC-3′). Target genes are selectively regulated by the distinct transcriptional activation potential of different NF-κB subunit combinations. TBP, TATA binding protein.

Proposed mechanisms of NF-κB activation in HIV-1–infected cells. Several mechanisms may regulate NF-κB activity in HIV-1–infected cells. Binding of HIV-1 to CD4 leads to NF-κB activation via Lck/Raf and PI-3K/Akt. CD4 crosslinking induces Ras activation, which also leads to NF-κB activation. PKR, induced by low level IFN and HIV-1 transcripts, may induce IKK activation. Autocrine release of cytokines such as TNF-α and IL-1 may constitutively stimulate the signaling pathways leading to NF-κB activation. Activation of the IKK complex either directly by HIV-1 regulatory proteins or by cytokine release leads to the phosphorylation and degradation of IκBα and IκBβ, thus releasing NF-κB to translocate to the nucleus and transactivate responsive genes. Newly synthesized IκBβ enters the nucleus and prevents IκBα-mediated termination of the NF-κB response, thus maintaining constitutive NF-κB activity at the protein-DNA level and creating an intracellular environment conducive to viral replication.

Modulation of the NF-κB pathway by viruses. Mechanisms of activation of the NF-κB pathway by HTLV-1–Tax protein include direct association of Tax and IKK-γ or latent NF-κB/IκBα complexes. EBV LMP1–mediated signaling results in the recruitment of TRADD, which interacts with TRAF2 and RIP kinase to activate NF-κB. TRAF2 potentially activates NIK and MEKK1, which phosphorylate and activate the IKK complex. Other mechanisms of activation of the NF-κB pathway by viruses include direct activation of MEKK1 and PKC by HBx protein from HBV, persistent degradation of IκBα by SV, ER overload by influenza and adenovirus, and generation of reactive oxygen intermediates by influenza virus. NF-κB activation is inhibited at either the IKK activation step by E1A of adenovirus or at the IκBα degradation step by MV and HCV core C protein. Lines in green with a + indicate activation of NF-κB, while lines in red with a – indicate inhibition of NF-κB.