NF-κB in defense and disease serine residues. Phosphorylated IκBα is then ubiquitinated, which targets it for degradation by the 26S proteasome (13), thereby releasing NF-κB dimers from the cytoplasmic NF-κB–IκB complex and allowing them to translocate to the nucleus. NF-κB then binds to κB enhancer elements of target genes, inducing transcription of proinflammatory genes. IKK also phosphorylates IκBβ and IκBε. Phosphorylation of IκBβ leads to prolonged NF-κB activation (14), which can in part be explained by the delay in IκBβ resynthesis after degradation. IκBε is degraded with relatively slow kinetics like IκBβ, but it may also be resynthesized at a rate comparable with that of IκBα.

In many cell types, IKK resides at a key convergence site for multiple signaling pathways that lead to NF-κB activation (15). IKK-β knockout mice develop liver failure due to hepatocyte apoptosis, especially in the presence of TNF-α (16). Although NF-κB blockade appears to be hepatotoxic during embryonic development, the use of an inducible IκBα super-repressor transgene suggests that NF-κB inhibition is well tolerated in adult mice (17). However, even in that model, NF-κB blockade compromises normal host defense and leaves mice unable to clear opportunistic infections with Listeria monocytogenes. IKK-α knockouts exhibit abnormal morphogenesis. IKK-α appears to be involved in keratinocyte differentiation and formation of the epidermis (18).