NF-κB was recognized as a DNA-binding factor that exists in the cytoplasm of resting cells and that accumulates in the nucleus under appropriate conditions (1
). The ability of NF-κB to shuttle between the cytoplasm and nucleus in a tightly regulated manner led to the exploration of a complex series of events leading to activation-induced gene expression, and to the discovery of factors that prevent the transit of NF-κB into the nucleus (2
). Receptor-mediated NF-κB activation of gene transcription and its stringent control are fundamental to cell development, survival, and function. In this issue of the JCI
, Courtois and colleagues report a novel human mutation in a protein that negatively regulates NF-κB activation (3
). The resultant mutant dominantly inhibits the activation of NF-κB (see below) and gives rise to a clinical syndrome of ectodermal dysplasia (ED) and susceptibility to infection.
NF-κB activity is imparted by a protein dimer selected from five mammalian homologues: p50, p52, p65 (RelA), Rel, and RelB (p50 and p52 are derived from larger precursors, p105 and p100, respectively). The majority of dimers formed by these individual NF-κB members are capable of activating transcription by binding to κB sites in DNA. The dimerization of these molecules occurs through a conserved N-terminal Rel homology domain (RHD). Importantly, the RHD also serves as the binding site for one of several inhibitors of NF-κB (IκBs). An IκB can physically interfere with NF-κB dimerization or block nuclear localization sequences within the NF-κB member. The family of molecules possessing these activities consists of at least seven members: IκBα, IκBβ, IκBε, IκBγ, Bcl-3, and inhibitory domains of the p105 and p100 precursor proteins. The cytoplasmic association of an IκB and a NF-κB member is controlled by the phosphorylation of the IκB, which leads to its ubiquitination and proteosomal degradation (Figure ). The release of an NF-κB protein from IκB allows it to participate in dimer formation, translocate to the nucleus, and activate transcription. The phosphorylation of IκB, therefore, is a critical regulatory step in NF-κB function.
Figure 1 Receptor-induced NF-κB nuclear translocation and inhibition by a dominant negative IκB. A variety of cell surface receptors are capable of inducing associated specific signaling complexes that can activate the IKK signalosome to phosphorylate (more ...)