The transcriptional activator protein NF-κB mediates key immune and inflammatory responses (1). NF-κB, present in the cytoplasm of most cell types, is normally bound to a member of a family of inhibitor proteins known as IκB (Inhibitor κB). The best-characterized member of this family, IκB-α, binds the p50/p65 heterodimer of NF-κB in the cytoplasm. When cells are exposed to inducers of NF-κB, such as the cytokines tumor necrosis factor-α (TNF-α) or interleukin-1 (IL-1), two serine residues of IκB-α (Ser 32 and Ser 36) are specifically phosphorylated. This phosphorylation is a signal for ubiquitination and degradation of IκB-α by the 26S proteasome (2, 3). NF-κB is thus released to translocate to the nucleus and activate transcription of target genes.

Because NF-κB can be activated by an extraordinarily large number of different signals, ranging from ultraviolet irradiation to T cell activation (1), the mechanism by which these signals converge on IκB-α is of wide interest. During the past 2 years, many components from certain signaling pathways that lead to activation of NF-κB (3, 4) have been described. The recent identification of a high molecular mass IκB kinase complex (5) and the identification of two unusual IκB kinases, reported in this issue on pages 860 and 866 (6, 7), and elsewhere (8, 9) now provide a framework for resolving the problem of integrating multiple NF-κB signaling pathways.