IκB kinase complexes: gateways to NF-κB activation and transcription

Transcription factors of the NF-κB family regulate hundreds of genes in the context of multiple important physiological and pathological processes. NF-κB activation depends on phosphorylation-induced proteolysis of inhibitory IκB molecules and NF-κB precursors by the ubiquitin-proteasome system. Most of the diverse signaling pathways that activate NF-κB converge on IκB kinases (IKK), which are essential for signal transmission. Many important details of the composition, regulation and biological function of IKK have been revealed in the last years. This review summarizes current aspects of structure and function of the regular stoichiometric components, the regulatory transient protein interactions of IKK and the mechanisms that contribute to its activation, deactivation and homeostasis. Both phosphorylation and ubiquitinatin (destructive as well as non-destructive) are crucial post-translational events in these processes. In addition to controlling induced IκB degradation in the cytoplasm and processing of the NF-κB precursor p100, nuclear IKK components have been found to act directly at the chromatin level of induced genes and to mediate responses to DNA damage. Finally, IKK is engaged in cross talk with other pathways and confers functions independently of NF-κB.