The IKK Complex, a Central Regulator of NF-kB Activation

The IKK kinase complex is the core element of the NF-kB cascade. It is essentially made of two kinases (IKKa and IKKb) and a regulatory subunit, NEMO/IKKg. Additional components may exist, transiently or permanently, but their characterization is still unsure. In addition, it has been shown that two separate NF-kB pathways exist, depending on the activating signal and the cell type, the canonical (depending on IKKb and NEMO) and the noncanonical pathway (depending solely on IKKa). The main question, which is still only partially answered, is to understand how an NF-kB activating signal leads to the activation of the kinase subunits, allowing them to phosphorylate their targets and eventually induce nuclear translocation of the NF-kB dimers. I will review here the genetic, biochemical, and structural data accumulated during the last 10 yr regarding the function of the three IKK subunits. NF-kB represents a family of transcriptionfactors that are normally kept inactive in the cytoplasm through interaction with inhibitory molecules of the IkB family. In response to multiple stimuli such as inflamma-tory cytokines, bacterial or viral products, or various types of stress, the IkB molecules become phosphorylated on two critical serine residues. This modification allows their polyubiquitination and destruction by the proteasome. As a consequence, free NF-kB enters the nucleus and activates transcription of a variety of genes participating in the immune and inflammatory response, cell adhe-sion, growth control, and protection against apoptosis. The kinase(s) responsible for the phos-phorylation of the IkB inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular-weight complex migrating around 700–900 kDa and containing two related catalytic subunits, IKKa and IKKb (Chen et al. 1996; Didonato et al. 1997). An additional component of the so-called IKK complex, NEMO/IKKg (there-after referred to as NEMO), has subsequently been identified through genetic complementa-tion of an NF-kB activation-defective cell line (Yamaoka et al. 1998) and sequencing of IKK-associated polypeptides (Rothwarf et al