The IκB kinase (IKK) complex as a critical regulator of immune responses

The IκB kinase (IKK) is a tripartite signaling complex composed of two catalytic (protein kinase) subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ (a.k.a. NEMO). The major function of IKK is to connect pro-inflammatory stimuli and signals generated by pathogen-associated molecular patterns (PAMPs) to the activation of transcription factor NF-κB. This function is mainly dependent on the IKKβ catalytic subunit, whose activation requires the ubiquitination of IKKγ. IKKβ is the major kinase that leads to phosphorylation-induced degradation of IκBs, the inhibitors of NF-κB, and the consequent translocation of NF-κB dimers, containing RelA or c-Rel as activating subunits, to the nucleus. This results in induction of pro-inflammatory cytokines, chemokines, inhibitors of apoptosis, and other molecules required for a successful innate immune response. The function of IKKα in this pathway has been puzzling, but we recently found that IKKα serves an anti-inflammatory function by phosphorylating RelA and c-Rel at sites that accelerate their nuclear turnover. This seems to occur concomitantly with IκB phosphorylation by IKKβ. Thus, the IKK complex is responsible both for the onset of NF-κB activation and for the proper termination of this response. Another function unique for IKKα, which occurs independently of IKKβ and IKKγ, is the phosphorylation and processing of the NF-κB2/p100 protein, leading to specific activation of p52:RelB dimers. This response is critical for coupling innate immunity to certain adaptive responses involving B cells.