THE IκB KINASE (IKK) AND THE CONTROL OF IMMUNITY, INFLAMMATION AND CANCER

proteins can assemble into a variety of homo- and heterodimers that bind to κB sites on DNA and induce transcription of genes whose products play key roles in activation of innate and adaptive immune responses, inflammation and prevention of apoptosis. NF-κB1 and NF-κB2 require proteolytic processing to produce the mature p50 and p52 NF-κB subunits that can associate with any of the other Rel proteins. Once formed, NF-κB dimers are stored in the cytoplasm through interaction with the IκB proteins, which need to be degraded via the 26S proteasome before NF-κB can enter into the nucleus and regulate transcription (1). Ubiquitin-dependent degradation of IκBs requires their phosphorylation by the IκB kinase (IKK) complex, whose activity is rapidly stimulated in response to microbial and viral infections, proinflammatory cytokines and ionizing radiation. IKK is composed of two related catalytic subunits IKKα and IKKβ and a regulatory subunit IKKγ/NEMO, that is essential for activation of the complex (2). We found that IKKα and IKKβ differ in their substrate specificities and as a result have distinct biological functions. Whereas IKKβ is a true IκB kinase, IKKα is a poor IκB kinase and instead is an efficient NF-κB2 kinase, whose activity is required for production of p52. As a result, IKKβ is required for general NF-κB functions