ikK

IKK, short for I-kappa-B kinase, is a protein kinase complex that orchestrates a major signaling pathway controlling inflammatory and immune responses. The canonical IKK complex is composed of two catalytic subunits, IKKα (CHUK) and IKKβ (IKBKB), and a regulatory subunit, NEMO (IKKγ, encoded by IKBKG). NEMO acts as a scaffold that brings the catalytic subunits into contact with upstream activators.

In canonical NF-κB signaling, various stimuli activate the TAK1 kinase, which phosphorylates and activates IKKβ (and to a lesser extent IKKα) within the complex. Activated IKK catalyzes the phosphorylation of IκB proteins, notably IκBα, at serine residues that target IκBα for ubiquitination and proteasomal degradation. Degradation of IκB permits NF-κB heterodimers, typically p65/RelA and p50, to enter the nucleus and regulate transcription of genes involved in inflammation, immunity, and cell survival. A non-canonical pathway also involves IKKα-containing complexes and the kinase NIK, which drives processing of p100 to p52 and activation of RelB-containing NF-κB dimers.

Physiological roles of IKK signaling include control of innate and adaptive immune responses, development, and cell survival. Dysregulation or chronic activation of IKK/NF-κB signaling has been linked to inflammatory diseases, autoimmune disorders, and various cancers. Genetic defects in IKBKG, encoding NEMO, cause incontinentia pigmenti in females and immunodeficiency syndromes in males.

Pharmacological inhibition of IKK has been pursued as a strategy to treat inflammatory diseases, cancers, and neurodegenerative disorders. Inhibitors that target IKKβ, such as MLN120B and BMS-345541, reduce NF-κB activity but may compromise host defense and have encountered challenges related to toxicity and specificity.