IKKs

IκB kinases, abbreviated IKKs, are a family of serine/threonine kinases that regulate the NF-κB signaling pathway. In the canonical pathway, the IKK complex is a heterotrimer composed of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ, also known as NEMO. A related group of kinases, TBK1 and IKKε, are IKK-related kinases but are typically distinguished from the canonical IKK complex.

Activation and function: In response to stimuli such as proinflammatory cytokines (TNF, IL-1), lipopolysaccharide, or cellular stress, upstream kinases like TAK1 activate the IKK complex. Activated IKKβ (and to a lesser extent IKKα) phosphorylates IκB proteins, notably IκBα, on serine residues. This phosphorylation targets IκB for ubiquitination and proteasomal degradation, freeing NF-κB dimers (p65/RelA–p50) to translocate to the nucleus and regulate genes involved in inflammation, immunity, cell survival, and development. IKKα also participates in the non-canonical (alternative) NF-κB pathway via processing of p100 to p52 when activated with other signals.

Regulation and clinical relevance: IKK activity is tightly regulated by deubiquitinases and feedback mechanisms, including resynthesis of IκBα. Abnormal IKK signaling is associated with chronic inflammatory diseases and cancer. Genetic mutations affecting NEMO or IKKβ can cause immunodeficiency or ectodermal dysplasias, while pharmacological IKK inhibitors are being explored as therapies for inflammatory disorders and certain cancers.

Structure and notes: IKKα and IKKβ contain kinase domains in their C-termini, with NEMO facilitating complex assembly and signaling in most cell types. The canonical pathway contrasts with the non-canonical NF-κB pathway, which relies on IKKα homodimers activated by NIK to process p100.