IκB kinase

IKK is a multi-subunit kinase complex composed of two catalytic subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ/NEMO). It sits at the convergence point of multiple signaling pathways activated by cytokines (TNF-α, IL-1), pathogen-associated molecular patterns (via Toll-like receptors), and other stress signals. Upon activation, IKK phosphorylates serine residues on IκB proteins (e.g., IκBα), which normally sequester NF-κB dimers in the cytoplasm. Phosphorylated IκB is recognized by E3 ubiquitin ligases, polyubiquitinated, and degraded by the 26S proteasome. This liberates NF-κB (typically p50/p65 heterodimer) to translocate into the nucleus, where it induces transcription of genes involved in inflammation, immune cell activation, cell survival, and proliferation (e.g., cytokines, chemokines, adhesion molecules, anti-apoptotic proteins). Clinical relevance: Dysregulated NF-κB/IKK signaling is implicated in chronic inflammatory diseases (rheumatoid arthritis, IBD), autoimmune disease, and cancer (many tumors exploit constitutive NF-κB activation for survival and proliferation). NEMO (IKKγ) mutations cause incontinentia pigmenti (X-linked dominant, lethal in males unless Klinefelter) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) due to impaired NF-κB signaling, leading to recurrent infections. IKK is a therapeutic target for anti-inflammatory and anticancer drugs; corticosteroids indirectly inhibit NF-κB activity by upregulating IκB and inhibiting IKK-related pathways. Bortezomib (proteasome inhibitor) indirectly stabilizes IκB, preventing NF-κB activation, used in multiple myeloma treatment.