IKBKB Gene

The IKBKB gene (IKBKB stands for "Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Beta") is a protein-coding gene located on chromosome 8p11.21. Several transcript variants have been found for this gene, some of which encode the protein and others do not.

The protein encoded by this gene, a serine kinase, plays an essential role in the NF-kappa B signaling pathway, which is activated by various stimuli such as inflammatory cytokines, bacterial or viral products, DNA damage or other cellular stress factors. Phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, leading to dissociation of the inhibitor and activation of NF-kappa-B (Hayden MS et al. 2011). The encoded protein itself is located in a complex of proteins.

Diseases associated with IKB include:

• Immunodeficiency 15A (OMIM: 618204)
• and
• immunodeficiency 15B.

Associated signaling pathways include NF-kappaB pathway and estrogen signaling pathway. The encoded protein phosphorylates inhibitors of NF-kappa-B at 2 critical serine residues. These modifications enable polyubiquitination of the inhibitors and subsequent degradation by the proteasome. Free NF-kappa-B, in turn, is translocated to the cell nucleus and activates the transcription of numerous genes involved in the immune response, growth control or protection against apoptosis. In addition to NF-kappa-B inhibitors, this serine kinase phosphorylates several other components of the signaling pathway, including NEMO/IKBKG, the NF-kappa-B subunits RELA and NFKB1, and the IKK-related kinases TBK1 and IKBKE.

Phosphorylates FOXO3, mediating TNF-dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates such as NCOA3, BCL10 and IRS1. Acts in the nucleus as an adapter protein for NFKBIA degradation during UV-induced NF-kappa-B activation. Phosphorylates RIPK1 at 'Ser-25', which suppresses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death. Phosphorylates the C-terminus of IRF5 and stimulates IRF5 homodimerization and translocation to the nucleus.

1. Cardinez C et al (2018) Gain-of-function IKBKB mutation causes human combined immune deficiency. J Exp Med 215: 2715-2724.
2. Fukumura K et al (2016) Genomic characterization of primary central nervous system lymphoma. Acta Neuropath131: 865-875.
3. Hayden MS et al (2011) NF-κB in immunobiology. Cell Res 21:223-244.