IKBKB

The protein encoded by this gene phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, causing dissociation of the inhibitor and activation of NF-kappa-B. The encoded protein itself is found in a complex of proteins. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Sep 2011]

Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Beta

Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses (PubMed:30337470).

Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE (PubMed:11297557, PubMed:20410276).

IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor (PubMed:15084260).

Also phosphorylates other substrates including NCOA3, BCL10 and IRS1 (PubMed:17213322).

Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (PubMed:11297557).

Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity).

Phosphorylates the C-terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus (PubMed:25326418).

Antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent Source: Reactome
Cellular response to tumor necrosis factor Source: UniProtKB
Cortical actin cytoskeleton organization Source: UniProtKB
Fc-epsilon receptor signaling pathway Source: Reactome
I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Inflammatory response Source: UniProtKB
Innate immune response Source: UniProtKB
Interleukin-1-mediated signaling pathway Source: UniProtKB
Negative regulation of bicellular tight junction assembly Source: UniProtKB
Negative regulation of myosin-light-chain-phosphatase activity Source: UniProtKB
Peptidyl-serine phosphorylation Source: UniProtKB
Positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Positive regulation of NF-kappaB transcription factor activity Source: MGI
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Protein localization to plasma membrane Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of establishment of endothelial barrier Source: UniProtKB
Regulation of phosphorylation Source: ParkinsonsUK-UCL
Regulation of tumor necrosis factor-mediated signaling pathway Source: Reactome
Response to virus Source: UniProtKB
Stimulatory C-type lectin receptor signaling pathway Source: Reactome
Stress-activated MAPK cascade Source: Reactome
T cell receptor signaling pathway Source: Reactome
Tumor necrosis factor-mediated signaling pathway Source: UniProtKB

Nucleus; Cytoplasm; Membrane raft. Colocalized with DPP4 in membrane rafts.

Immunodeficiency 15B (IMD15B):
An autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T-cells, and impaired differentiation and activation of immune cells.
Immunodeficiency 15A (IMD15A):
An autosomal dominant primary immunodeficiency disorder characterized by lymphopenia, inflammation and immune activation of both CD4+ and CD8+ T cells. Patients suffer from recurrent respiratory tract infections, oral candidiasis, and otitis media.

Upon cytokine stimulation, phosphorylated on Ser-177 and Ser-181 by MEKK1 and/or MAP3K14/NIK as well as TBK1 and PRKCZ; which enhances activity. Once activated, autophosphorylates on the C-terminal serine cluster; which decreases activity and prevents prolonged activation of the inflammatory response. Phosphorylated by the IKK-related kinases TBK1 and IKBKE, which is associated with reduced CHUK/IKKA and IKBKB activity and NF-kappa-B-dependent gene transcription. Dephosphorylated at Ser-177 and Ser-181 by PPM1A and PPM1B.
(Microbial infection) Acetylation of Thr-180 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the I-kappa-B pathway.
Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. According to PubMed:19675099, 'Ser-163' does not serve as a monoubiquitination site. According to PubMed:16267042, ubiquitination on 'Ser-163' modulates phosphorylation on C-terminal serine residues.
(Microbial infection) Monoubiquitination by TRIM21 is disrupted by Yersinia YopJ.
Hydroxylated by PHD1/EGLN2, loss of hydroxylation under hypoxic conditions results in activation of NF-kappa-B.