Inhibitor of nuclear factor kappa-B kinase subunit beta

UniProt O14920 Organism Homo sapiens Gene IKBKB, IKKB EC 2.7.11.10, 2.7.11.1

Also known as: IKBKB, IKKB

Function

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. Acts as a 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. 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. Also phosphorylates other substrates including NAA10, NCOA3, BCL10 and IRS1. 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. Following bacterial lipopolysaccharide (LPS)-induced TLR4 endocytosis, phosphorylates STAT1 at 'Thr-749' which restricts interferon signaling and anti-inflammatory responses and promotes innate inflammatory responses. IKBKB-mediated phosphorylation of STAT1 at 'Thr-749' promotes binding of STAT1 to the ARID5A promoter, resulting in transcriptional activation of ARID5A and subsequent ARID5A-mediated stabilization of IL6. It also promotes binding of STAT1 to the IL12B promoter and activation of IL12B transcription.

Classification

Family (Pfam): PF18397 IKBKB_SDD, PF12179 IKKbetaNEMObind, PF00069 Pkinase
InterPro: IKBKB_SDD, IKBKB_SDD_sf, IKK, IKKbetaNEMObind, Kinase-like_dom_sf, Prot_kinase_dom, Ser/Thr_kinase_AS, Ubiquitin-like_dom, Ubiquitin-like_domsf
Functional cluster: Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 5

3BRT X-ray 2.25A
3BRV X-ray 2.20A
4E3C X-ray 3.98A
4KIK X-ray 2.83A
8OMV X-ray 4.16A

A predicted model is available from AlphaFold.

Gene Ontology · 45

Disease associations

severe combined immunodeficiency due to IKK2 deficiency MONDO:0014267
immunodeficiency 15a MONDO:0032599

Drugs targeting this protein · 4

AS-602868 inhibitor
BARDOXOLONE METHYL inhibitor
MLN-0415 inhibitor
IMD-0354 inhibitor

Neighborhood · nearest proteins

Nearest neighbours of Inhibitor of nuclear factor kappa-B kinase subunit beta: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Inhibitor of nuclear factor kappa-B kinase subunit alpha 21 shared papers
NF-kappa-B essential modulator 10 shared papers
Protein OPG200 1 shared papers
Interferon regulatory factor 5 1 shared papers
Inhibitor of nuclear factor kappa-B kinase subunit beta 5 shared papers
Protein kinase C zeta type 1 shared papers
Inhibitor of nuclear factor kappa-B kinase subunit beta 3 shared papers
Inhibitor of nuclear factor kappa-B kinase subunit epsilon 6 shared papers
Peptidyl-prolyl cis-trans isomerase FKBP5 2 shared papers
Trafficking protein particle complex subunit 9 1 shared papers
AT-rich interactive domain-containing protein 5A 1 shared papers
Leucine-rich repeat-containing protein 14 1 shared papers

Literature · 74 cited papers

Threonine phosphorylation of STAT1 restricts interferon signaling and promotes innate inflammatory responses. Proc. Natl. Acad. Sci. U.S.A. · 2024
Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2. EMBO J. · 2020
Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production. Sci. Signal. · 2020
Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses. J. Virol. · 2019
Gain-of-function IKBKB mutation causes human combined immune deficiency. J. Exp. Med. · 2018
Mechanism of vaccinia viral protein B14 mediated inhibition of IkappaB kinase beta activation. J. Biol. Chem. · 2018
LRRC14 attenuates Toll-like receptor-mediated NF-kappa-B signaling through disruption of IKK complex. Exp. Cell Res. · 2016
IFIT5 positively regulates NF-kappaB signaling through synergizing the recruitment of IkappaB kinase (IKK) to TGF-beta-activated kinase 1 (TAK1). Cell. Signal. · 2015
Dimer of arfaptin 2 regulates NF-kappaB signaling by interacting with IKKbeta/NEMO and inhibiting IKKbeta kinase activity. Cell. Signal. · 2015
FKBP51 employs both scaffold and isomerase functions to promote NF-kappaB activation in melanoma. Nucleic Acids Res. · 2015
N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
Protein kinase IKKbeta-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. Proc. Natl. Acad. Sci. U.S.A. · 2014
… and 62 more in the literature graph

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