IKBKG phospho S85
Domain
The leucine-zipper domain and the CCHC NOA-type zinc-fingers constitute the UBAN region and are essential for polyubiquitin binding and for the activation of IRF3.
Function
Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor (PubMed:14695475, PubMed:20724660, PubMed:21518757, PubMed:9751060). Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways (PubMed:16547522, PubMed:18287044, PubMed:19033441, PubMed:19185524, PubMed:21606507, PubMed:27777308, PubMed:33567255). Can recognize and bind both 'Lys-63'-linked and linear polyubiquitin upon cell stimulation, with a much higher affinity for linear polyubiquitin (PubMed:16547522, PubMed:18287044, PubMed:19033441, PubMed:19185524, PubMed:21606507, PubMed:27777308). Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3 (PubMed:19854139). Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination (PubMed:20724660).
(Microbial infection) Also considered to be a mediator for HTLV-1 Tax oncoprotein activation of NF-kappa-B.
Involvement in disease
Ectodermal dysplasia and immunodeficiency 1
EDAID1
A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. EDAID1 is an X-linked recessive disorder characterized by absence of sweat glands, sparse scalp hair, rare conical teeth and immunological abnormalities resulting in severe infectious diseases. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, and may be fatal in childhood.
None
The disease is caused by variants affecting the gene represented in this entry.
Immunodeficiency 33
IMD33
An X-linked recessive disorder characterized by variably impaired immunologic function and early-onset recurrent infections, usually due to pneumococcus, H. influenzae, and atypical mycobacteria. Features of hypohidrotic ectodermal dysplasia are generally not present, although some patients may have conical teeth or hypodontia.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry.
Incontinentia pigmenti
IP
A genodermatosis usually prenatally lethal in males. In affected females, it causes abnormalities of the skin, hair, eyes, nails, teeth, skeleton, heart, and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring.
None
The disease is caused by variants affecting the gene represented in this entry.
Autoinflammatory disease, systemic, X-linked
SAIDX
An X-linked disorder characterized by systemic autoinflammation appearing in the first months of life. Clinical manifestations are variable, including lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional features may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylation at Ser-68 attenuates aminoterminal homodimerization.
Polyubiquitinated on Lys-285 via 'Lys-63'-linked ubiquitin; the ubiquitination is mediated downstream of NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway (PubMed:15620648, PubMed:17562858, PubMed:19136968). Polyubiquitinated on Lys-285 and Lys-399 through 'Lys-63'-linked ubiquitin; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway (PubMed:14695475, PubMed:17562858, PubMed:19136968). Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear export (PubMed:14651848). Polyubiquitinated through 'Lys-27' by TRIM23; involved in antiviral innate and inflammatory responses (PubMed:20724660). Linear polyubiquitinated on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination is mediated by the LUBAC complex and plays a key role in NF-kappa-B activation (PubMed:21455181). Deubiquitinated by USP10 in a TANK-dependent and -independent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage (PubMed:25861989). Ubiquitinated at Lys-326 by MARCHF2 following bacterial and viral infection which leads to its degradation (PubMed:32935379). Polyubiquitinated via 'Lys-29'-linked ubiquitin; leading to lysosomal degradation (PubMed:21518757).
Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues.
Neddylated by TRIM40, resulting in stabilization of NFKBIA and down-regulation of NF-kappa-B activity.
(Microbial infection) Cleaved by hepatitis A virus (HAV) protease 3C allowing the virus to disrupt the host innate immune signaling.
(Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1 on both 'Lys-48' and 'Lys-63'-linked ubiquitin chains; leading to NF-kappa-B signaling inhibition.
(Microbial infection) Polyubiquitinated on Lys-309 and Lys-321 via 'Lys-27'-linked ubiquitin by Shigella flexneri E3 ubiquitin-protein ligase ipah9.8, leading to its degradation by the proteasome.
(Microbial infection) Polyubiquitination through 'Lys-63' is interrupted by interaction with SARS coronavirus-2/SARS-CoV-2 virus protein ORF9B which inhibits the NF-kappa-B pathway.
Tissue Specificity
Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Cellular localization
- Cytoplasm
- Nucleus
- Sumoylated NEMO accumulates in the nucleus in response to genotoxic stress.
Alternative names
FIP3, NEMO, IKBKG, NF-kappa-B essential modulator, FIP-3, IkB kinase-associated protein 1, Inhibitor of nuclear factor kappa-B kinase subunit gamma, NF-kappa-B essential modifier, IKKAP1, I-kappa-B kinase subunit gamma, IKK-gamma, IKKG, IkB kinase subunit gamma