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Symbol IKBKG contributors: mct/npt/pgu - updated : 27-01-2010
HGNC name inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma
HGNC id 5961
Corresponding disease
EDAID ectodermal dysplasia, hypohidrotic, with immune deficiency
IP2 incontinentia pigmenti 2
OLEDAID ectodermal dysplasia, anhidrotic, with immunodeficiency, osteopetrosis, and lymphedema
Location Xq28      Physical location : 153.770.458 - 153.793.260
Synonym name
  • nuclear factor-kappaB (NF-kappaB) essential modulator
  • IkB kinase-associated protein 1
  • NF-kappa-B essential modifier
  • lymphocyte-specific G protein-coupled peptide receptor
  • EBV-induced G protein-coupled receptor 1
  • Synonym symbol(s) NEMO, IKKG, FIP3, IP, IP1, IPD2, Fip3p, IKK-gamma, IKKG
    TYPE functioning gene
    SPECIAL FEATURE head to head, overlapping, gene in gene, opposite orientation
  • sharing exon 1 with G6PD
  • partially overlapping G6PD head to head
  • part of a segmental duplication or low copy repeat (LCR1-LCR2, >99p100 identical) containing the gene and its pseudogene copy (IKBKGP)
  • in the opposite direction and outside LCR1, IKBKG partially overlaps G6PD
  • STRUCTURE 22.80 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence alternative promoter
    text structure two alternative promoters
  • promoter A (distal) located in G6PD intron 2
  • promoter B (proximal) lied in the CpG island (in common with the G6PD gene)
  • each 5' UTR alternative transcript has different expression profiles indicating that the control of its expression is mediated through tissue-specific transcription initiation sites and multiple regulatory regions
  • MAPPING cloned Y linked N status confirmed
    Map cen - DXS1193 - EMD EMD - G6PD - IKBKG - MPP1 - F8 - BGN - qter
    Authors GeneMap (98), (PMID: 11709543)
    Physical map
    CXorf2 Xq28 chromosome X open reading frame 2 TKTL1 Xq28 transketolase-like 1 FLNA Xq28 filamin A, alpha (actin binding protein 280) EMD Xq28 emerin (Emery-Dreifuss muscular dystrophy) RPL10 Xq28 ribosomal protein L10 DNASE1L1 Xq28 deoxyribonuclease I-like 1 TAZ Xq28 tafazzin (cardiomyopathy, dilated 3A (X-linked); endocardial fibroelastosis 2; Barth syndrome) ATP6AP1 Xq28 ATPase, H+ transporting, lysosomal accessory protein 1 GDI1 Xq28 GDP dissociation inhibitor 1 DXS9928E Xq28 DNA segment on chromosome X (unique) 9928 expressed sequence PLXN3 Xq28 likely ortholog of mouse plexin 3 DXS9879E Xq28 DNA segment on chromosome X (unique) 9879 expressed sequence UBL4 Xq28 ubiquitin-like 4 SLC10A3 Xq28 solute carrier family 10 (sodium/bile acid cotransporter family), member 3 FAM3A Xq28 family with sequence similarity 3, member A G6PD Xq28 glucose-6-phosphate dehydrogenase IKBKG Xq28 inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma SPCX Xq28 SPCX LAGE2A  cancer/testis antigen 1-A CTAG1 Xq28 cancer/testis antigen 1 LOC340600 Xq28 cyclic-AMP-dependent transcription factor ATF-4 pseudogene deltaNEMO Xq28 deltaNEMO CTAG2 Xq28 cancer/testis antigen 2 LOC392561 X similar to olfactory receptor MOR255-2 GAB3 Xq28 GRB2-associated binding protein 3
    TRANSCRIPTS type messenger
    text 4 distinctive transcription start sites, each corresponding to an alternative first exon
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 - 2120 - 419 - 1999 10087442
  • isoform a
  • 8 - 1982 - 320 - 1999 10087442
  • isoform c
  • 10 - 2279 - 419 - 1999 10087442
  • isoform a
  • 10 - 2086 - 487 - 1999 10087442
  • isoform b
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/ImmuneB cell
    cell lineage
    cell lines
    at STAGE
    physiological period embryo, pregnancy
    Text placenta
  • two coiled-coil motifs, with the IKK binding region overlapping the first CC1 and the regulatory region including CC2
  • four helix alpha helix domains
  • a NEMO ubiquitin-binding domain (NUB)
  • a small domain called NOA/UBAN has been suggested to be involved in recognizing poly-ubiquitin chains, and together with ZF they form a bipartite high-affinity K63-specific ubiquitin-binding domain
  • a proline-rich domain
  • a leucine zipper required for IKKA and IKKB association
  • a C terminal zinc finger motif, containing interactions domains absolutely required for connecting the IKK complex to the upstream activators (ZF is also a functional ubiquitin-binding domain, and forms a specific complex with ubiquitin) (Cordier 2009)
  • secondary structure alpha helix
    interspecies homolog to rattus Ikbkg (88.83 pc)
    homolog to murine Ikbkg (88.08 pc)
    CATEGORY immunity/defense , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • required for the activation of NFKB and control in immune, inflammatory and apoptotic pathways
  • activating NFKB after stimulation by EDAR
  • playing an important role in B cell survival (but not in B cell development)and in T-cell development and/or survival
  • ubiquitylated through genotoxic stress-induced SUMO1 modification and ATM activation, permitting NFKB survival pathway
  • its ubiquitination plays an essential role in signaling pathways activating NFK-B through TRAF6
  • playing a critical role in IKK and NFKB activation
  • IKBKG, like VISA, acts as an adaptor protein that allows DDX58 to activate both the NF-kappaB and IRF signaling)pathways
  • regulates TNF alpha signaling by coordinating cell responses mediated by the AP-1 and NF-kappa B pathways
  • regulatory protein essential to the canonical NF-kappaB signaling pathway, notably involved in immune and inflammatory responses, apoptosis, and oncogenesis
  • having ability to specifically recognize poly-ubiquitin chains
  • novel function for IKBKG and NFKB modulating the DNA-damage checkpoint response, allowing the cell to integrate different signalling pathways with the DNA-damage response
  • IKBKB, IKBKG and REL control the levels of Claspin in the cells by an alternative mechanism to cell cycle
  • caused phosphorylation and stabilization of MYC protein in the nucleus through direct interaction
  • involved in stabilization of MYC by direct interaction which stabilization of c-Myc by direct interaction is a unique function of NEMO, which is a new mechanism to regulate MYC activity
  • a IKBKG- and RIPK1-based switch mechanism involving TNF-TNFR1 feedforward signaling that mediates ATM-induced cytokine secretion and caspase activation selectively in the context of severe DNA damage
  • regulates necroptosis independently of NFKB
  • CELLULAR PROCESS cell life, cell death/apoptosis
    signaling signal transduction
    NF-kappa B cascade
    a component
  • complexing with IKBKA and IKBKB, associating preferentially with IKBKB, required for the activation of the complex (noncatalytic regulatory component)
  • IKK complex regulator
  • core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent
    small molecule other,
  • Zn2+
  • protein
  • activating NFKB after stimulation by EDAR
  • interaction with KAI1, NOTCH1, PEA15, GADD45B, ISG15, CD36, DUSP2, SLPI, CST7 (stimulated or repressed by IKBKG)
  • binds to linear di-ubiquitin
  • important interaction between IKBKG and TRAF6 (a new binding site for TRAF6 located at the N-terminus of IKBKG and recognized by the coiled-coil domain of TRAF6)
  • interacting with TRIM23 (both the CC1 and LZ domains of IKBKG are essential for this interaction)
  • interacting with FBXW7 and MYC (interaction caused reduced ubiquitination of MYC by inhibiting ubiquitinating activity of FBXW7 without blocking the interaction between MYC and FBXW7)
  • RPAP3 interacts with IKBKG and inhibits its ubiquitination and RPAP3 enhances cell death through the inhibition of NF-kappaB pathway
  • interacting with ATM (in the context of excessive DNA damage, ATM employs IKBKG and RIPK1 through autocrine TNF signaling to switch on cytokine production and caspase activation)
  • crucial for osteoclastogenesis and interacts with CSK in osteoclast
  • TRAF7 interacting with IKBKG, and RELA (promotes Lys-29-linked polyubiquitination of IKBKG and RELA that results in lysosomal degradation of both proteins and altered activation)
  • ubiquitin chain-dependent, but persistent, interactions between NKX3-2 and IKBKG can give rise to constitutive IKBKB activation in the nucleus
  • SENP2 can efficiently associate with IKBKG, deSUMOylate IKBKG, and inhibit NFKB activation induced by DNA damage
  • binding to polyubiquitin is essential for NFKB activation
  • cell & other
    inhibited by CYLD
    Other leading to the T cell receptor resulting in NF-kappa B activation
    corresponding disease(s) IP2 , OLEDAID , EDAID
    related resource IKBKGbase: Mutation registry for Nemo deficiency
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    in the adult epidermis, causing an inflammatory skin phenotype
  • to mycobacteria
  • to Behçet disease
  • Variant & Polymorphism other
  • mutations impairing CD40-dependent IL-12 production linked to susceptibility to mycobacteria
  • heterozygous mutation is a cause of familial occurrence of Behçet disease in female patients
  • Candidate gene
    Therapy target
    IKK-targeted gene therapy can be used in the treatment of hepatocellular carcinoma, a cancer that is notoriously resistant to radiation and chemotherapy