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FLASH GENE
Symbol IKBKG contributors: mct/npt/pgu - updated : 14-03-2018
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
IMD33 Immunodeficiency 33
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
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head, overlapping, gene in gene, opposite orientation
    text
  • 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
    cytosine-phosphate-guanine/HTF
    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)
    RNA
    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
    		•
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestiveliver    
    Endocrinepancreas    
    Nervousbrain    
    Respiratorylung    
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    Muscularstriatumskeletal  
    Nervouscentral   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/ImmuneB cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES acid
    STRUCTURE
    motifs/domains
  • 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
  • elongated homodimer comprising mostly alpha-helix
    • mono polymer homomer , dimer
    HOMOLOGY
    interspecies homolog to rattus Ikbkg (88.83 pc)
    homolog to murine Ikbkg (88.08 pc)
    Homologene
    FAMILY
    CATEGORY immunity/defense , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
    intracellular,nucleus
    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
  • functions as a high affinity receptor for linear ubiquitin chains and a low affinity receptor for long lysine-linked ubiquitin chains
  • essential for IKBKB activation by inflammatory stimuli, and also a specificity factor that directs IKBKB activity toward CHUK
  • role for scaffolds such as IKBKG in determining stimulus-specific signal transduction via the pleiotropic signaling hub IKK
  • scaffolding protein that, together with the catalytic subunits CHUK and IKBKB, plays an essential role in the formation of the IKK complex and in the activation of the canonical NFKB pathway
    • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    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
  • IKBKG together with catalytic subunits CHUK and IKBKB, forms the IKB kinase (IKK) complex, a key regulator of NFKB pathway signaling
    • INTERACTION
    DNA
    RNA
    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
  • novel IKBKG-interacting protein, RUSC1, an adapter molecule previously shown to be involved in the NGF-pathway via the NTRK1
  • 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
  • binding to polyubiquitin is essential for NFKB activation
  • SENP2 can efficiently associate with IKBKG, deSUMOylate IKBKG, and inhibit NFKB activation induced by DNA damage
  • recruitment of IKBKG to ubiquitinated RIPK1 is a key step in the TNFR1 signaling pathway that determines whether RIPK1 triggers a necrotic death response
  • NSFL1C associates with the IKBKG subunit of the IKB kinase (IKK) complex upon TNF or IL1 stimulation, and inhibits IKK activation
  • by mediating USP10-dependent deubiquitination of IKBKG, ZC3H12A induction serves as a negative feedback mechanism for attenuating genotoxic NFKB activation
  • NMRAL1 interacts with IKBKG and suppresses polyubiquitination of IKBKG by interacting with the deubiquitinase USP7
  • NMRAL1 and USP7 function in concert in inhibiting polyubiquination of IKBKG, thus inhibiting NFKB activity
  • SENP1-mediated IKBKG deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
  • interactions of UBASH3A with nondegradative polyubiquitin chains, NR2C2 and IKBKG, suggesting that UBASH3A regulates the NFKB1 signaling pathway by an ubiquitin-dependent mechanism
  • SMC4 promotes inflammatory innate immune responses by enhancing IKBKG transcription
  • MARCHF2 is a novel negative regulator of IKBKG-mediated signaling upon bacterial or viral infection
  • N4BP1 negatively regulates NFKB1 by binding and inhibiting IKBKG oligomerization
    • cell & other
    REGULATION
    inhibited by CYLD
    Other leading to the T cell receptor resulting in NF-kappa B activation
    ASSOCIATED DISORDERS
    corresponding disease(s) IP2 , OLEDAID , EDAID , IMD33
    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
    Susceptibility
  • 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
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestiveliver
    IKK-targeted gene therapy can be used in the treatment of hepatocellular carcinoma, a cancer that is notoriously resistant to radiation and chemotherapy
    ANIMAL & CELL MODELS