The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

IKBKG  -  inhibitor of kappa light polypeptide gene...

Homo sapiens

Synonyms: AMCBX1, FIP-3, FIP3, Fip3p, I-kappa-B kinase subunit gamma, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of IKBKG

  • Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID) [1].
  • FIP-3 (14.7K interacting protein) was discovered during a search for cell proteins that could interact with an adenovirus protein (Ad E3-14.7K) that had been shown to prevent tumor necrosis factor (TNF)-alpha-induced cytolysis [2].
  • Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility [3].
  • Boys with an expressed NEMO mutation have an X-linked syndrome characterized by hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) [4].
  • Recently, mutations in IKK-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (IP) [5].

Psychiatry related information on IKBKG


High impact information on IKBKG

  • Upon genotoxic stress, a complex between PIDD, the kinase RIP1, and a component of the NF-kappaB-activating kinase complex, NEMO, is formed [7].
  • Germline loss-of-function mutations in IKBKG are lethal in male fetuses [1].
  • Block of IP-1 function is obtained by PKA-mediated phosphorylation, possibly suggesting a cross talk mechanism at transcriptional level [8].
  • Competition experiments with synthetic peptides suggest that IP-1 could interact with Fos and/or Jun leucine zippers [8].
  • We speculate that IP-1 might act as a transcriptional antioncogene [8].

Chemical compound and disease context of IKBKG


Biological context of IKBKG

  • Enforced expression of NEMO in cells revealed that NEMO can both promote and block NF-kappaB activation and dramatically augments the phosphorylation of c-Jun [14].
  • Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis [2].
  • Because the activation of NF-kappaB has been shown to inhibit apoptosis, FIP-3 appears both to activate a cell-death pathway and to inhibit an NF-kappaB-dependent survival mechanism [2].
  • IKK contains two structurally related catalytic subunits termed IKKalpha and IKKbeta as well as a noncatalytic subunit called IKKgamma/NEMO [15].
  • The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-kappa B activation [3].

Anatomical context of IKBKG

  • METHODS: We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm [3].
  • The immunophenotype resulting from NEMO mutation is highly variable, with deficits in both T and B cell responses [4].
  • Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations [4].
  • Taken together, these results suggest that long-term activation of PKC by PMA inhibits NF-kappaB system in case of colon cancer cells by disrupting the interaction of IKK-gamma with Hsp90, which may represent a novel regulatory mechanism of PKC-dependent cellular differentiation and limited proliferation of colonic epithelial cells [9].
  • We also found that IKK-gamma strongly associates with heat shock protein 90 (Hsp90) in HCT-116 cells, and that this interaction was dramatically reduced after exposure to PMA [9].

Associations of IKBKG with chemical compounds

  • FIP-3, which contains leucine zippers and a zinc finger domain, inhibits both basal and induced transcriptional activity of NF-kappaB and causes a late-appearing apoptosis with unique morphologic manifestations [2].
  • The use of Ro-318220 and GO-6983, general PKC inhibitors as well as MG-132, a proteasome-specific inhibitor, abrogated PMA-induced degradation of IKK-gamma and recovered the activation of IKK by TNF, suggesting that IKK complex is predominantly degraded by the proteasome pathway in a PKC-dependent manner [9].
  • ATM is also exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS) [16].
  • Dimerization of the I{kappa}B Kinase-Binding Domain of NEMO Is Required for Tumor Necrosis Factor Alpha-Induced NF-{kappa}B Activity [17].
  • In contrast, EDI DCs stimulated with the TLR4 ligand lipopolysaccharide (LPS) showed normal downstream NF-kappaB activity, DC maturation, and NEMO ubiquitination [18].

Physical interactions of IKBKG

  • The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component [19].
  • CARMA1 participates to an inducible large molecular complex that contains IkappaKgamma/NEMO, Bcl10, and IkappaKalpha/beta kinases [20].
  • IKKalpha and IKKbeta are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-kappaB essential modulator)/IKKgamma [21].
  • Recently, it was reported that CYLD directly interacts with NEMO/IKKgamma and TRAF2 in the NF-kappaB signaling pathway [22].
  • RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF-alpha-treated cells [23].

Enzymatic interactions of IKBKG


Regulatory relationships of IKBKG

  • The same region of c-Src is also required for IL-1-induced IKK activation and the association with IKK gamma [24].
  • These data suggest that NEMO participates in signaling pathways leading to NK cell cytotoxicity and that IL-2 can activate NF-kappaB and partially overcome the NK cell defect in patients with NEMO mutations [4].
  • These results reveal the biochemical mechanism underlying the essential signaling function of NEMO and provide direct evidence that signal-induced site-specific ubiquitination of RIP1 is required for IKK activation [25].
  • Expression of NEMO/IKKgamma greatly promotes binding of Tax to IKKalpha and IKKbeta and stimulates Tax-mediated IKK activation [26].
  • As both TNF and PMA rapidly induce NF-kappaB activation this suggests that NEMO/IKKgamma-dependent activation of the NF-kappaB pathway is necessary but not sufficient for up-regulation of TRAIL in T cells [27].
  • NEMO-deficient Jurkat cells transiently expressing a non-cleavable mutant of NEMO were less sensitive to TNF-alpha-induced apoptosis [28].

Other interactions of IKBKG

  • It also induces binding of NEMO to the signaling inhibitor A20, and recruitment of A20 to the receptor [14].
  • The TANK binding domain within NEMO/IKK gamma is required for proper functioning of this IKK subunit [29].
  • Here we have shown that CARMA1 and CARMA3 physically associate with Ikappa kinase gamma/NFkappaB essential modulator (IkappaKgamma-NEMO) in lymphoid and non-lymphoid cells [20].
  • Furthermore, a physiological interaction between c-Src and I kappa B kinase gamma (IKK gamma) was observed, implying the involvement of c-Src in the IKK-complex [24].
  • IKAP and IKK gamma belong to distinct cellular complexes [19].

Analytical, diagnostic and therapeutic context of IKBKG


  1. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Döffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S.H., Headon, D.J., Overbeek, P.A., Le Deist, F., Holland, S.M., Belani, K., Kumararatne, D.S., Fischer, A., Shapiro, R., Conley, M.E., Reimund, E., Kalhoff, H., Abinun, M., Munnich, A., Israël, A., Courtois, G., Casanova, J.L. Nat. Genet. (2001) [Pubmed]
  2. Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis. Li, Y., Kang, J., Friedman, J., Tarassishin, L., Ye, J., Kovalenko, A., Wallach, D., Horwitz, M.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. Orange, J.S., Levy, O., Brodeur, S.R., Krzewski, K., Roy, R.M., Niemela, J.E., Fleisher, T.A., Bonilla, F.A., Geha, R.S. J. Allergy Clin. Immunol. (2004) [Pubmed]
  4. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. Orange, J.S., Brodeur, S.R., Jain, A., Bonilla, F.A., Schneider, L.C., Kretschmer, R., Nurko, S., Rasmussen, W.L., Köhler, J.R., Gellis, S.E., Ferguson, B.M., Strominger, J.L., Zonana, J., Ramesh, N., Ballas, Z.K., Geha, R.S. J. Clin. Invest. (2002) [Pubmed]
  5. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Zonana, J., Elder, M.E., Schneider, L.C., Orlow, S.J., Moss, C., Golabi, M., Shapira, S.K., Farndon, P.A., Wara, D.W., Emmal, S.A., Ferguson, B.M. Am. J. Hum. Genet. (2000) [Pubmed]
  6. Finding Nemo: Molecular phylogeny and evolution of the unusual life style of anemonefish. Santini, S., Polacco, G. Gene (2006) [Pubmed]
  7. PIDD mediates NF-kappaB activation in response to DNA damage. Janssens, S., Tinel, A., Lippens, S., Tschopp, J. Cell (2005) [Pubmed]
  8. IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation. Auwerx, J., Sassone-Corsi, P. Cell (1991) [Pubmed]
  9. Sustained activation of protein kinase C downregulates nuclear factor-{kappa}B signaling by dissociation of IKK-{gamma} and Hsp90 complex in human colonic epithelial cells. Park, K.A., Byun, H.S., Won, M., Yang, K.J., Shin, S., Piao, L., Kim, J.M., Yoon, W.H., Junn, E., Park, J., Seok, J.H., Hur, G.M. Carcinogenesis (2007) [Pubmed]
  10. Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma). Aradhya, S., Courtois, G., Rajkovic, A., Lewis, R.A., Levy, M., Israël, A., Nelson, D.L. Am. J. Hum. Genet. (2001) [Pubmed]
  11. AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth. Auwerx, J., Sassone-Corsi, P. Oncogene (1992) [Pubmed]
  12. PET studies of parkinsonism associated with mutation in the alpha-synuclein gene. Samii, A., Markopoulou, K., Wszolek, Z.K., Sossi, V., Dobko, T., Mak, E., Calne, D.B., Stoessl, A.J. Neurology (1999) [Pubmed]
  13. Characterization of the effect of SR48692 on inositol monophosphate, cyclic GMP and cyclic AMP responses linked to neurotensin receptor activation in neuronal and non-neuronal cells. Oury-Donat, F., Thurneyssen, O., Gonalons, N., Forgez, P., Gully, D., Le Fur, G., Soubrie, P. Br. J. Pharmacol. (1995) [Pubmed]
  14. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Zhang, S.Q., Kovalenko, A., Cantarella, G., Wallach, D. Immunity (2000) [Pubmed]
  15. In vivo identification of inducible phosphoacceptors in the IKKgamma/NEMO subunit of human IkappaB kinase. Carter, R.S., Pennington, K.N., Ungurait, B.J., Ballard, D.W. J. Biol. Chem. (2003) [Pubmed]
  16. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Wu, Z.H., Shi, Y., Tibbetts, R.S., Miyamoto, S. Science (2006) [Pubmed]
  17. Dimerization of the I{kappa}B Kinase-Binding Domain of NEMO Is Required for Tumor Necrosis Factor Alpha-Induced NF-{kappa}B Activity. Marienfeld, R.B., Palkowitsch, L., Ghosh, S. Mol. Cell. Biol. (2006) [Pubmed]
  18. Impaired dendritic-cell function in ectodermal dysplasia with immune deficiency is linked to defective NEMO ubiquitination. Temmerman, S.T., Ma, C.A., Borges, L., Kubin, M., Liu, S., Derry, J.M., Jain, A. Blood (2006) [Pubmed]
  19. The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component. Krappmann, D., Hatada, E.N., Tegethoff, S., Li, J., Klippel, A., Giese, K., Baeuerle, P.A., Scheidereit, C. J. Biol. Chem. (2000) [Pubmed]
  20. Physical and functional interaction of CARMA1 and CARMA3 with Ikappa kinase gamma-NFkappaB essential modulator. Stilo, R., Liguoro, D., Di Jeso, B., Formisano, S., Consiglio, E., Leonardi, A., Vito, P. J. Biol. Chem. (2004) [Pubmed]
  21. CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Leonardi, A., Chariot, A., Claudio, E., Cunningham, K., Siebenlist, U. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  22. The CAP-Gly domain of CYLD associates with the proline-rich sequence in NEMO/IKKgamma. Saito, K., Kigawa, T., Koshiba, S., Sato, K., Matsuo, Y., Sakamoto, A., Takagi, T., Shirouzu, M., Yabuki, T., Nunokawa, E., Seki, E., Matsuda, T., Aoki, M., Miyata, Y., Hirakawa, N., Inoue, M., Terada, T., Nagase, T., Kikuno, R., Nakayama, M., Ohara, O., Tanaka, A., Yokoyama, S. Structure (Camb.) (2004) [Pubmed]
  23. NEMO is a sensor of Lys 63-linked polyubiquitination and functions in NF-kappaB activation. Wu, C.J., Conze, D.B., Li, T., Srinivasula, S.M., Ashwell, J.D. Nat. Cell Biol. (2006) [Pubmed]
  24. Functional role of c-Src in IL-1-induced NF-kappa B activation: c-Src is a component of the IKK complex. Funakoshi-Tago, M., Tago, K., Andoh, K., Sonoda, Y., Tominaga, S., Kasahara, T. J. Biochem. (2005) [Pubmed]
  25. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Ea, C.K., Deng, L., Xia, Z.P., Pineda, G., Chen, Z.J. Mol. Cell (2006) [Pubmed]
  26. IKKgamma serves as a docking subunit of the IkappaB kinase (IKK) and mediates interaction of IKK with the human T-cell leukemia virus Tax protein. Harhaj, E.W., Sun, S.C. J. Biol. Chem. (1999) [Pubmed]
  27. Tumor necrosis factor (TNF) and phorbol ester induce TNF-related apoptosis-inducing ligand (TRAIL) under critical involvement of NF-kappa B essential modulator (NEMO)/IKKgamma. Siegmund, D., Hausser, A., Peters, N., Scheurich, P., Wajant, H. J. Biol. Chem. (2001) [Pubmed]
  28. Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO. Frelin, C., Imbert, V., Bottero, V., Gonthier, N., Samraj, A.K., Schulze-Osthoff, K., Auberger, P., Courtois, G., Peyron, J.F. Cell Death Differ. (2008) [Pubmed]
  29. Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. Chariot, A., Leonardi, A., Muller, J., Bonif, M., Brown, K., Siebenlist, U. J. Biol. Chem. (2002) [Pubmed]
  30. CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways. Bouchier-Hayes, L., Conroy, H., Egan, H., Adrain, C., Creagh, E.M., MacFarlane, M., Martin, S.J. J. Biol. Chem. (2001) [Pubmed]
  31. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Rothwarf, D.M., Zandi, E., Natoli, G., Karin, M. Nature (1998) [Pubmed]
  32. Domain-specific interaction with the I kappa B kinase (IKK)regulatory subunit IKK gamma is an essential step in tax-mediated activation of IKK. Xiao, G., Harhaj, E.W., Sun, S.C. J. Biol. Chem. (2000) [Pubmed]
  33. Isolation of full-length cDNA and chromosomal localization of human NF-kappaB modulator NEMO to Xq28. Jin, D.Y., Jeang, K.T. J. Biomed. Sci. (1999) [Pubmed]
WikiGenes - Universities