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Gene Review

Ikbkg  -  inhibitor of kappaB kinase gamma

Mus musculus

Synonyms: 1110037D23Rik, AI848108, AI851264, AW124339, I-kappa-B kinase subunit gamma, ...
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Disease relevance of Ikbkg

  • More importantly, blockade of NEMO assembly with the IKK complex is a viable strategy to avert inflammatory osteolysis [1].
  • NEMO/IKK gamma-deficient mice model incontinentia pigmenti [2].
  • Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID) [3].
  • Nuclear factor-kappaB essential modulator (NEMO), also called IKKgamma, has been proposed as a 'universal' adaptor of the I-kappaB kinase (IKK) complex for stimuli such as proinflammatory cytokines, microbes, and the HTLV-I Tax oncoprotein [4].
  • The stimulation of whole blood by live BCG thus triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes [5].
  • These results reveal that NEMO-mediated NF-kappaB activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver [6].

High impact information on Ikbkg

  • The NEMO cDNA was also able to complement another NF-kappaB-unresponsive cell line, 1.3E2, in which the protein is also absent, allowing us to demonstrate that this factor is required not only for Tax but also for LPS, PMA, and IL-1 stimulation of NF-kappaB activity [7].
  • IKKbeta and the IKKgamma/NEMO regulatory subunit are required for activating NF-kappaB by pro-inflammatory stimuli and preventing apoptosis induced by tumour necrosis factor-alpha (refs 5,6,7,8,9,10,11) [8].
  • Our data provide in vivo evidence that NEMO/IKKgamma is the first essential, noncatalytic component of the IKK complex [9].
  • Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice [9].
  • T cell-specific ablation of NEMO or replacement of IKK2 with a kinase-dead mutant prevent development of peripheral T cells altogether [10].

Chemical compound and disease context of Ikbkg

  • Inhibition of IKK activation, through sequestering NEMO, blocks PMMA-induced osteoclastogenesis and calvarial inflammatory osteolysis [11].

Biological context of Ikbkg


Anatomical context of Ikbkg

  • This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells [16].
  • These results identify the NEMO-deficient keratinocyte as a potent initiator of skin inflammation and provide novel insights into the mechanism leading to the pathogenesis of IP [17].
  • Disruption of the X-linked gene encoding NF-kappa B essential modulator (NEMO) produces male embryonic lethality, completely blocks NF-kappa B activation by proinflammatory cytokines, and interferes with the generation and/or persistence of lymphocytes [2].
  • Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction [18].
  • Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes [5].

Regulatory relationships of Ikbkg


Other interactions of Ikbkg


Analytical, diagnostic and therapeutic context of Ikbkg


  1. The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis. Dai, S., Hirayama, T., Abbas, S., Abu-Amer, Y. J. Biol. Chem. (2004) [Pubmed]
  2. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Schmidt-Supprian, M., Bloch, W., Courtois, G., Addicks, K., Israël, A., Rajewsky, K., Pasparakis, M. Mol. Cell (2000) [Pubmed]
  3. The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Smahi, A., Courtois, G., Rabia, S.H., Döffinger, R., Bodemer, C., Munnich, A., Casanova, J.L., Israël, A. Hum. Mol. Genet. (2002) [Pubmed]
  4. Segregation of NF-kappaB activation through NEMO/IKKgamma by Tax and TNFalpha: implications for stimulus-specific interruption of oncogenic signaling. Iha, H., Kibler, K.V., Yedavalli, V.R., Peloponese, J.M., Haller, K., Miyazato, A., Kasai, T., Jeang, K.T. Oncogene (2003) [Pubmed]
  5. Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. Feinberg, J., Fieschi, C., Doffinger, R., Feinberg, M., Leclerc, T., Boisson-Dupuis, S., Picard, C., Bustamante, J., Chapgier, A., Filipe-Santos, O., Ku, C.L., de Beaucoudrey, L., Reichenbach, J., Antoni, G., Baldé, R., Alcaïs, A., Casanova, J.L. Eur. J. Immunol. (2004) [Pubmed]
  6. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Luedde, T., Beraza, N., Kotsikoris, V., van Loo, G., Nenci, A., De Vos, R., Roskams, T., Trautwein, C., Pasparakis, M. Cancer. Cell (2007) [Pubmed]
  7. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Yamaoka, S., Courtois, G., Bessia, C., Whiteside, S.T., Weil, R., Agou, F., Kirk, H.E., Kay, R.J., Israël, A. Cell (1998) [Pubmed]
  8. IKKalpha controls formation of the epidermis independently of NF-kappaB. Hu, Y., Baud, V., Oga, T., Kim, K.I., Yoshida, K., Karin, M. Nature (2001) [Pubmed]
  9. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Rudolph, D., Yeh, W.C., Wakeham, A., Rudolph, B., Nallainathan, D., Potter, J., Elia, A.J., Mak, T.W. Genes Dev. (2000) [Pubmed]
  10. Mature T cells depend on signaling through the IKK complex. Schmidt-Supprian, M., Courtois, G., Tian, J., Coyle, A.J., Israël, A., Rajewsky, K., Pasparakis, M. Immunity (2003) [Pubmed]
  11. Inhibition of IKK activation, through sequestering NEMO, blocks PMMA-induced osteoclastogenesis and calvarial inflammatory osteolysis. Clohisy, J.C., Yamanaka, Y., Faccio, R., Abu-Amer, Y. J. Orthop. Res. (2006) [Pubmed]
  12. Myosin motor Myo1c and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1. Nakamori, Y., Emoto, M., Fukuda, N., Taguchi, A., Okuya, S., Tajiri, M., Miyagishi, M., Taira, K., Wada, Y., Tanizawa, Y. J. Cell Biol. (2006) [Pubmed]
  13. Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury. Luedde, T., Assmus, U., Wüstefeld, T., Meyer zu Vilsendorf, A., Roskams, T., Schmidt-Supprian, M., Rajewsky, K., Brenner, D.A., Manns, M.P., Pasparakis, M., Trautwein, C. J. Clin. Invest. (2005) [Pubmed]
  14. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex. Mercurio, F., Murray, B.W., Shevchenko, A., Bennett, B.L., Young, D.B., Li, J.W., Pascual, G., Motiwala, A., Zhu, H., Mann, M., Manning, A.M. Mol. Cell. Biol. (1999) [Pubmed]
  15. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Makris, C., Godfrey, V.L., Krähn-Senftleben, G., Takahashi, T., Roberts, J.L., Schwarz, T., Feng, L., Johnson, R.S., Karin, M. Mol. Cell (2000) [Pubmed]
  16. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Claudio, E., Brown, K., Park, S., Wang, H., Siebenlist, U. Nat. Immunol. (2002) [Pubmed]
  17. Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. Nenci, A., Huth, M., Funteh, A., Schmidt-Supprian, M., Bloch, W., Metzger, D., Chambon, P., Rajewsky, K., Krieg, T., Haase, I., Pasparakis, M. Hum. Mol. Genet. (2006) [Pubmed]
  18. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M.F., Pasparakis, M. Nature (2007) [Pubmed]
  19. Lymphotoxin-beta receptor mediates NEMO-independent NF-kappaB activation. Saitoh, T., Nakano, H., Yamamoto, N., Yamaoka, S. FEBS Lett. (2002) [Pubmed]
  20. Human-mouse comparative sequence analysis of the NEMO gene reveals an alternative promoter within the neighboring G6PD gene. Galgóczy, P., Rosenthal, A., Platzer, M. Gene (2001) [Pubmed]
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