IKBKG
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NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the IKBKG gene. NEMO is a subunit of the IκB kinase complex that activates NF-κB.[5] The human gene for IKBKG is located on the chromosome band Xq28.[6] Multiple transcript variants encoding different isoforms have been found for this gene.
Function
NEMO (IKK-γ) is the regulatory subunit of the inhibitor of IκB kinase (IKK) complex, which activates NF-κB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways.
Clinical significance
Mutations in the IKBKG gene results in incontinentia pigmenti,[7] hypohidrotic ectodermal dysplasia,[8] and several other types of immunodeficiencies.
Incontinentia Pigmenti (IP) is an X-linked dominant disease caused by a mutation in the IKBKG gene. Since IKBKG helps activate NF-κB, which protects cells against
Moreover, NEMO has been shown to play a role in preeclampsia and may offer insights into the genetic etiology of this condition. An increased level of NEMO gene expression was found in the blood of pregnant women with preeclampsia and their children.[9] However, a decrease of the mRNA levels of total NEMO and the transcripts 1A, 1B, and 1C in placentas derived from preeclamptic women may be the main reason for intensified apoptosis.[9] Sanger sequencing has indicated two distinct variations in the 3’ UTR region of the NEMO gene in preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T).[10] The occurrence of a maternal TT genotype and either a TT genotype in the daughter or T allele in the son increases the risk of preeclampsia by 2.59 fold. The configuration of those maternal and fetal genotypes (TT mother/TT daughter or TT mother/T son) is also associated with the level of NEMO gene expression.[10]
NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG. It mostly affects males and has a highly variable set of symptoms and prognoses.[11]
As a drug target
A drug called NEMO Binding Domain (NBD) has been designed to inhibit activation of
The NBD
Despite the potential for NBD peptide as a viable NF- κB inhibitory drug, disadvantages arise because of its peptide form. Peptides as drugs lack membrane permeability, are poorly orally viable, and generally have lower metabolic stability than
Interactions
IKBKG has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000269335 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000004221 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 4421659.
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- ^ PMID 26571191.
- ^ a b http://content.ebscohost.com/ContentServer.asp?T=P&P=AN&K=28654673&S=R&D=mdc&EbscoContent=dGJyMNHX8kSep7I4v%2BbwOLCmr1Cep7VSsq%2B4TLWWxWXS&ContentCustomer=dGJyMPGus0m0q7JQuePfgeyx43zx#page14 [dead link]
- Great Ormond Street Hospital for Children
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Further reading
- Rothwarf DM, Zandi E, Natoli G, Karin M (September 1998). "IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex". Nature. 395 (6699): 297–300. S2CID 4421659.
- Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM (February 1999). "IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex". Molecular and Cellular Biology. 19 (2): 1526–38. PMID 9891086.
- Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D, Horwitz MS (February 1999). "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". Proceedings of the National Academy of Sciences of the United States of America. 96 (3): 1042–7. PMID 9927690.
- Jin DY, Jeang KT (1999). "Isolation of full-length cDNA and chromosomal localization of human NF-kappaB modulator NEMO to Xq28". Journal of Biomedical Science. 6 (2): 115–20. S2CID 202651606.
- Jin DY, Giordano V, Kibler KV, Nakano H, Jeang KT (June 1999). "Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma". The Journal of Biological Chemistry. 274 (25): 17402–5. PMID 10364167.
- Zhang SQ, Kovalenko A, Cantarella G, Wallach D (March 2000). "Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation". Immunity. 12 (3): 301–11. PMID 10755617.
- Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israël A, Heiss NS, Klauck SM, Kioschis P, Wiemann S, Poustka A, Esposito T, Bardaro T, Gianfrancesco F, Ciccodicola A, D'Urso M, Woffendin H, Jakins T, Donnai D, Stewart H, Kenwrick SJ, Aradhya S, Yamagata T, Levy M, Lewis RA, Nelson DL (May 2000). "Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium". Nature. 405 (6785): 466–72. S2CID 4416325.
- Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Núñez G (September 2000). "An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways". The Journal of Biological Chemistry. 275 (36): 27823–31. PMID 10880512.
- Ye Z, Connor JR (August 2000). "cDNA cloning by amplification of circularized first strand cDNAs reveals non-IRE-regulated iron-responsive mRNAs". Biochemical and Biophysical Research Communications. 275 (1): 223–7. PMID 10944468.
- Li X, Commane M, Nie H, Hua X, Chatterjee-Kishore M, Wald D, Haag M, Stark GR (September 2000). "Act1, an NF-kappa B-activating protein". Proceedings of the National Academy of Sciences of the United States of America. 97 (19): 10489–93. PMID 10962024.
- Leonardi A, Chariot A, Claudio E, Cunningham K, Siebenlist U (September 2000). "CIKS, a connection to Ikappa B kinase and stress-activated protein kinase". Proceedings of the National Academy of Sciences of the United States of America. 97 (19): 10494–9. PMID 10962033.
- May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (September 2000). "Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex". Science. 289 (5484): 1550–4. PMID 10968790.
- Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM (December 2000). "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)". American Journal of Human Genetics. 67 (6): 1555–62. PMID 11047757.
- Xiao G, Sun SC (October 2000). "Activation of IKKalpha and IKKbeta through their fusion with HTLV-I tax protein". Oncogene. 19 (45): 5198–203. S2CID 29415593.
- Li XH, Fang X, Gaynor RB (February 2001). "Role of IKKgamma/nemo in assembly of the Ikappa B kinase complex". The Journal of Biological Chemistry. 276 (6): 4494–500. PMID 11080499.
- Poyet JL, Srinivasula SM, Alnemri ES (February 2001). "vCLAP, a caspase-recruitment domain-containing protein of equine Herpesvirus-2, persistently activates the Ikappa B kinases through oligomerization of IKKgamma". The Journal of Biological Chemistry. 276 (5): 3183–7. PMID 11113112.
- Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W (March 2001). "Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia". Nature Immunology. 2 (3): 223–8. S2CID 9425501.
- Döffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israël A, Courtois G, Casanova JL (March 2001). "X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling". Nature Genetics. 27 (3): 277–85. S2CID 24898789.
- Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (September 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. PMID 11256614.
- Galgóczy P, Rosenthal A, Platzer M (June 2001). "Human-mouse comparative sequence analysis of the NEMO gene reveals an alternative promoter within the neighboring G6PD gene". Gene. 271 (1): 93–8. PMID 11410370.
External links
- IKBKG+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- GeneReviews/NIH/NCBI/UW entry on Incontinentia Pigmenti
- OMIM IKBKG
- GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
