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Ikbkg

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Title: Ikbkg  
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Subject: Incontinentia pigmenti, Ataxia telangiectasia and Rad3 related, CGMP-dependent protein kinase, Serine/threonine-specific protein kinase, Protein dimer
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Ikbkg

Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma
Rendering based on PDB .
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; AMCBX1; FIP-3; FIP3; Fip3p; IKK-gamma; IMD33; IP; IP1; IP2; IPD2; NEMO; ZC2HC9
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
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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.[1] The human gene for IKBKG is located on chromosome Xq28.[2] Multiple transcript variants encoding different isoforms have been found for this gene.

Contents

  • Function 1
  • Clinical significance 2
  • As a Drug Target 3
  • Interactions 4
  • References 5
  • Further reading 6
  • External links 7

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,[3] hypohidrotic ectodermal dysplasia,[4] 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 TNF-alpha induced apoptosis, a lack of IKBKG (and hence a lack of active NF-κB) makes cells more prone to apoptosis.

As a Drug Target

A drug called NEMO Binding Domain (NBD) has been designed to inhibit activation of NF-κB.[5] NBD is a peptide that acts by binding to regulatory subunit NEMO (IKK-γ) thereby preventing it from binding subunits IKK-α and IKK-β and activating the IKK complex. In the absence of regulatory subunit IKK-γ the IKK complex is inactive, preventing the downstream signal transduction cascade leading to NF-κB activation. Binding of IKK-γ to IKK-α and IKK-β subunits activates the IKK complex leading to phosphorylation of IκB kinase, IκBα, and release of NF-κB dimers p105 and RELA to translocate to the nucleus and activate transcription of NF-κB responsive genes. In the presence of the NBD peptide, the IKK complex remains inactive and IκBα sequesters NF-κB dimers in the cytoplasm inhibiting transcription of NF-κB responsive genes. While NF-kB inhibitory drugs have previously been attractive to disease such as chronic inflammation and diabetes, specific cancers have been shown to have constitutive NF-kB activity.[6] Advanced B-cell lymphoma (ABC), a subtype of Diffuse large B-cell lymphoma (DLBCL) has been shown to have fundamental and upregulated NF-κB activity.[7] ABC lymphoma also has the lowest survival rate compared to DLBCL subtypes, Germinal Center B-cell-like and Undefined Type 3 lymphoma, highlighting the great clinical need to define targets for cancer therapy.[7] Notably, the NBD peptide targets the inflammation induced NF-κB activation pathway sparing the protective functions of basal NF-κB activity allowing for greater therapeutic value and fewer undesired side effects.

The NBD peptide was designed by identifying the amino acid binding sequence on IKK-α and IKK-β to which NEMO binds.[8] Studies reveal that a small region on the carboxyl terminus of IKK-α (L738-L743) and IKK-β (L737-L742) is essential for a stable interaction with NEMO and for the assembly of the active IKK complex. Henceforth this region is called the NEMO binding domain (NBD). The NBD peptide consists of the region from T735 to E745 of the IKK-β subunit fused with a sequence derived from the Antennapedia homeodomain that mediates membrane translocation. Furthermore, in vitro studies with the wild type NBD peptide has been shown to does-dependently inhibit interaction of IKKB with NEMO compared to mutant controls.[9] Additionally, NF-κB activation was suppressed in HeLa cells after incubation with NBD wild type peptides.[9] Moreover, to better understand the potential efficacy of the NBD peptide in suppressing inflammation, NBD peptide was tested on collagen induced rheumatoid arthritis mouse models. Notably, aberrant NF-κB activity is strongly associated with many aspects of the pathology of rheumatoid arthritis. Mice injected with wild-type NBD peptide showed only slightly visual signs of paw and joint swelling whereas mice injected with PBS or mutant NBD control peptides developed severe joint inflammation.[10] Additionally, analysis of the number of osteoclasts present in the joints of rheumatoid arthritic showed to be more prevalent in mice treated with PBS or the mutant NBD peptide compared to the NBD wild type peptide.[10] Markedly, throughout the mouse model studies neither toxicity or lethality nor damage to kidneys or livers, was observed.

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 small molecule drugs.[11] Therefore, the NBD peptide is unable to be an orally available compound and must be administered either intravenously or via intraperitoneal injection.

Interactions

IKBKG has been shown to interact with:

References

  1. ^ Rothwarf DM, Zandi E, Natoli G, Karin M (Sep 1998). "IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex". Nature 395 (6699): 297–300.  
  2. ^ 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.  
  3. ^ Aradhya S, Woffendin H, Jakins T, Bardaro T, Esposito T, Smahi A, Shaw C, Levy M, Munnich A, D'Urso M, Lewis RA, Kenwrick S, Nelson DL (Sep 2001). "A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations". Human Molecular Genetics 10 (19): 2171–9.  
  4. ^ Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM (Dec 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.  
  5. ^ May, Michael (2000). "Selective Inhibition of NF-κB Activation by a Peptide That Blocks the Interaction of NEMO with the I κB Kinase Complex". Science.  
  6. ^ Nogai, H; Wenzel, S; Grau, M (2013). "I B- Controls the Constitutive NF- B Target Gene Network and Survival of ABC DLBCL". Blood 122. 
  7. ^ a b Nogai, H (Sep 26, 2013). "IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL". Blood.  
  8. ^ May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (Sep 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.  
  9. ^ a b May, M.J (2000). "Selective Inhibition of NF-kappa B Activation by a Peptide That Blocks the Interaction of NEMO with the Ikappa B Kinase Complex". Science. 
  10. ^ a b Strickland I, Ghosh S (Nov 2006). "Use of cell permeable NBD peptides for suppression of inflammation". Annals of the Rheumatic Diseases. 65 Suppl 3: iii75–82.  
  11. ^ Craik, David (2012). "The Future of Peptide-based Drugs". Chemical Biology & Drug Design 81 (1). 
  12. ^ Wu CJ, Ashwell JD (Feb 2008). "NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation". Proceedings of the National Academy of Sciences of the United States of America 105 (8): 3023–8.  
  13. ^ Hayden MS, Ghosh S (Feb 2004). "Keeping cartographers busy". Nature Cell Biology 6 (2): 87–9.  
  14. ^ a b c Chen G, Cao P, Goeddel DV (Feb 2002). "TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90". Molecular Cell 9 (2): 401–10.  
  15. ^ Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Israël A, Véron M (May 2002). "NEMO trimerizes through its coiled-coil C-terminal domain". The Journal of Biological Chemistry 277 (20): 17464–75.  
  16. ^ a b Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (Oct 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell 103 (2): 351–61.  
  17. ^ a b Shifera AS, Horwitz MS (Mar 2008). "Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes". Molecular Immunology 45 (6): 1633–45.  
  18. ^ a b Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U (Oct 2002). "Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases". The Journal of Biological Chemistry 277 (40): 37029–36.  
  19. ^ a b Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW (May 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase". Molecular and Cellular Biology 22 (10): 3549–61.  
  20. ^ Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD (May 2008). "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation". Molecular and Cellular Biology 28 (10): 3538–47.  
  21. ^ a b Windheim M, Stafford M, Peggie M, Cohen P (Mar 2008). "Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase". Molecular and Cellular Biology 28 (5): 1783–91.  
  22. ^ Prajapati S, Verma U, Yamamoto Y, Kwak YT, Gaynor RB (Jan 2004). "Protein phosphatase 2Cbeta association with the IkappaB kinase complex is involved in regulating NF-kappaB activity". The Journal of Biological Chemistry 279 (3): 1739–46.  
  23. ^ Zhang SQ, Kovalenko A, Cantarella G, Wallach D (Mar 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.  
  24. ^ Leonardi A, Chariot A, Claudio E, Cunningham K, Siebenlist U (Sep 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.  
  25. ^ Li X, Commane M, Nie H, Hua X, Chatterjee-Kishore M, Wald D, Haag M, Stark GR (Sep 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.  
  26. ^ Lamothe B, Campos AD, Webster WK, Gopinathan A, Hur L, Darnay BG (Sep 2008). "The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL". The Journal of Biological Chemistry 283 (36): 24871–80.  

Further reading

  • Rothwarf DM, Zandi E, Natoli G, Karin M (Sep 1998). "IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex". Nature 395 (6699): 297–300.  
  • Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM (Feb 1999). "IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex". Molecular and Cellular Biology 19 (2): 1526–38.  
  • Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D, Horwitz MS (Feb 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.  
  • 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.  
  • Jin DY, Giordano V, Kibler KV, Nakano H, Jeang KT (Jun 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.  
  • Zhang SQ, Kovalenko A, Cantarella G, Wallach D (Mar 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.  
  • 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.  
  • Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Núñez G (Sep 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.  
  • Ye Z, Connor JR (Aug 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.  
  • Li X, Commane M, Nie H, Hua X, Chatterjee-Kishore M, Wald D, Haag M, Stark GR (Sep 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.  
  • Leonardi A, Chariot A, Claudio E, Cunningham K, Siebenlist U (Sep 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.  
  • May MJ, D'Acquisto F, Madge LA, Glöckner J, Pober JS, Ghosh S (Sep 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.  
  • Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM (Dec 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.  
  • Xiao G, Sun SC (Oct 2000). "Activation of IKKalpha and IKKbeta through their fusion with HTLV-I tax protein". Oncogene 19 (45): 5198–203.  
  • Li XH, Fang X, Gaynor RB (Feb 2001). "Role of IKKgamma/nemo in assembly of the Ikappa B kinase complex". The Journal of Biological Chemistry 276 (6): 4494–500.  
  • Poyet JL, Srinivasula SM, Alnemri ES (Feb 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.  
  • Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W (Mar 2001). "Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia". Nature Immunology 2 (3): 223–8.  
  • 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 (Mar 2001). "X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling". Nature Genetics 27 (3): 277–85.  
  • Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (Sep 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports 1 (3): 287–92.  
  • Galgóczy P, Rosenthal A, Platzer M (Jun 2001). "Human-mouse comparative sequence analysis of the NEMO gene reveals an alternative promoter within the neighboring G6PD gene". Gene 271 (1): 93–8.  

External links

  • IKBKG protein, human at the US 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
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