3brv

Structural highlights

Disease

[NEMO_HUMAN] Defects in IKBKG are the cause of ectodermal dysplasia anhidrotic with immunodeficiency X-linked (EDAID) [MIM:300291]; also known as hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID). Is a form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Characterized by absence of sweat glands, sparse scalp hair, rare conical teeth and immunological abnormalities resulting in severe infectious diseases.^{[1] [2] [3] [4] [5] [6] [7] [8] [9]} Defects in IKBKG are the cause of ectodermal dysplasia anhidrotic with immunodeficiency-osteopetrosis-lymphedema (OLEDAID) [MIM:300301]. Defects in IKBKG are a cause of immunodeficiency NEMO-related without anhidrotic ectodermal dysplasia (NEMOID) [MIM:300584]; also called immunodeficiency without anhidrotic ectodermal dysplasia, isolated immunodeficiency or pure immunodeficiency. Patients manifest immunodeficiency not associated with other abnormalities, and resulting in increased infection susceptibility. Patients suffer from multiple episodes of infectious diseases.^{[10] [11]} Defects in IKBKG are the cause of susceptibility to X-linked familial atypical micobacteriosis type 1 (AMCBX1) [MIM:300636]; also known as X-linked disseminated atypical mycobacterial infection type 1 or X-linked susceptibility to mycobacterial disease type 1. AMCBX1 is the X-linked recessive form of Mendelian susceptibility to mycobacterial disease (MSMD). MSMD is a congenital syndrome resulting in predisposition to clinical disease caused by weakly virulent mycobacterial species, such as bacillus Calmette-Guerin vaccines and non-tuberculous, environmental mycobacteria. Patients are also susceptible to the more virulent species Mycobacterium tuberculosis.^{[12] [13]} Defects in IKBKG are the cause of recurrent isolated invasive pneumococcal disease type 2 (IPD2) [MIM:300640]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.^[14] Defects in IKBKG are the cause of incontinentia pigmenti (IP) [MIM:308300]; formerly designed familial incontinentia pigmenti type II (IP2). IP is a genodermatosis usually prenatally lethal in males. In affected females, it causes abnormalities of the skin, hair, eyes, nails, teeth, skeleton, heart, and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring.^{[15] [16] [17] [18] [19] [20] [21] [22]}

Function

[IKKB_HUMAN] Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.^{[23] [24] [25] [26] [27] [28]} [NEMO_HUMAN] Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Its binding to scaffolding polyubiquitin seems to play a role in IKK activation by multiple signaling receptor pathways. However, the specific type of polyubiquitin recognized upon cell stimulation (either 'Lys-63'-linked or linear polyubiquitin) and its functional importance is reported conflictingly. Also considered to be a mediator for TAX activation of NF-kappa-B. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity (By similarity). Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination.^{[29] [30] [31]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell. 2003 Nov 26;115(5):565-76. PMID:14651848
2. ↑ Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol. 2006 Apr;8(4):398-406. Epub 2006 Mar 19. PMID:16547522 doi:10.1038/ncb1384
3. ↑ Nanda SK, Venigalla RK, Ordureau A, Patterson-Kane JC, Powell DW, Toth R, Arthur JS, Cohen P. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J Exp Med. 2011 Jun 6;208(6):1215-28. doi: 10.1084/jem.20102177. Epub 2011 May, 23. PMID:21606507 doi:10.1084/jem.20102177
4. ↑ Lo YC, Lin SC, Rospigliosi CC, Conze DB, Wu CJ, Ashwell JD, Eliezer D, Wu H. Structural basis for recognition of diubiquitins by NEMO. Mol Cell. 2009 Mar 13;33(5):602-15. Epub 2009 Jan 29. PMID:19185524 doi:10.1016/j.molcel.2009.01.012
5. ↑ Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM. 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). Am J Hum Genet. 2000 Dec;67(6):1555-62. Epub 2000 Oct 24. PMID:11047757 doi:S0002-9297(07)63223-6
6. ↑ Doffinger 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, Israel A, Courtois G, Casanova JL. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001 Mar;27(3):277-85. PMID:11242109 doi:10.1038/85837
7. ↑ Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol. 2001 Mar;2(3):223-8. PMID:11224521 doi:10.1038/85277
8. ↑ Orange JS, Brodeur SR, Jain A, Bonilla FA, Schneider LC, Kretschmer R, Nurko S, Rasmussen WL, Kohler JR, Gellis SE, Ferguson BM, Strominger JL, Zonana J, Ramesh N, Ballas ZK, Geha RS. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest. 2002 Jun;109(11):1501-9. PMID:12045264 doi:10.1172/JCI14858
9. ↑ Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol. 2004 Apr;113(4):725-33. PMID:15100680 doi:10.1016/j.jaci.2004.01.762
10. ↑ Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol. 2004 Apr;113(4):725-33. PMID:15100680 doi:10.1016/j.jaci.2004.01.762
11. ↑ Orange JS, Levy O, Brodeur SR, Krzewski K, Roy RM, Niemela JE, Fleisher TA, Bonilla FA, Geha RS. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol. 2004 Sep;114(3):650-6. PMID:15356572 doi:10.1016/j.jaci.2004.06.052
12. ↑ Lo YC, Lin SC, Rospigliosi CC, Conze DB, Wu CJ, Ashwell JD, Eliezer D, Wu H. Structural basis for recognition of diubiquitins by NEMO. Mol Cell. 2009 Mar 13;33(5):602-15. Epub 2009 Jan 29. PMID:19185524 doi:10.1016/j.molcel.2009.01.012
13. ↑ Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, Frucht DM, Christel K, von Bernuth H, Jouanguy E, Feinberg J, Durandy A, Senechal B, Chapgier A, Vogt G, de Beaucoudrey L, Fieschi C, Picard C, Garfa M, Chemli J, Bejaoui M, Tsolia MN, Kutukculer N, Plebani A, Notarangelo L, Bodemer C, Geissmann F, Israel A, Veron M, Knackstedt M, Barbouche R, Abel L, Magdorf K, Gendrel D, Agou F, Holland SM, Casanova JL. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. 2006 Jul 10;203(7):1745-59. Epub 2006 Jul 3. PMID:16818673 doi:10.1084/jem.20060085
14. ↑ Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, von Bernuth H, Filipe-Santos O, Chang HH, Lawrence T, Raes M, Marodi L, Bossuyt X, Casanova JL. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. 2007 Jan;44(1):16-23. Epub 2006 Sep 1. PMID:16950813 doi:jmg.2006.044446
15. ↑ Ashida H, Kim M, Schmidt-Supprian M, Ma A, Ogawa M, Sasakawa C. A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat Cell Biol. 2010 Jan;12(1):66-73; sup pp 1-9. doi: 10.1038/ncb2006. Epub 2009 , Dec 13. PMID:20010814 doi:10.1038/ncb2006
16. ↑ Sebban-Benin H, Pescatore A, Fusco F, Pascuale V, Gautheron J, Yamaoka S, Moncla A, Ursini MV, Courtois G. Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti. Hum Mol Genet. 2007 Dec 1;16(23):2805-15. Epub 2007 Aug 29. PMID:17728323 doi:10.1093/hmg/ddm237
17. ↑ Lo YC, Lin SC, Rospigliosi CC, Conze DB, Wu CJ, Ashwell JD, Eliezer D, Wu H. Structural basis for recognition of diubiquitins by NEMO. Mol Cell. 2009 Mar 13;33(5):602-15. Epub 2009 Jan 29. PMID:19185524 doi:10.1016/j.molcel.2009.01.012
18. ↑ Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, von Bernuth H, Filipe-Santos O, Chang HH, Lawrence T, Raes M, Marodi L, Bossuyt X, Casanova JL. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. 2007 Jan;44(1):16-23. Epub 2006 Sep 1. PMID:16950813 doi:jmg.2006.044446
19. ↑ Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israel 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. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000 May 25;405(6785):466-72. PMID:10839543 doi:10.1038/35013114
20. ↑ Cordier F, Grubisha O, Traincard F, Veron M, Delepierre M, Agou F. The zinc finger of NEMO is a functional ubiquitin-binding domain. J Biol Chem. 2009 Jan 30;284(5):2902-7. doi: 10.1074/jbc.M806655200. Epub 2008, Nov 25. PMID:19033441 doi:10.1074/jbc.M806655200
21. ↑ 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. A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet. 2001 Sep 15;10(19):2171-9. PMID:11590134
22. ↑ Fusco F, Bardaro T, Fimiani G, Mercadante V, Miano MG, Falco G, Israel A, Courtois G, D'Urso M, Ursini MV. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet. 2004 Aug 15;13(16):1763-73. Epub 2004 Jun 30. PMID:15229184 doi:10.1093/hmg/ddh192
23. ↑ Salmeron A, Janzen J, Soneji Y, Bump N, Kamens J, Allen H, Ley SC. Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J Biol Chem. 2001 Jun 22;276(25):22215-22. Epub 2001 Apr 10. PMID:11297557 doi:10.1074/jbc.M101754200
24. ↑ Lobry C, Lopez T, Israel A, Weil R. Negative feedback loop in T cell activation through IkappaB kinase-induced phosphorylation and degradation of Bcl10. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):908-13. Epub 2007 Jan 9. PMID:17213322 doi:10.1073/pnas.0606982104
25. ↑ Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF. NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010 Apr 30;141(3):483-96. doi: 10.1016/j.cell.2010.03.040. PMID:20434986 doi:10.1016/j.cell.2010.03.040
26. ↑ Yoboua F, Martel A, Duval A, Mukawera E, Grandvaux N. Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta. J Virol. 2010 Jul;84(14):7267-77. doi: 10.1128/JVI.00142-10. Epub 2010 Apr 21. PMID:20410276 doi:10.1128/JVI.00142-10
27. ↑ Tsuchiya Y, Asano T, Nakayama K, Kato T Jr, Karin M, Kamata H. Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UV-induced NF-kappaB activation. Mol Cell. 2010 Aug 27;39(4):570-82. doi: 10.1016/j.molcel.2010.07.030. PMID:20797629 doi:10.1016/j.molcel.2010.07.030
28. ↑ Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P. Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. doi: 10.1042/BJ20101701. PMID:21138416 doi:10.1042/BJ20101701
29. ↑ Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature. 2004 Jan 8;427(6970):167-71. Epub 2003 Dec 24. PMID:14695475 doi:10.1038/nature02273
30. ↑ Zeng W, Xu M, Liu S, Sun L, Chen ZJ. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell. 2009 Oct 23;36(2):315-25. doi: 10.1016/j.molcel.2009.09.037. PMID:19854139 doi:10.1016/j.molcel.2009.09.037
31. ↑ Arimoto K, Funami K, Saeki Y, Tanaka K, Okawa K, Takeuchi O, Akira S, Murakami Y, Shimotohno K. Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15856-61. doi:, 10.1073/pnas.1004621107. Epub 2010 Aug 19. PMID:20724660 doi:10.1073/pnas.1004621107
32. ↑ Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A. Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure. 2008 May;16(5):798-808. PMID:18462684 doi:10.1016/j.str.2008.02.012