Reviewed, UniProtKB/Swiss-Prot Q9Y6K9 (NEMO_HUMAN)

Names and origin

Protein names

Recommended name:
    NF-kappa-B essential modulator
      Short name=NEMO
Alternative name(s):
    NF-kappa-B essential modifier
    Inhibitor of nuclear factor kappa-B kinase subunit gamma
      Short name=IkB kinase subunit gamma
      Short name=I-kappa-B kinase gamma
      Short name=IKK-gamma
      Short name=IKKG
    IkB kinase-associated protein 1
      Short name=IKKAP1
    FIP-3

Gene names

Name:	IKBKG
Synonyms:	FIP3, NEMO

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	419 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	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. 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.
Subunit structure	Homodimer; disulfide-linked. Component of the I-kappa-B-kinase (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG subunits. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Interacts with COPS3, CYLD, NALP2, TRPC4AP and LRDD. Interacts with ATM; the complex is exported from the nucleus. Interacts with TRAF6. Interacts with HTLV-1 Tax oncoprotein; the interaction activates IKBKG. Interacts with TANK; the interaction is enhanced by IKBKE and TBK1. Part of a ternary complex consisting of TANK, IKBKB and IKBKG.
Subcellular location	Cytoplasm. Nucleus.
Tissue specificity	Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Post-translational modification	Phosphorylation at Ser-68 attenuates aminoterminal homodimerization. Polyubiquitinated on Lys-285 through 'Lys-63'; the ubiquitination is mediated by NOD2 and RIPK2 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Polyubiquitinated on Lys-399 through 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and probably plays a role in signaling by facilitating interactions with ubiquitin domain-containing proteins and activates the NF-kappa-B pathway. Sumoylated on Lys-277 and Lys-309 by SUMO1; the modification results in phosphorylation of Ser-85 by ATM leading to a replacement of the sumoylation by mono-ubiquitination on these residues. Mono-ubiquitinated on Lys-277 and Lys-309; promotes nuclear export.
Involvement in disease	Defects in IKBKG are the cause of ectodermal dysplasia anhidrotic with immunodeficiency X-linked (EDAXID) [MIM:300291]; also known as hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID). Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. EDAXID is characterized by absence of sweat glands, sparse scalp hair, rare conical teeth and immunological abnormalities resulting in severe infectious diseases. 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 without anhidrotic ectodermal dysplasia [MIM:300584]; also called 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. 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. 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. 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.
Sequence similarities	Contains 1 C2HC-type zinc finger.

Ontologies

Keywords
Biological process	Host-virus interaction Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation Ectodermal dysplasia Osteopetrosis
Domain	Coiled coil Zinc-finger
Ligand	Metal-binding Zinc
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	I-kappaB kinase/NF-kappaB cascade Ref.1 Traceable author statement. Source: ProtInc T cell receptor signaling pathway Ref.21 Traceable author statement. Source: UniProtKB induction of apoptosis Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	protein binding Ref.3 Ref.11 Ref.14 Inferred from physical interaction. Source: UniProtKB signal transducer activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CHUK	O15111	3	EBI-81279,EBI-81249
COPS3	Q9UNS2	1	EBI-81279,EBI-350590
IKBKB	O14920	3	EBI-81279,EBI-81266
NCOA3	Q9Y6Q9	1	EBI-81279,EBI-81196
RIPK1	Q13546	1	EBI-81279,EBI-358507
SRC	P12931	1	EBI-81279,EBI-621482
TNIP2	Q8NFZ5	2	EBI-81279,EBI-359372

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 419

419

NF-kappa-B essential modulator

PRO_0000096782

Regions

Domain

322 – 343

22

Leucine-zipper Potential

Zinc finger

396 – 417

22

C2HC-type

Region

44 – 111

68

Interaction with CHUK/IKBKB

Region

246 – 365

120

Self-association

Region

382 – 419

38

Interaction with CYLD

Coiled coil

49 – 356

308

Potential

Amino acid modifications

Modified residue

31

1

Phosphoserine; by IKKB

Modified residue

43

1

Phosphoserine; by IKKB

Modified residue

68

1

Phosphoserine

Modified residue

85

1

Phosphoserine; by ATM

Modified residue

376

1

Phosphoserine; by IKKB

Disulfide bond

54

Interchain

Disulfide bond

347

Interchain

Cross-link

277

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

Cross-link

283

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Cross-link

309

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

Cross-link

399

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Natural variant

57

1

E → K in IP; shows the same luciferase activity as the control.

VAR_026491

Natural variant

90

1

Missing in IP; only 46.3% of the activation obtained with the wild-type protein.

VAR_026492

Natural variant

113

1

D → N in IP; shows the same luciferase activity as the control.

VAR_026493

Natural variant

123

1

R → W in IP; shows the same luciferase activity as the control.

VAR_026494

Natural variant

153

1

L → R in EDAXID.

VAR_026495

Natural variant

173

1

R → G in IPD2.

VAR_031958

Natural variant

175

1

R → P in EDAXID.

VAR_011320

Natural variant

227

1

L → P in EDAXID.

VAR_011321

Natural variant

288

1

A → G in EDAXID.

VAR_011322

Natural variant

311

1

D → N in EDAXID.

VAR_011323

Natural variant

315

1

E → A in AMCBX1.

VAR_031959

Natural variant

319

1

R → Q in AMCBX1.

VAR_031960

Natural variant

323

1

A → P in IP; diminishes interaction with TRAF6 and polyubiquitination.

VAR_042666

Natural variant

406

1

D → V in EDAXID.

VAR_011324

Natural variant

407

1

M → V in IP.

VAR_009182

Natural variant

417

1

C → F in EDAXID.

VAR_011325

Natural variant

417

1

C → R in EDAXID.

VAR_011326

Natural variant

417

1

C → Y in EDAXID.

VAR_026496

Experimental info

Mutagenesis

68

1

S → A: Increases formation of homodimers

Mutagenesis

68

1

S → E: Abolishes interaction with IKBKB; abolishes TNF-alpha induced NF-kappa-B activity

Mutagenesis

85

1

S → A: Decreases ubiquitination and abolishes nuclear export

Mutagenesis

277

1

K → A: Abolishes sumoylation and IKK activation; when associated with A-309

Mutagenesis

309

1

K → A: Abolishes sumoylation and IKK activation; when associated with A-277

Mutagenesis

399

1

K → R: Abolishes ubiquitination mediated by BCL10

Sequence conflict

341

1

S → R in AAD12183. Ref.1

Sequence conflict

387

1

S → R in AAD12183. Ref.1

Secondary structure

1

.

.

.

.

.

.

419

Helix Strand Turn

Details...

Helix

50 – 108

59

Turn

194 – 196

3

Helix

197 – 249

53

Sequences

	Sequence		Length	Mass (Da)
	Q9Y6K9-1 [UniParc]. Last modified May 30, 2000. Version 2. Checksum: 322D1037881447FF	FASTA	419	48,198
	10 20 30 40 50 60 MNRHLWKSQL CEMVQPSGGP AADQDVLGEE SPLGKPAMLH LPSEQGAPET LQRCLEENQE 70 80 90 100 110 120 LRDAIRQSNQ ILRERCEELL HFQASQREEK EFLMCKFQEA RKLVERLGLE KLDLKRQKEQ 130 140 150 160 170 180 ALREVEHLKR CQQQMAEDKA SVKAQVTSLL GELQESQSRL EAATKECQAL EGRARAASEQ 190 200 210 220 230 240 ARQLESEREA LQQQHSVQVD QLRMQGQSVE AALRMERQAA SEEKRKLAQL QVAYHQLFQE 250 260 270 280 290 300 YDNHIKSSVV GSERKRGMQL EDLKQQLQQA EEALVAKQEV IDKLKEEAEQ HKIVMETVPV 310 320 330 340 350 360 LKAQADIYKA DFQAERQARE KLAEKKELLQ EQLEQLQREY SKLKASCQES ARIEDMRKRH 370 380 390 400 410 VEVSQAPLPP APAYLSSPLA LPSQRRSPPE EPPDFCCPKC QYQAPDMDTL QIHVMECIE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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. 96:1042-1047(1999) [PubMed: 9927690] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"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. 6:115-120(1999) [PubMed: 10087442] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Mammary cancer.
[3]	"IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex." Rothwarf D.M., Zandi E., Natoli G., Karin M. Nature 395:297-300(1998) [PubMed: 9751060] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Cervix carcinoma.
[4]	"Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti." Smahi A., Courtois G., Vabres P., Yamaoka S., Heuertz S., Munnich A., Israel A., Heiss N.S., Klauck S.M., 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 S.J., Aradhya S., Yamagata T., Levy M., Lewis R.A., Nelson D.L. Nature 405:466-472(2000) [PubMed: 10839543] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT IP VAL-407.
[5]	"cDNA cloning by amplification of circularized first strand cDNAs reveals non-IRE-regulated iron-responsive mRNAs." Ye Z., Connor J.R. Biochem. Biophys. Res. Commun. 275:223-227(2000) [PubMed: 10944468] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Astrocytoma.
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung, Placenta and Skin.
[8]	"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. 19:1526-1538(1999) [PubMed: 9891086] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 51-419, PROTEIN SEQUENCE OF 144-159. Tissue: Cervix carcinoma.
[9]	"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." Jin D.-Y., Giordano V., Kibler K.V., Nakano H., Jeang K.-T. J. Biol. Chem. 274:17402-17405(1999) [PubMed: 10364167] [Abstract] Cited for: INTERACTION WITH HTLV-1 TAX-1.
[10]	"Activation of IKKalpha and IKKbeta through their fusion with HTLV-I tax protein." Xiao G., Sun S.C. Oncogene 19:5198-5203(2000) [PubMed: 11064457] [Abstract] Cited for: INTERACTION WITH HTLV-1 TAX-1.
[11]	"CSN3 interacts with IKKgamma and inhibits TNF- but not IL-1-induced NF-kappaB activation." Hong X., Xu L.-G., Li X., Zhai Z., Shu H.-B. FEBS Lett. 499:133-136(2001) [PubMed: 11418127] [Abstract] Cited for: INTERACTION WITH COPS3.
[12]	"Role of ikkgamma/nemo in assembly of the IkappaB kinase complex." Li X.-H., Fang X., Gaynor R.B. J. Biol. Chem. 276:4494-4500(2001) [PubMed: 11080499] [Abstract] Cited for: SUBUNIT OF THE IKK COMPLEX.
[13]	"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. 277:37029-37036(2002) [PubMed: 12133833] [Abstract] Cited for: INTERACTION WITH TANK AND IKBKB.
[14]	"Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator activity by I kappa B kinase." Wu R.-C., Qin J., Hashimoto Y., Wong J., Xu J., Tsai S.Y., Tsai M.-J., O'Malley B.W. Mol. Cell. Biol. 22:3549-3561(2002) [PubMed: 11971985] [Abstract] Cited for: SUBUNIT OF A COMPLEX CONTAINING CREBBP; NCOA2; NCOA3; IKKA AND IKKB.
[15]	"Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress." Huang T.T., Wuerzberger-Davis S.M., Wu Z.H., Miyamoto S. Cell 115:565-576(2003) [PubMed: 14651848] [Abstract] Cited for: SUMOYLATION AT LYS-277 AND LYS-309, UBIQUITINATION AT LYS-277 AND LYS-309, MUTAGENESIS OF LYS-277 AND LYS-309.
[16]	"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. 278:19642-19648(2003) [PubMed: 12657630] [Abstract] Cited for: PHOSPHORYLATION AT SER-31; SER-43 AND SER-376.
[17]	"Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation." Tegethoff S., Behlke J., Scheidereit C. Mol. Cell. Biol. 23:2029-2041(2003) [PubMed: 12612076] [Abstract] Cited for: SELF-ASSOCIATION, COMPOSITION OF THE IKK COMPLEX.
[18]	"The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination." Kovalenko A., Chable-Bessia C., Cantarella G., Israeel A., Wallach D., Courtois G. Nature 424:801-805(2003) [PubMed: 12917691] [Abstract] Cited for: INTERACTION WITH CYLD.
[19]	"The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO." Abbott D.W., Wilkins A., Asara J.M., Cantley L.C. Curr. Biol. 14:2217-2227(2004) [PubMed: 15620648] [Abstract] Cited for: UBIQUITINATION AT LYS-285.
[20]	"PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages." Bruey J.-M., Bruey-Sedano N., Newman R., Chandler S., Stehlik C., Reed J.C. J. Biol. Chem. 279:51897-51907(2004) [PubMed: 15456791] [Abstract] Cited for: INTERACTION WITH NALP2.
[21]	"The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes." Sun L., Deng L., Ea C.-K., Xia Z.-P., Chen Z.J. Mol. Cell 14:289-301(2004) [PubMed: 15125833] [Abstract] Cited for: UBIQUITINATION.
[22]	"Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO." Zhou H., Wertz I., O'Rourke K., Ultsch M., Seshagiri S., Eby M., Xiao W., Dixit V.M. Nature 427:167-171(2004) [PubMed: 14695475] [Abstract] Cited for: UBIQUITINATION AT LYS-399, MUTAGENESIS OF LYS-399.
[23]	"PIDD mediates NF-kappaB activation in response to DNA damage." Janssens S., Tinel A., Lippens S., Tschopp J. Cell 123:1079-1092(2005) [PubMed: 16360037] [Abstract] Cited for: INTERACTION WITH LRDD.
[24]	"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 311:1141-1146(2006) [PubMed: 16497931] [Abstract] Cited for: INTERACTION WITH ATM, PHOSPHORYLATION AT SER-85, MUTAGENESIS OF SER-85.
[25]	"Intermolecular disulfide bond formation in the NEMO dimer requires Cys54 and Cys347." Herscovitch M., Comb W., Ennis T., Coleman K., Yong S., Armstead B., Kalaitzidis D., Chandani S., Gilmore T.D. Biochem. Biophys. Res. Commun. 367:103-108(2008) [PubMed: 18164680] [Abstract] Cited for: SUBUNIT, DISULFIDE BONDS.
[26]	"Phosphorylation of serine 68 in the IkappaB kinase (IKK)-binding domain of NEMO interferes with the structure of the IKK complex and tumor necrosis factor-alpha-induced NF-kappaB activity." Palkowitsch L., Leidner J., Ghosh S., Marienfeld R.B. J. Biol. Chem. 283:76-86(2008) [PubMed: 17977820] [Abstract] Cited for: INTERACTION WITH IKBKB, PHOSPHORYLATION AT SER-68, MUTAGENESIS OF SER-68.
[27]	"Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation." Cordier F., Vinolo E., Veron M., Delepierre M., Agou F. J. Mol. Biol. 377:1419-1432(2008) [PubMed: 18313693] [Abstract] Cited for: STRUCTURE BY NMR OF 394-419 OF WILD-TYPE AND MUTANT PHE-417, ZINC-FINGER.
[28]	"Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site." Rushe M., Silvian L., Bixler S., Chen L.L., Cheung A., Bowes S., Cuervo H., Berkowitz S., Zheng T., Guckian K., Pellegrini M., Lugovskoy A. Structure 16:798-808(2008) [PubMed: 18462684] [Abstract]