UniProt Accession

 NEMO_HUMAN; Q9Y6K9; Q7LBY6; Q7Z7F1 

Genbank Protein ID

 AF062089; AF091453; AF074382; AJ271718; AF261086; AY114157; AK000593; BT019621; AF277315; BC000299; BC012114; BC046922; BC050612 

Genbank Nucleotide ID

 AAD12183.1; AAD38081.1; AAC36330.1; CAB93146.1; AAF99679.1; AAM44073.1; AAV38427.1; AAL27012.1; AAH00299.1; AAH12114.1; AAH46922.1; AAH50612.1 

Protein Name

 NF-kappa-B essential modulator 

Protein Synonyms/Alias

 NEMO; FIP-3; IkB kinase-associated protein 1; IKKAP1; Inhibitor of nuclear factor kappa-B kinase subunit gamma; I-kappa-B kinase subunit gamma; IKK-gamma; IKKG; IkB kinase subunit gamma; NF-kappa-B essential modifier 

Gene Name

 IKBKG 

Gene Synonyms/Alias

 FIP3; NEMO 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
111	VERLGLEKLDLKRQK	ubiquitination	[1]
139	QQQMAEDKASVKAQV	ubiquitination	[1]
143	AEDKASVKAQVTSLL	ubiquitination	[1]
226	AASEEKRKLAQLQVA	ubiquitination	[1]
246	QEYDNHIKSSVVGSE	ubiquitination	[1]
264	GMQLEDLKQQLQQAE	ubiquitination	[1]
277	AEEALVAKQEVIDKL	sumoylation	[2, 3, 4]
277	AEEALVAKQEVIDKL	ubiquitination	[1]
283	AKQEVIDKLKEEAEQ	ubiquitination	[1]
285	QEVIDKLKEEAEQHK	ubiquitination	[1, 5]
292	KEEAEQHKIVMETVP	ubiquitination	[1]
302	METVPVLKAQADIYK	ubiquitination	[1]
309	KAQADIYKADFQAER	sumoylation	[2, 3]
309	KAQADIYKADFQAER	ubiquitination	[1, 2, 6, 7, 8, 9, 10, 11, 12]
321	AERQAREKLAEKKEL	ubiquitination	[1]
344	QREYSKLKASCQESA	ubiquitination	[5]
399	PPDFCCPKCQYQAPD	ubiquitination	[1, 13]

Reference

 [1] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [2] Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress.
 Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S.
 Cell. 2003 Nov 26;115(5):565-76. [PMID: 14651848]
 [3] PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress.
 Mabb AM, Wuerzberger-Davis SM, Miyamoto S.
 Nat Cell Biol. 2006 Sep;8(9):986-93. [PMID: 16906147]
 [4] Nonproteolytic functions of ubiquitin in cell signaling.
 Chen ZJ, Sun LJ.
 Mol Cell. 2009 Feb 13;33(3):275-86. [PMID: 19217402]
 [5] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [6] Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti.
 Sebban-Benin H, Pescatore A, Fusco F, Pascuale V, Gautheron J, Yamaoka S, Moncla A, Ursini MV, Courtois G.
 Hum Mol Genet. 2007 Dec 1;16(23):2805-15. [PMID: 17728323]
 [7] Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.
 Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K.
 Nat Cell Biol. 2009 Feb;11(2):123-32. [PMID: 19136968]
 [8] A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response.
 Ashida H, Kim M, Schmidt-Supprian M, Ma A, Ogawa M, Sasakawa C.
 Nat Cell Biol. 2010 Jan;12(1):66-73; sup pp 1-9. [PMID: 20010814]
 [9] Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense.
 Arimoto K, Funami K, Saeki Y, Tanaka K, Okawa K, Takeuchi O, Akira S, Murakami Y, Shimotohno K.
 Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15856-61. [PMID: 20724660]
 [10] LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ubiquitination of NEMO.
 Niu J, Shi Y, Iwai K, Wu ZH.
 EMBO J. 2011 Aug 2;30(18):3741-53. [PMID: 21811235]
 [11] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [12] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [13] Computational identification of ubiquitylation sites from protein sequences.
 Tung CW, Ho SY.
 BMC Bioinformatics. 2008 Jul 15;9:310. [PMID: 18625080] 

Functional Description

 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. 

Sequence Annotation

 ZN_FING 396 417 C2HC-type.
 REGION 44 111 Interaction with CHUK/IKBKB.
 REGION 150 257 Interaction with TANK.
 REGION 242 350 Ubiquitin-binding (UBD).
 REGION 246 365 Self-association.
 REGION 251 419 Required for interaction with TNFAIP3.
 REGION 322 343 Leucine-zipper (Potential).
 REGION 382 419 Interaction with CYLD.
 MOD_RES 31 31 Phosphoserine; by IKKB.
 MOD_RES 43 43 Phosphoserine; by IKKB.
 MOD_RES 68 68 Phosphoserine.
 MOD_RES 85 85 Phosphoserine; by ATM.
 MOD_RES 376 376 Phosphoserine; by IKKB.
 DISULFID 54 54 Interchain.
 DISULFID 347 347 Interchain.
 CROSSLNK 111 111 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 139 139 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 143 143 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 226 226 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 246 246 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 264 264 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 277 277 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 277 277 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 283 283 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 285 285 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 292 292 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 302 302 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 309 309 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 309 309 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 321 321 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 325 325 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 326 326 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 399 399 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Alternative splicing; Coiled coil; Complete proteome; Cytoplasm; Direct protein sequencing; Disease mutation; Disulfide bond; Ectodermal dysplasia; Host-virus interaction; Isopeptide bond; Metal-binding; Nucleus; Osteopetrosis; Phosphoprotein; Reference proteome; Transcription; Transcription regulation; Ubl conjugation; Zinc; Zinc-finger. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 419 AA 

Protein Sequence

Gene Ontology

 GO:0008385; C:IkappaB kinase complex; TAS:UniProtKB.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO:0004871; F:signal transducer activity; TAS:ProtInc.
 GO:0000187; P:activation of MAPK activity; TAS:Reactome.
 GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IEA:Compara.
 GO:0001782; P:B cell homeostasis; IEA:Compara.
 GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; TAS:UniProtKB.
 GO:0006917; P:induction of apoptosis; TAS:ProtInc.
 GO:0006954; P:inflammatory response; TAS:UniProtKB.
 GO:0045087; P:innate immune response; TAS:UniProtKB.
 GO:0007254; P:JNK cascade; TAS:Reactome.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
 GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; TAS:Reactome.
 GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
 GO:0032481; P:positive regulation of type I interferon production; TAS:Reactome.
 GO:0006974; P:response to DNA damage stimulus; IDA:UniProtKB.
 GO:0009615; P:response to virus; TAS:UniProtKB.
 GO:0050852; P:T cell receptor signaling pathway; NAS:UniProtKB.
 GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
 GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
 GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
 GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW. 

Interpro

 IPR021063; NEMO_N. 

Pfam

 PF11577; NEMO 

SMART

  

PROSITE

  

PRINTS