NEMO_PIG
ID NEMO_PIG Reviewed; 419 AA.
AC A9QT41; F1RZ22; K7GSV8;
DT 07-NOV-2018, integrated into UniProtKB/Swiss-Prot.
DT 05-FEB-2008, sequence version 1.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=NF-kappa-B essential modulator;
DE Short=NEMO;
DE AltName: Full=FIP-3;
DE AltName: Full=IkB kinase-associated protein 1;
DE Short=IKKAP1;
DE AltName: Full=Inhibitor of nuclear factor kappa-B kinase subunit gamma;
DE Short=I-kappa-B kinase subunit gamma;
DE Short=IKK-gamma;
DE Short=IKKG;
DE Short=IkB kinase subunit gamma;
DE AltName: Full=NF-kappa-B essential modifier;
GN Name=IKBKG;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Fang Y., Wang D., Li T., Xiao S., Fang L.;
RL Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RG Porcine genome sequencing project;
RL Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP CLEAVAGE BY PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS SERINE
RP PROTEASE NSP4 AT GLU-349 (MICROBIAL INFECTION).
RX PubMed=25008936; DOI=10.1128/jvi.01396-14;
RA Huang C., Zhang Q., Guo X.K., Yu Z.B., Xu A.T., Tang J., Feng W.H.;
RT "Porcine reproductive and respiratory syndrome virus nonstructural protein
RT 4 antagonizes beta interferon expression by targeting the NF-kappaB
RT essential modulator.";
RL J. Virol. 88:10934-10945(2014).
CC -!- FUNCTION: Regulatory subunit of the IKK core complex which
CC phosphorylates inhibitors of NF-kappa-B thus leading to the
CC dissociation of the inhibitor/NF-kappa-B complex and ultimately the
CC degradation of the inhibitor. Its binding to scaffolding polyubiquitin
CC plays a key role in IKK activation by multiple signaling receptor
CC pathways. Can recognize and bind both 'Lys-63'-linked and linear
CC polyubiquitin upon cell stimulation, with a much highr affinity for
CC linear polyubiquitin. Could be implicated in NF-kappa-B-mediated
CC protection from cytokine toxicity. Essential for viral activation of
CC IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response;
CC this function requires 'Lys-27'-linked polyubiquitination.
CC {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Component of the I-kappa-B-kinase
CC (IKK) core complex consisting of CHUK, IKBKB and IKBKG; probably four
CC alpha/CHUK-beta/IKBKB dimers are associated with four gamma/IKBKG
CC subunits. The IKK core complex seems to associate with regulatory or
CC adapter proteins to form a IKK-signalosome holo-complex (By
CC similarity). The IKK complex associates with TERF2IP/RAP1, leading to
CC promote IKK-mediated phosphorylation of RELA/p65 (By similarity). Part
CC of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and
CC CREBBP. Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1. Interacts
CC with ATM; the complex is exported from the nucleus. Interacts with
CC TRAF6. Interacts with IKBKE. Interacts with TANK; the interaction is
CC enhanced by IKBKE and TBK1. Part of a ternary complex consisting of
CC TANK, IKBKB and IKBKG. Interacts with ZFAND5. Interacts with RIPK2.
CC Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-
CC mediated de-ubiquitination of IKBKG. Interacts with TNFAIP3; the
CC interaction is induced by TNF stimulation and by polyubiquitin. Binds
CC (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear
CC polyubiquitin, with higher affinity for linear ubiquitin. Interacts
CC with NLRP10. Interacts with TANK; this interaction increases in
CC response to DNA damage. Interacts with USP10; this interaction
CC increases in response to DNA damage. Interacts with ZC3H12A; this
CC interaction increases in response to DNA damage. Interacts with IFIT5;
CC the interaction synergizes the recruitment of IKK to MAP3K7 and
CC enhances IKK phosphorylation. Interacts with TRIM29; this interaction
CC induces IKBKG/NEMO ubiquitination and proteolytic degradation.
CC Interacts with TRIM13; this interaction leads to IKBKG/NEMO
CC ubiquitination. Interacts with ARFIP2 (By similarity). Interacts with
CC RIPK1 (By similarity). Interacts with (ubiquitinated) BCL10;
CC interaction with polyubiquitinated BCL10 via both 'Lys-63'-linked and
CC linear ubiquitin is required for TCR-induced NF-kappa-B activation (By
CC similarity). Interacts with MARCHF2; during the late stages of
CC macrophage viral and bacterial infection; the interaction leads to
CC ubiquitination and degradation of IKBKG/NEMO (By similarity).
CC {ECO:0000250|UniProtKB:O88522, ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y6K9}. Nucleus
CC {ECO:0000250|UniProtKB:Q9Y6K9}. Note=Sumoylated NEMO accumulates in the
CC nucleus in response to genotoxic stress.
CC {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- DOMAIN: The leucine-zipper domain and the CCHC NOA-type zinc-fingers
CC constitute the UBAN region and are essential for polyubiquitin binding
CC and for the activation of IRF3. {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- PTM: Phosphorylation at Ser-68 attenuates aminoterminal
CC homodimerization. {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- PTM: Polyubiquitinated on Lys-285 through 'Lys-63'; the ubiquitination
CC is mediated by NOD2 and RIPK2 and probably plays a role in signaling by
CC facilitating interactions with ubiquitin domain-containing proteins and
CC activates the NF-kappa-B pathway. Polyubiquitinated on Lys-399 through
CC 'Lys-63'; the ubiquitination is mediated by BCL10, MALT1 and TRAF6 and
CC probably plays a role in signaling by facilitating interactions with
CC ubiquitin domain-containing proteins and activates the NF-kappa-B
CC pathway. Monoubiquitinated on Lys-277 and Lys-309; promotes nuclear
CC export. Polyubiquitinated through 'Lys-27' by TRIM23; involved in
CC antiviral innate and inflammatory responses. Linear polyubiquitinated
CC on Lys-111, Lys-143, Lys-226, Lys-246, Lys-264, Lys-277, Lys-285, Lys-
CC 292, Lys-302, Lys-309 and Lys-326; the head-to-tail polyubiquitination
CC is mediated by the LUBAC complex and plays a key role in NF-kappa-B
CC activation. Deubiquitinated by USP10 in a TANK-dependent and
CC -independent manner, leading to the negative regulation of NF-kappa-B
CC signaling upon DNA damage. Ubiquitinated at Lys-326 by MARCHF2
CC following bacterial and viral infection which leads to its degradation
CC (By similarity). {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- PTM: Sumoylated on Lys-277 and Lys-309 with SUMO1; the modification
CC results in phosphorylation of Ser-85 by ATM leading to a replacement of
CC the sumoylation by mono-ubiquitination on these residues.
CC {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- PTM: Neddylated by TRIM40, resulting in stabilization of NFKBIA and
CC down-regulation of NF-kappa-B activity. {ECO:0000250|UniProtKB:Q9Y6K9}.
CC -!- PTM: (Microbial infection) Cleaved by porcine reproductive and
CC respiratory syndrome virus serine protease nsp4 after Glu-349. The
CC cleavage inhibits NEMO proper function. {ECO:0000269|PubMed:25008936}.
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DR EMBL; AEMK02000122; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; EU258760; ABX57883.1; -; mRNA.
DR RefSeq; NP_001106524.1; NM_001113053.1.
DR RefSeq; XP_005674095.1; XM_005674038.2.
DR RefSeq; XP_005674097.1; XM_005674040.2.
DR RefSeq; XP_013842025.1; XM_013986571.1.
DR AlphaFoldDB; A9QT41; -.
DR SMR; A9QT41; -.
DR STRING; 9823.ENSSSCP00000031038; -.
DR PaxDb; A9QT41; -.
DR PRIDE; A9QT41; -.
DR Ensembl; ENSSSCT00000048167; ENSSSCP00000059040; ENSSSCG00000012825.
DR Ensembl; ENSSSCT00015037010; ENSSSCP00015014717; ENSSSCG00015027234.
DR Ensembl; ENSSSCT00025017296; ENSSSCP00025006922; ENSSSCG00025012844.
DR Ensembl; ENSSSCT00030095898; ENSSSCP00030044189; ENSSSCG00030068530.
DR Ensembl; ENSSSCT00035059651; ENSSSCP00035023987; ENSSSCG00035044882.
DR Ensembl; ENSSSCT00040068051; ENSSSCP00040028929; ENSSSCG00040050271.
DR Ensembl; ENSSSCT00045064285; ENSSSCP00045045401; ENSSSCG00045037264.
DR Ensembl; ENSSSCT00050058363; ENSSSCP00050024992; ENSSSCG00050042920.
DR Ensembl; ENSSSCT00055014307; ENSSSCP00055011250; ENSSSCG00055007278.
DR Ensembl; ENSSSCT00060011074; ENSSSCP00060004090; ENSSSCG00060008639.
DR Ensembl; ENSSSCT00065008059; ENSSSCP00065003382; ENSSSCG00065005991.
DR GeneID; 100127355; -.
DR KEGG; ssc:100127355; -.
DR CTD; 8517; -.
DR VGNC; VGNC:89072; IKBKG.
DR eggNOG; ENOG502R4ZD; Eukaryota.
DR GeneTree; ENSGT00530000063808; -.
DR InParanoid; A9QT41; -.
DR OMA; QHRCIEH; -.
DR TreeFam; TF326608; -.
DR Reactome; R-SSC-1169091; Activation of NF-kappaB in B cells.
DR Reactome; R-SSC-1810476; RIP-mediated NFkB activation via ZBP1.
DR Reactome; R-SSC-202424; Downstream TCR signaling.
DR Reactome; R-SSC-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-SSC-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR Reactome; R-SSC-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-SSC-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-SSC-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-SSC-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR Reactome; R-SSC-5689880; Ub-specific processing proteases.
DR Reactome; R-SSC-9020702; Interleukin-1 signaling.
DR Reactome; R-SSC-933542; TRAF6 mediated NF-kB activation.
DR Reactome; R-SSC-937039; IRAK1 recruits IKK complex.
DR Reactome; R-SSC-937041; IKK complex recruitment mediated by RIP1.
DR Reactome; R-SSC-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR Proteomes; UP000008227; Chromosome X.
DR Proteomes; UP000314985; Unplaced.
DR Bgee; ENSSSCG00000012825; Expressed in blood and 45 other tissues.
DR ExpressionAtlas; A9QT41; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0008385; C:IkappaB kinase complex; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; ISS:UniProtKB.
DR GO; GO:0016301; F:kinase activity; IEA:UniProtKB-KW.
DR GO; GO:1990450; F:linear polyubiquitin binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0050862; P:positive regulation of T cell receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR InterPro; IPR032419; CC2-LZ_dom.
DR InterPro; IPR021063; NEMO_N.
DR InterPro; IPR034735; NEMO_ZF.
DR Pfam; PF16516; CC2-LZ; 1.
DR Pfam; PF11577; NEMO; 1.
DR PROSITE; PS51801; ZF_CCHC_NOA; 1.
PE 1: Evidence at protein level;
KW Coiled coil; Cytoplasm; Disulfide bond; DNA damage; Isopeptide bond;
KW Kinase; Metal-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Transferase; Ubl conjugation;
KW Zinc; Zinc-finger.
FT CHAIN 1..419
FT /note="NF-kappa-B essential modulator"
FT /id="PRO_0000445606"
FT ZN_FING 389..419
FT /note="CCHC NOA-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01142"
FT REGION 1..197
FT /note="Required for interaction with and ubiquitination by
FT MARCHF2"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT REGION 1..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 44..111
FT /note="Interaction with CHUK/IKBKB"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT REGION 150..257
FT /note="Interaction with TANK"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT REGION 242..350
FT /note="Ubiquitin-binding (UBAN)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT REGION 246..365
FT /note="Self-association"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT REGION 251..419
FT /note="Required for interaction with TNFAIP3"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT REGION 322..343
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255"
FT REGION 363..394
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 382..419
FT /note="Interaction with CYLD"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT COILED 100..353
FT /evidence="ECO:0000255"
FT BINDING 397
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01142"
FT BINDING 400
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01142"
FT BINDING 413
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01142"
FT BINDING 417
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01142"
FT SITE 349..350
FT /note="(Microbial infection) Cleavage; by porcine
FT reproductive and respiratory syndrome virus serine protease
FT nsp4"
FT /evidence="ECO:0000269|PubMed:25008936"
FT MOD_RES 31
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT MOD_RES 43
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT MOD_RES 68
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT MOD_RES 85
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT MOD_RES 376
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT MOD_RES 387
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT DISULFID 54
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT DISULFID 347
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 111
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 139
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 143
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 226
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 246
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 264
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 277
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 277
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 283
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 285
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 292
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 302
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 309
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 309
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 326
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
FT CROSSLNK 399
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y6K9"
SQ SEQUENCE 419 AA; 48637 MW; 12B7AF4B2583B883 CRC64;
MSRTPWKSQP CEMVQPSGGP AGDQDVLGEE SSLGKPTMLH LPSEQGAPET FQRCLEENQE
LRDAIRQSNQ MLRERCEELQ RFQGSQREEK EFLMQKFCEA RRLVERLSLE KLELRRQREQ
ALQEVELLKT CQQQMAEDKA SVKAQVTSLL GELQESQSRL EAATKERQAL ESRVRATSEQ
VRQLENEREA LQQQHSVQVD QLRLQSQSME AALRMERQAA SEEKRKLAQL QVAYHQLFQE
YDNHIKSSVV SSERNRGLQL EDLKQQLQQA EEALVAKQEV IDKLKEEAEQ HKIVMETVPV
LKAQADIYKA DFQAERQARE QLAERKELLQ EQLEQLQREY SRLKTSCQES ARIEDMRKRH
VEVSQPTLPP APAHHSFHPA LPSQRRSPPE EPPNFCCPKC QYQAPDMDTL QIHVMECIE
