ID IKKE_HUMAN Reviewed; 716 AA. AC Q14164; D3DT78; Q3B754; Q3KR43; Q5JTS6; DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 09-DEC-2015, entry version 165. DE RecName: Full=Inhibitor of nuclear factor kappa-B kinase subunit epsilon; DE Short=I-kappa-B kinase epsilon; DE Short=IKK-E; DE Short=IKK-epsilon; DE Short=IkBKE; DE EC=2.7.11.10; DE AltName: Full=Inducible I kappa-B kinase; DE Short=IKK-i; GN Name=IKBKE; Synonyms=IKKE, IKKI, KIAA0151; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF LYS-38; RP GLU-168 AND SER-172. RX PubMed=10421793; DOI=10.1093/intimm/11.8.1357; RA Shimada T., Kawai T., Takeda K., Matsumoto M., Inoue J., Tatsumi Y., RA Kanamaru A., Akira S.; RT "IKK-i, a novel lipopolysaccharide-inducible kinase that is related to RT IkappaB kinases."; RL Int. Immunol. 11:1357-1362(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Leukocyte; RX PubMed=10882136; DOI=10.1016/S1097-2765(00)80445-1; RA Peters R.T., Liao S.-M., Maniatis T.; RT "IKK epsilon is part of a novel PMA-inducible IkappaB kinase RT complex."; RL Mol. Cell 5:513-522(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Bone marrow; RX PubMed=8590280; DOI=10.1093/dnares/2.4.167; RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.; RT "Prediction of the coding sequences of unidentified human genes. IV. RT The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by RT analysis of cDNA clones from human cell line KG-1."; RL DNA Res. 2:167-174(1995). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-128; THR-371; RP ASP-515; MET-543; VAL-602 AND LEU-713. RG SeattleSNPs variation discovery resource; RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C., RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., RA Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP INTERACTION WITH AZI2. RX PubMed=14560022; DOI=10.1128/MCB.23.21.7780-7793.2003; RA Fujita F., Taniguchi Y., Kato T., Narita Y., Furuya A., Ogawa T., RA Sakurai H., Joh T., Itoh M., Delhase M., Karin M., Nakanishi M.; RT "Identification of NAP1, a regulatory subunit of IkappaB kinase- RT related kinases that potentiates NF-kappaB signaling."; RL Mol. Cell. Biol. 23:7780-7793(2003). RN [9] RP INTERACTION WITH TICAM1. RX PubMed=14739303; DOI=10.1074/jbc.M311629200; RA Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B.; RT "Mechanisms of the TRIF-induced interferon-stimulated response element RT and NF-kappaB activation and apoptosis pathways."; RL J. Biol. Chem. 279:15652-15661(2004). RN [10] RP INTERACTION WITH SIKE1; IRF3; TICAM1 AND DDX58. RX PubMed=16281057; DOI=10.1038/sj.emboj.7600863; RA Huang J., Liu T., Xu L.-G., Chen D., Zhai Z., Shu H.-B.; RT "SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus- RT triggered IRF-3 activation pathways."; RL EMBO J. 24:4018-4028(2005). RN [11] RP INTERACTION WITH MAVS. RX PubMed=16177806; DOI=10.1038/nature04193; RA Meylan E., Curran J., Hofmann K., Moradpour D., Binder M., RA Bartenschlager R., Tschopp J.; RT "Cardif is an adaptor protein in the RIG-I antiviral pathway and is RT targeted by hepatitis C virus."; RL Nature 437:1167-1172(2005). RN [12] RP FUNCTION, AND INTERACTION WITH AZI2; TANK AND TBKBP1. RX PubMed=17568778; DOI=10.1038/sj.emboj.7601743; RA Ryzhakov G., Randow F.; RT "SINTBAD, a novel component of innate antiviral immunity, shares a RT TBK1-binding domain with NAP1 and TANK."; RL EMBO J. 26:3180-3190(2007). RN [13] RP INTERACTION WITH IFIH1. RX PubMed=17600090; DOI=10.1073/pnas.0700544104; RA Diao F., Li S., Tian Y., Zhang M., Xu L.G., Zhang Y., Wang R.P., RA Chen D., Zhai Z., Zhong B., Tien P., Shu H.B.; RT "Negative regulation of MDA5- but not RIG-I-mediated innate antiviral RT signaling by the dihydroxyacetone kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 104:11706-11711(2007). RN [14] RP FUNCTION IN PHOSPHORYLATION OF DDX3X. RX PubMed=18583960; DOI=10.1038/emboj.2008.126; RA Soulat D., Burckstummer T., Westermayer S., Goncalves A., Bauch A., RA Stefanovic A., Hantschel O., Bennett K.L., Decker T., RA Superti-Furga G.; RT "The DEAD-box helicase DDX3X is a critical component of the TANK- RT binding kinase 1-dependent innate immune response."; RL EMBO J. 27:2135-2146(2008). RN [15] RP INTERACTION WITH DDX3X. RX PubMed=18636090; DOI=10.1038/emboj.2008.143; RA Schroder M., Baran M., Bowie A.G.; RT "Viral targeting of DEAD box protein 3 reveals its role in RT TBK1/IKKepsilon-mediated IRF activation."; RL EMBO J. 27:2147-2157(2008). RN [16] RP INTERACTION WITH CYLD. RX PubMed=18636086; DOI=10.1038/embor.2008.136; RA Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A., RA Cardenas W.B., Yount J.S., Moran T.M., Basler C.F., Komuro A., RA Horvath C.M., Xavier R., Ting A.T.; RT "The tumour suppressor CYLD is a negative regulator of RIG-I-mediated RT antiviral response."; RL EMBO Rep. 9:930-936(2008). RN [17] RP FUNCTION IN IRF3 PHOSPHORYLATION, INTERACTION WITH EBOLAVIRUS PROTEIN RP VP35, AND AUTOPHOSPHORYLATION. RX PubMed=19153231; DOI=10.1128/JVI.01875-08; RA Prins K.C., Cardenas W.B., Basler C.F.; RT "Ebola virus protein VP35 impairs the function of interferon RT regulatory factor-activating kinases IKKepsilon and TBK-1."; RL J. Virol. 83:3069-3077(2009). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-664, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [19] RP FUNCTION, INTERACTION WITH TOPORS, SUMOYLATION AT LYS-231 BY TOPORS, RP DESUMOYLATION BY SENP1, MUTAGENESIS OF LYS-231, AND SUBCELLULAR RP LOCATION. RX PubMed=20188669; DOI=10.1016/j.molcel.2010.01.018; RA Renner F., Moreno R., Schmitz M.L.; RT "SUMOylation-dependent localization of IKKepsilon in PML nuclear RT bodies is essential for protection against DNA-damage-triggered cell RT death."; RL Mol. Cell 37:503-515(2010). RN [20] RP INTERACTION WITH DDX3X. RX PubMed=20657822; DOI=10.1371/journal.ppat.1000986; RA Wang H., Ryu W.S.; RT "Hepatitis B virus polymerase blocks pattern recognition receptor RT signaling via interaction with DDX3: implications for immune RT evasion."; RL PLoS Pathog. 6:E1000986-E1000986(2010). RN [21] RP FUNCTION, AND PHOSPHORYLATION BY IKBKB/IKKB. RX PubMed=21138416; DOI=10.1042/BJ20101701; RA Clark K., Peggie M., Plater L., Sorcek R.J., Young E.R., Madwed J.B., RA Hough J., McIver E.G., Cohen P.; RT "Novel cross-talk within the IKK family controls innate immunity."; RL Biochem. J. 434:93-104(2011). RN [22] RP FUNCTION IN AKT PHOSPHORYLATION, AND SUBCELLULAR LOCATION. RX PubMed=21464307; DOI=10.1073/pnas.1016132108; RA Xie X., Zhang D., Zhao B., Lu M.K., You M., Condorelli G., Wang C.Y., RA Guan K.L.; RT "IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by RT direct phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 108:6474-6479(2011). RN [23] RP FUNCTION, AND INTERACTION WITH ARENAVIRUS PROTEIN N. RX PubMed=22532683; DOI=10.1128/JVI.00187-12; RA Pythoud C., Rodrigo W.W., Pasqual G., Rothenberger S., RA Martinez-Sobrido L., de la Torre J.C., Kunz S.; RT "Arenavirus nucleoprotein targets interferon regulatory factor- RT activating kinase IKKepsilon."; RL J. Virol. 86:7728-7738(2012). RN [24] RP FUNCTION, HOMODIMER, INTERACTION WITH IKBKB; IKBKG AND MYD88, RP INDUCTION BY LPS, UBIQUITINATION AT LYS-30 AND LYS-401, AND RP MUTAGENESIS OF LYS-30; LYS-401 AND LYS-416. RX PubMed=23453969; DOI=10.1016/j.celrep.2013.01.031; RA Zhou A.Y., Shen R.R., Kim E., Lock Y.J., Xu M., Chen Z.J., Hahn W.C.; RT "IKKepsilon-mediated tumorigenesis requires K63-linked RT polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase RT complex."; RL Cell Rep. 3:724-733(2013). RN [25] RP FUNCTION IN DDX3X AND IRF3 PHOSPHORYLATION, INTERACTION WITH DDX3X AND RP IRF3, AND PHOSPHORYLATION AT SER-172. RX PubMed=23478265; DOI=10.1128/MCB.01603-12; RA Gu L., Fullam A., Brennan R., Schroder M.; RT "Human DEAD box helicase 3 couples IkappaB kinase epsilon to RT interferon regulatory factor 3 activation."; RL Mol. Cell. Biol. 33:2004-2015(2013). RN [26] RP INTERACTION WITH TRIM6 AND POLYUBIQUITIN, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION AT THR-501. RX PubMed=24882218; DOI=10.1016/j.immuni.2014.04.018; RA Rajsbaum R., Versteeg G.A., Schmid S., Maestre A.M., RA Belicha-Villanueva A., Martinez-Romero C., Patel J.R., Morrison J., RA Pisanelli G., Miorin L., Laurent-Rolle M., Moulton H.M., Stein D.A., RA Fernandez-Sesma A., tenOever B.R., Garcia-Sastre A.; RT "Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin RT ligase TRIM6 stimulates the interferon-IKKepsilon kinase-mediated RT antiviral response."; RL Immunity 40:880-895(2014). RN [27] RP VARIANTS [LARGE SCALE ANALYSIS] THR-371; MET-483; VAL-602; GLU-660 AND RP LEU-713. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Serine/threonine kinase that plays an essential role in CC regulating inflammatory responses to viral infection, through the CC activation of the type I IFN, NF-kappa-B and STAT signaling. Also CC involved in TNFA and inflammatory cytokines, like Interleukin-1, CC signaling. Following activation of viral RNA sensors, such as RIG- CC I-like receptors, associates with DDX3X and phosphorylates CC interferon regulatory factors (IRFs), IRF3 and IRF7, as well as CC DDX3X. This activity allows subsequent homodimerization and CC nuclear translocation of the IRF3 leading to transcriptional CC activation of pro-inflammatory and antiviral genes including IFNB. CC In order to establish such an antiviral state, IKBKE forms several CC different complexes whose composition depends on the type of cell CC and cellular stimuli. Thus, several scaffolding molecules CC including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be CC recruited to the IKBKE-containing-complexes. Activated by CC polyubiquitination in response to TNFA and interleukin-1, CC regulates the NF-kappa-B signaling pathway through, at least, the CC phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B CC thus leading to the dissociation of the inhibitor/NF-kappa-B CC complex and ultimately the degradation of the inhibitor. In CC addition, is also required for the induction of a subset of ISGs CC which displays antiviral activity, may be through the CC phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at CC 'Ser-708' seems also to promote the assembly and DNA binding of CC ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) CC complexes, in this way regulating the balance between type I and CC type II IFN responses. Protects cells against DNA damage-induced CC cell death. Also plays an important role in energy balance CC regulation by sustaining a state of chronic, low-grade CC inflammation in obesity, wich leads to a negative impact on CC insulin sensitivity. Phosphorylates AKT1. CC {ECO:0000269|PubMed:17568778, ECO:0000269|PubMed:18583960, CC ECO:0000269|PubMed:19153231, ECO:0000269|PubMed:20188669, CC ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21464307, CC ECO:0000269|PubMed:22532683, ECO:0000269|PubMed:23453969, CC ECO:0000269|PubMed:23478265}. CC -!- CATALYTIC ACTIVITY: ATP + [I-kappa-B protein] = ADP + [I-kappa-B CC phosphoprotein]. CC -!- SUBUNIT: Homodimer. Interacts with MAVS/IPS1. Interacts with the CC adapter proteins AZI2/NAP1, TANK and TBKBP1/SINTBAD. Interacts CC with SIKE1. Interacts with TICAM1/TRIF, IRF3 and DDX58/RIG-I; CC interactions are disrupted by the interaction between IKBKE and CC SIKE1. Interacts with TOPORS; induced by DNA damage. Interacts CC with CYLD. Interacts (when polyubiquitinated) with IKBKB, IKBKG CC and MYD88. Interacts with IFIH1 (PubMed:17600090). Interacts with CC DDX3X; the interaction is found to be induced upon virus CC infection. Interacts (via Protein kinase domain) with arenavirus CC protein N; the interaction inhibits IKBKE kinase function. CC Interacts with Ebola virus protein VP35; the interaction leads to CC inhibition of cellular antiviral response by blocking necessary CC interactions between the IKBKE and MAVS/IPS as well as its CC substrates IRF3 and IRF7. Interacts with TRIM6 (via SPRY box) CC (PubMed:24882218). Interacts with unanchored K48-linked CC polyubiquitin chains; this leads to IKBKE activation CC (PubMed:24882218). {ECO:0000269|PubMed:14560022, CC ECO:0000269|PubMed:14739303, ECO:0000269|PubMed:16177806, CC ECO:0000269|PubMed:16281057, ECO:0000269|PubMed:17568778, CC ECO:0000269|PubMed:17600090, ECO:0000269|PubMed:18636086, CC ECO:0000269|PubMed:18636090, ECO:0000269|PubMed:19153231, CC ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:20657822, CC ECO:0000269|PubMed:22532683, ECO:0000269|PubMed:23453969, CC ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:24882218}. CC -!- INTERACTION: CC K7Y1A2:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-8788634; CC P27958:- (xeno); NbExp=2; IntAct=EBI-307369, EBI-6919131; CC Q92624:APPBP2; NbExp=4; IntAct=EBI-307369, EBI-743771; CC Q16543:CDC37; NbExp=3; IntAct=EBI-307369, EBI-295634; CC O00571:DDX3X; NbExp=4; IntAct=EBI-307369, EBI-353779; CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-307369, EBI-352572; CC Q14653:IRF3; NbExp=2; IntAct=EBI-307369, EBI-2650369; CC Q7Z434:MAVS; NbExp=4; IntAct=EBI-307369, EBI-995373; CC Q92844:TANK; NbExp=4; IntAct=EBI-307369, EBI-356349; CC Q9UHD2:TBK1; NbExp=2; IntAct=EBI-307369, EBI-356402; CC A7MCY6:TBKBP1; NbExp=4; IntAct=EBI-307369, EBI-359969; CC Q05127:VP35 (xeno); NbExp=3; IntAct=EBI-307369, EBI-6148294; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24882218}. CC Nucleus. Nucleus, PML body {ECO:0000269|PubMed:20188669}. CC Note=Targeting to PML nuclear bodies upon DNA damage is TOPORS- CC dependent (PubMed:20188669). Located diffusely throughout the CC cytoplasm but locates to punctate cytoplasmic bodies when CC coexpressed with TRIM6 (PubMed:24882218). CC {ECO:0000269|PubMed:20188669, ECO:0000269|PubMed:24882218}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q14164-1; Sequence=Displayed; CC Name=2; CC IsoId=Q14164-2; Sequence=VSP_044305; CC -!- TISSUE SPECIFICITY: Highly expressed in spleen followed by thymus, CC peripheral blood leukocytes, pancreas, placenta. Weakly expressed CC in lung, kidney, prostate, ovary and colon. CC -!- INDUCTION: Induced by lipopolysaccharide (LPS) and TNFA. CC {ECO:0000269|PubMed:23453969}. CC -!- PTM: Autophosphorylated and phosphorylated by IKBKB/IKKB. CC Phosphorylation at Ser-172 is enhanced by the interaction with CC DDX3X. Phosphorylated at Thr-501 upon IFN activation. CC {ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:23478265}. CC -!- PTM: Sumoylation by TOPORS upon DNA damage is required for CC protection of cells against DNA damage-induced cell death. CC Desumoylated by SENP1. {ECO:0000269|PubMed:20188669}. CC -!- PTM: 'Lys-63'-linked polyubiquitinated at Lys-30 and Lys-401 by CC TRAF2:BIRC2 and TRAF2:BIRC3 complexes. Ubiquitination is induced CC by LPS, TNFA and interleukin-1 and required for full kinase CC activity and KF-kappa-B pathway activation. CC {ECO:0000269|PubMed:23453969}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr CC protein kinase family. I-kappa-B kinase subfamily. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA09772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/ikbke/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D63485; BAA09772.2; ALT_INIT; mRNA. DR EMBL; AB016590; BAA85155.1; -; mRNA. DR EMBL; AF241789; AAF45307.1; -; mRNA. DR EMBL; DQ667176; ABG25921.1; -; Genomic_DNA. DR EMBL; AL354681; CAI15250.1; -; Genomic_DNA. DR EMBL; CH471100; EAW93549.1; -; Genomic_DNA. DR EMBL; BC105923; AAI05924.1; -; mRNA. DR EMBL; BC105924; AAI05925.1; -; mRNA. DR EMBL; BC107812; AAI07813.1; -; mRNA. DR CCDS; CCDS30996.1; -. [Q14164-1] DR CCDS; CCDS53464.1; -. [Q14164-2] DR RefSeq; NP_001180250.1; NM_001193321.1. [Q14164-2] DR RefSeq; NP_001180251.1; NM_001193322.1. DR RefSeq; NP_054721.1; NM_014002.3. [Q14164-1] DR RefSeq; XP_005273413.1; XM_005273356.2. [Q14164-1] DR UniGene; Hs.321045; -. DR ProteinModelPortal; Q14164; -. DR SMR; Q14164; 2-621. DR BioGrid; 115000; 69. DR DIP; DIP-27530N; -. DR IntAct; Q14164; 40. DR MINT; MINT-1132084; -. DR STRING; 9606.ENSP00000356087; -. DR BindingDB; Q14164; -. DR ChEMBL; CHEMBL3038486; -. DR GuidetoPHARMACOLOGY; 2040; -. DR PhosphoSite; Q14164; -. DR BioMuta; IKBKE; -. DR DMDM; 14548079; -. DR MaxQB; Q14164; -. DR PaxDb; Q14164; -. DR PRIDE; Q14164; -. DR DNASU; 9641; -. DR Ensembl; ENST00000581977; ENSP00000464030; ENSG00000263528. [Q14164-1] DR Ensembl; ENST00000584998; ENSP00000462396; ENSG00000263528. [Q14164-2] DR GeneID; 9641; -. DR KEGG; hsa:9641; -. DR UCSC; uc001hdz.2; human. [Q14164-1] DR CTD; 9641; -. DR GeneCards; IKBKE; -. DR H-InvDB; HIX0116011; -. DR HGNC; HGNC:14552; IKBKE. DR HPA; CAB025983; -. DR HPA; HPA015788; -. DR MIM; 605048; gene. DR neXtProt; NX_Q14164; -. DR PharmGKB; PA134962294; -. DR eggNOG; KOG4250; Eukaryota. DR eggNOG; ENOG410XRMU; LUCA. DR GeneTree; ENSGT00820000127009; -. DR HOGENOM; HOG000220867; -. DR HOVERGEN; HBG008494; -. DR InParanoid; Q14164; -. DR KO; K07211; -. DR OMA; CCLDKMY; -. DR OrthoDB; EOG7Z95KH; -. DR PhylomeDB; Q14164; -. DR TreeFam; TF324269; -. DR BRENDA; 2.7.11.10; 2681. DR Reactome; R-HSA-918233; TRAF3-dependent IRF activation pathway. DR Reactome; R-HSA-933541; TRAF6 mediated IRF7 activation. DR Reactome; R-HSA-936440; Negative regulators of RIG-I/MDA5 signaling. DR Reactome; R-HSA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon. DR SABIO-RK; Q14164; -. DR SignaLink; Q14164; -. DR ChiTaRS; IKBKE; human. DR GeneWiki; IKBKE; -. DR GenomeRNAi; 9641; -. DR NextBio; 36191; -. DR PRO; PR:Q14164; -. DR Proteomes; UP000005640; Chromosome 1. DR Bgee; Q14164; -. DR CleanEx; HS_IKBKE; -. DR ExpressionAtlas; Q14164; baseline and differential. DR Genevisible; Q14164; HS. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0031966; C:mitochondrial membrane; IMP:AgBase. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0008384; F:IkappaB kinase activity; IEA:UniProtKB-EC. DR GO; GO:0036435; F:K48-linked polyubiquitin binding; IMP:UniProtKB. DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; IDA:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0098586; P:cellular response to virus; IEA:Ensembl. DR GO; GO:0006955; P:immune response; NAS:UniProtKB. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:UniProtKB. DR GO; GO:0002756; P:MyD88-independent toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome. DR GO; GO:0038061; P:NIK/NF-kappaB signaling; IDA:GOC. DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEP:UniProtKB. DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0035456; P:response to interferon-beta; IMP:UniProtKB. DR GO; GO:0034340; P:response to type I interferon; IEA:Ensembl. DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome. DR GO; GO:0002224; P:toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR Pfam; PF00069; Pkinase; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Complete proteome; Cytoplasm; KW DNA damage; Isopeptide bond; Kinase; Nucleotide-binding; Nucleus; KW Phosphoprotein; Polymorphism; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Ubl conjugation. FT CHAIN 1 716 Inhibitor of nuclear factor kappa-B FT kinase subunit epsilon. FT /FTId=PRO_0000086017. FT DOMAIN 9 315 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 15 23 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT REGION 383 647 Interaction with DDX3X. FT REGION 436 457 Leucine-zipper. FT ACT_SITE 135 135 Proton acceptor. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT BINDING 38 38 ATP. {ECO:0000305}. FT MOD_RES 172 172 Phosphoserine; by autocatalysis and IKKB. FT {ECO:0000269|PubMed:23478265}. FT MOD_RES 501 501 Phosphothreonine. FT {ECO:0000269|PubMed:24882218}. FT MOD_RES 664 664 Phosphoserine. FT {ECO:0000244|PubMed:19369195}. FT CROSSLNK 30 30 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23453969}. FT CROSSLNK 231 231 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in SUMO1). FT CROSSLNK 401 401 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:23453969}. FT VAR_SEQ 1 85 Missing (in isoform 2). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_044305. FT VARIANT 128 128 E -> K (in dbSNP:rs41296028). FT {ECO:0000269|Ref.4}. FT /FTId=VAR_038816. FT VARIANT 371 371 A -> T (in dbSNP:rs17021877). FT {ECO:0000269|PubMed:17344846, FT ECO:0000269|Ref.4}. FT /FTId=VAR_038817. FT VARIANT 483 483 T -> M (in dbSNP:rs52817862). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040571. FT VARIANT 515 515 E -> D (in dbSNP:rs41299015). FT {ECO:0000269|Ref.4}. FT /FTId=VAR_038818. FT VARIANT 543 543 I -> M (in dbSNP:rs41299037). FT {ECO:0000269|Ref.4}. FT /FTId=VAR_038819. FT VARIANT 602 602 A -> V (in dbSNP:rs12059562). FT {ECO:0000269|PubMed:17344846, FT ECO:0000269|Ref.4}. FT /FTId=VAR_038820. FT VARIANT 660 660 G -> E (in dbSNP:rs55822317). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_040572. FT VARIANT 713 713 P -> L (in dbSNP:rs3748022). FT {ECO:0000269|PubMed:17344846, FT ECO:0000269|Ref.4}. FT /FTId=VAR_019989. FT MUTAGEN 30 30 K->A: Loss of ubiquitination and FT decreased kinase activity. No effect on FT homodimerization. FT {ECO:0000269|PubMed:23453969}. FT MUTAGEN 30 30 K->R: Loss of ubiquitination and FT decreased kinase activity. Decreases FT interaction with IKBKB, IKBKG and MYD88. FT No effect on homodimerization. FT {ECO:0000269|PubMed:23453969}. FT MUTAGEN 38 38 K->A: Loss of kinase activity and loss of FT nuclear import. FT {ECO:0000269|PubMed:10421793}. FT MUTAGEN 168 168 E->A: Slight decrease of kinase activity. FT {ECO:0000269|PubMed:10421793}. FT MUTAGEN 172 172 S->A: Loss of autophosphorylation and of FT kinase activity. FT {ECO:0000269|PubMed:10421793}. FT MUTAGEN 172 172 S->E: Decrease in kinase activity. FT {ECO:0000269|PubMed:10421793}. FT MUTAGEN 231 231 K->R: Loss of sumoylation and loss of FT targeting to nuclear bodies. FT {ECO:0000269|PubMed:20188669}. FT MUTAGEN 401 401 K->A: Loss of ubiquitination and FT decreased kinase activity. No effect on FT homodimerization. FT {ECO:0000269|PubMed:23453969}. FT MUTAGEN 401 401 K->R: Loss of ubiquitination and FT decreased kinase activity. Decreases FT interaction with IKBKB, IKBKG and MYD88. FT No effect on homodimerization. FT {ECO:0000269|PubMed:23453969}. FT MUTAGEN 416 416 K->A: No effect on ubiquitination. FT {ECO:0000269|PubMed:23453969}. FT MUTAGEN 416 416 K->R: No effect on ubiquitination. FT {ECO:0000269|PubMed:23453969}. FT CONFLICT 187 187 R -> Q (in Ref. 7; AAI05925). FT {ECO:0000305}. SQ SEQUENCE 716 AA; 80462 MW; 3E5FBE5840734D81 CRC64; MQSTANYLWH TDDLLGQGAT ASVYKARNKK SGELVAVKVF NTTSYLRPRE VQVREFEVLR KLNHQNIVKL FAVEETGGSR QKVLVMEYCS SGSLLSVLES PENAFGLPED EFLVVLRCVV AGMNHLRENG IVHRDIKPGN IMRLVGEEGQ SIYKLTDFGA ARELDDDEKF VSVYGTEEYL HPDMYERAVL RKPQQKAFGV TVDLWSIGVT LYHAATGSLP FIPFGGPRRN KEIMYRITTE KPAGAIAGAQ RRENGPLEWS YTLPITCQLS LGLQSQLVPI LANILEVEQA KCWGFDQFFA ETSDILQRVV VHVFSLSQAV LHHIYIHAHN TIAIFQEAVH KQTSVAPRHQ EYLFEGHLCV LEPSVSAQHI AHTTASSPLT LFSTAIPKGL AFRDPALDVP KFVPKVDLQA DYNTAKGVLG AGYQALRLAR ALLDGQELMF RGLHWVMEVL QATCRRTLEV ARTSLLYLSS SLGTERFSSV AGTPEIQELK AAAELRSRLR TLAEVLSRCS QNITETQESL SSLNRELVKS RDQVHEDRSI QQIQCCLDKM NFIYKQFKKS RMRPGLGYNE EQIHKLDKVN FSHLAKRLLQ VFQEECVQKY QASLVTHGKR MRVVHETRNH LRLVGCSVAA CNTEAQGVQE SLSKLLEELS HQLLQDRAKG AQASPPPIAP YPSPTRKDLL LHMQELCEGM KLLASDLLDN NRIIERLNRV PAPPDV //