ID IKBA_HUMAN Reviewed; 317 AA. AC P25963; B2R8L6; DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1992, sequence version 1. DT 27-MAR-2024, entry version 239. DE RecName: Full=NF-kappa-B inhibitor alpha; DE AltName: Full=I-kappa-B-alpha; DE Short=IkB-alpha; DE Short=IkappaBalpha; DE AltName: Full=Major histocompatibility complex enhancer-binding protein MAD3; GN Name=NFKBIA; Synonyms=IKBA, MAD3, NFKBI; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION. RC TISSUE=Monocyte; RX PubMed=1829648; DOI=10.1016/0092-8674(91)90022-q; RA Haskill S., Beg A.A., Tompkins S.M., Morris J.S., Yurochko A.D., RA Sampson-Johannes A., Mondal K., Ralph P., Baldwin A.S. Jr.; RT "Characterization of an immediate-early gene induced in adherent monocytes RT that encodes I kappa B-like activity."; RL Cell 65:1281-1289(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Lymph node; RX PubMed=10637284; DOI=10.1084/jem.191.2.395; RA Jungnickel B., Staratschek-Jox A., Braeuninger A., Spieker T., Wolf J., RA Diehl V., Hansmann M.-L., Rajewsky K., Kueppers R.; RT "Clonal deleterious mutations in the IkappaB alpha gene in the malignant RT cells in Hodgkin's lymphoma."; RL J. Exp. Med. 191:395-402(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Liu B., Huang A.; RT "Homo sapiens IkBa mRNA."; RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Kidney; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP FUNCTION, AND INTERACTION WITH RELA. RX PubMed=1493333; DOI=10.1091/mbc.3.12.1339; RA Ganchi P.A., Sun S.C., Greene W.C., Ballard D.W.; RT "I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B p65 RT and requires the transactivation domain to inhibit NF-kappa B p65 DNA RT binding."; RL Mol. Biol. Cell 3:1339-1352(1992). RN [11] RP FUNCTION, PHOSPHORYLATION AT SER-32 AND SER-36, AND MUTAGENESIS OF SER-32 RP AND SER-36. RX PubMed=7796813; DOI=10.1002/j.1460-2075.1995.tb07287.x; RA Traenckner E.B., Pahl H.L., Henkel T., Schmidt K.N., Wilk S., RA Baeuerle P.A.; RT "Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I RT kappa B-alpha proteolysis and NF-kappa B activation in response to diverse RT stimuli."; RL EMBO J. 14:2876-2883(1995). RN [12] RP FUNCTION, UBIQUITINATION, PHOSPHORYLATION AT SER-32 AND SER-36, AND RP MUTAGENESIS OF SER-32 AND SER-36. RX PubMed=7628694; DOI=10.1101/gad.9.13.1586; RA Chen Z., Hagler J., Palombella V.J., Melandri F., Scherer D., Ballard D., RA Maniatis T.; RT "Signal-induced site-specific phosphorylation targets I kappa B alpha to RT the ubiquitin-proteasome pathway."; RL Genes Dev. 9:1586-1597(1995). RN [13] RP UBIQUITINATION AT LYS-21 AND LYS-22, FUNCTION, AND MUTAGENESIS OF LYS-21; RP LYS-22; LYS-38 AND LYS-47. RX PubMed=7479976; DOI=10.1073/pnas.92.24.11259; RA Scherer D.C., Brockman J.A., Chen Z., Maniatis T., Ballard D.W.; RT "Signal-induced degradation of IkappaB alpha requires site-specific RT ubiquitination."; RL Proc. Natl. Acad. Sci. U.S.A. 92:11259-11263(1995). RN [14] RP FUNCTION, PHOSPHORYLATION AT SER-32 AND SER-36, AND MUTAGENESIS OF SER-32 RP AND SER-36. RX PubMed=7878466; DOI=10.1126/science.7878466; RA Brown K., Gerstberger S., Carlson L., Franzoso G., Siebenlist U.; RT "Control of I kappa B-alpha proteolysis by site-specific, signal-induced RT phosphorylation."; RL Science 267:1485-1488(1995). RN [15] RP PHOSPHORYLATION AT TYR-42, AND MUTAGENESIS OF TYR-42. RX PubMed=8797825; DOI=10.1016/s0092-8674(00)80153-1; RA Imbert V., Rupec R.A., Livolsi A., Pahl H.L., Traenckner E.B.-M., RA Mueller-Dieckmann C., Farahifar D., Rossi B., Auberger P., Baeuerle P.A., RA Peyron J.-F.; RT "Tyrosine phosphorylation of IkappaB-alpha activates NF-kappaB without RT proteolytic degradation of IkappaB-alpha."; RL Cell 86:787-798(1996). RN [16] RP UBIQUITINATION, PHOSPHORYLATION AT SER-32 AND SER-36, AND MUTAGENESIS OF RP SER-32 AND SER-36. RX PubMed=8631829; DOI=10.1074/jbc.271.13.7844; RA Roff M., Thompson J., Rodriguez M.S., Jacque J.M., Baleux F., RA Arenzana-Seisdedos F., Hay R.T.; RT "Role of IkappaBalpha ubiquitination in signal-induced activation of RT NFkappaB in vivo."; RL J. Biol. Chem. 271:7844-7850(1996). RN [17] RP PHOSPHORYLATION AT TYR-42. RX PubMed=8940099; DOI=10.1074/jbc.271.49.31049; RA Singh S., Darnay B.G., Aggarwal B.B.; RT "Site-specific tyrosine phosphorylation of IkappaBalpha negatively RT regulates its inducible phosphorylation and degradation."; RL J. Biol. Chem. 271:31049-31054(1996). RN [18] RP PHOSPHORYLATION AT SER-283; SER-288; SER-293 AND THR-291. RX PubMed=8622692; DOI=10.1128/mcb.16.3.899; RA McElhinny J.A., Trushin S.A., Bren G.D., Chester N., Paya C.V.; RT "Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, RT and T-291 and is required for its degradation."; RL Mol. Cell. Biol. 16:899-906(1996). RN [19] RP MUTAGENESIS OF LYS-21; LYS-22; ASP-31; SER-32; ASP-35; SER-36; SER-234; RP SER-262 AND THR-263. RX PubMed=8657102; DOI=10.1128/mcb.16.4.1295; RA DiDonato J.A., Mercurio F., Rosette C., Wu-Li J., Suyang H., Ghosh S., RA Karin M.; RT "Mapping of the inducible IkappaB phosphorylation sites that signal its RT ubiquitination and degradation."; RL Mol. Cell. Biol. 16:1295-1304(1996). RN [20] RP PHOSPHORYLATION AT THR-291; SER-283 AND THR-299. RX PubMed=8657113; DOI=10.1128/mcb.16.4.1401; RA Lin R., Beauparlant P., Makris C., Meloche S., Hiscott J.; RT "Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein RT kinase II affects intrinsic protein stability."; RL Mol. Cell. Biol. 16:1401-1409(1996). RN [21] RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF RP 115-LEU--ILE-120. RX PubMed=9566872; DOI=10.1128/mcb.18.5.2524; RA Sachdev S., Hoffmann A., Hannink M.; RT "Nuclear localization of IkappaB alpha is mediated by the second ankyrin RT repeat: the IkappaB alpha ankyrin repeats define a novel class of cis- RT acting nuclear import sequences."; RL Mol. Cell. Biol. 18:2524-2534(1998). RN [22] RP IDENTIFICATION IN A COMPLEX WITH CHUK; IKBKB; RELA; ELP1 AND MAP3K14. RX PubMed=9751059; DOI=10.1038/26254; RA Cohen L., Henzel W.J., Baeuerle P.A.; RT "IKAP is a scaffold protein of the IkappaB kinase complex."; RL Nature 395:292-296(1998). RN [23] RP UBIQUITINATION, AND PHOSPHORYLATION AT SER-32 AND SER-36. RX PubMed=9701247; DOI=10.1038/nm0898-939; RA Sharipo A., Imreh M., Leonchiks A., Imreh S., Masucci M.G.; RT "A minimal glycine-alanine repeat prevents the interaction of ubiquitinated RT I kappaB alpha with the proteasome: a new mechanism for selective RT inhibition of proteolysis."; RL Nat. Med. 4:939-944(1998). RN [24] RP UBIQUITINATION BY THE SCF(FBXW11) COMPLEX. RX PubMed=10437795; DOI=10.1016/s0014-5793(99)00895-9; RA Vuillard L., Nicholson J., Hay R.T.; RT "A complex containing betaTrCP recruits Cdc34 to catalyse ubiquitination of RT IkappaBalpha."; RL FEBS Lett. 455:311-314(1999). RN [25] RP PHOSPHORYLATION AT SER-32 AND SER-36, MUTAGENESIS OF SER-32 AND SER-36, AND RP UBIQUITINATION BY UBE2D2 AND UBE2D3. RX PubMed=10329681; DOI=10.1074/jbc.274.21.14823; RA Gonen H., Bercovich B., Orian A., Carrano A., Takizawa C., Yamanaka K., RA Pagano M., Iwai K., Ciechanover A.; RT "Identification of the ubiquitin carrier proteins, E2s, involved in signal- RT induced conjugation and subsequent degradation of IkappaBalpha."; RL J. Biol. Chem. 274:14823-14830(1999). RN [26] RP PHOSPHORYLATION AT SER-32, UBIQUITINATION AT LYS-21 AND LYS-22, AND RP MUTAGENESIS OF LYS-21; LYS-22; SER-32 AND SER-36. RX PubMed=10574930; DOI=10.1074/jbc.274.49.34657; RA Zhang Y., Sun X., Muraoka K., Ikeda A., Miyamoto S., Shimizu H., RA Yoshioka K., Yamamoto K.; RT "Immunosuppressant FK506 activates NF-kappaB through the proteasome- RT mediated degradation of IkappaBalpha. Requirement for Ikappabalpha n- RT terminal phosphorylation but not ubiquitination sites."; RL J. Biol. Chem. 274:34657-34662(1999). RN [27] RP INTERACTION WITH HEPATITIS B VIRUS/HBV PROTEIN X (MICROBIAL INFECTION). RX PubMed=10454581; DOI=10.1128/mcb.19.9.6345; RA Weil R., Sirma H., Giannini C., Kremsdorf D., Bessia C., Dargemont C., RA Brechot C., Israel A.; RT "Direct association and nuclear import of the hepatitis B virus X protein RT with the NF-kappaB inhibitor IkappaBalpha."; RL Mol. Cell. Biol. 19:6345-6354(1999). RN [28] RP UBIQUITINATION BY THE SCF(BTRC). RX PubMed=10644755; DOI=10.1074/jbc.275.4.2877; RA Suzuki H., Chiba T., Suzuki T., Fujita T., Ikenoue T., Omata M., RA Furuichi K., Shikama H., Tanaka K.; RT "Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to RT IkappaBalpha for signal-dependent ubiquitination."; RL J. Biol. Chem. 275:2877-2884(2000). RN [29] RP PHOSPHORYLATION AT SER-32 AND SER-36. 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 complex."; RL Mol. Cell 5:513-522(2000). RN [30] RP PHOSPHORYLATION BY TBK1. RX PubMed=10783893; DOI=10.1038/35008109; RA Tojima Y., Fujimoto A., Delhase M., Chen Y., Hatakeyama S., Nakayama K., RA Kaneko Y., Nimura Y., Motoyama N., Ikeda K., Karin M., Nakanishi M.; RT "NAK is an IkappaB kinase-activating kinase."; RL Nature 404:778-782(2000). RN [31] RP INTERACTION WITH NKIRAS1 AND NKIRAS2. RX PubMed=10657303; DOI=10.1126/science.287.5454.869; RA Fenwick C., Na S.-Y., Voll R.E., Zhong H., Im S.-Y., Lee J.W., Ghosh S.; RT "A subclass of Ras proteins that regulate the degradation of IkappaB."; RL Science 287:869-873(2000). RN [32] RP SUBCELLULAR LOCATION, NUCLEAR EXPORT SIGNAL, AND MUTAGENESIS OF RP 45-MET--ILE-52. RX PubMed=10655476; DOI=10.1073/pnas.97.3.1014; RA Huang T.T., Kudo N., Yoshida M., Miyamoto S.; RT "A nuclear export signal in the N-terminal regulatory domain of RT IkappaBalpha controls cytoplasmic localization of inactive NF- RT kappaB/IkappaBalpha complexes."; RL Proc. Natl. Acad. Sci. U.S.A. 97:1014-1019(2000). RN [33] RP SUMOYLATION AT LYS-21, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-21 AND RP LYS-22. RX PubMed=11124955; DOI=10.1074/jbc.m009476200; RA Rodriguez M.S., Dargemont C., Hay R.T.; RT "SUMO-1 conjugation in vivo requires both a consensus modification motif RT and nuclear targeting."; RL J. Biol. Chem. 276:12654-12659(2001). RN [34] RP INTERACTION WITH PRKACA. RX PubMed=20356841; DOI=10.1074/jbc.m109.077602; RA Gambaryan S., Kobsar A., Rukoyatkina N., Herterich S., Geiger J., RA Smolenski A., Lohmann S.M., Walter U.; RT "Thrombin and collagen induce a feedback inhibitory signaling pathway in RT platelets involving dissociation of the catalytic subunit of protein kinase RT A from an NFkappaB-IkappaB complex."; RL J. Biol. Chem. 285:18352-18363(2010). RN [35] RP INTERACTION WITH PRMT2, AND SUBCELLULAR LOCATION. RX PubMed=16648481; DOI=10.1128/mcb.26.10.3864-3874.2006; RA Ganesh L., Yoshimoto T., Moorthy N.C., Akahata W., Boehm M., Nabel E.G., RA Nabel G.J.; RT "Protein methyltransferase 2 inhibits NF-kappaB function and promotes RT apoptosis."; RL Mol. Cell. Biol. 26:3864-3874(2006). RN [36] RP HYDROXYLATION AT ASN-210 AND ASN-244, AND MUTAGENESIS OF ASN-210 AND RP ASN-244. RX PubMed=17003112; DOI=10.1073/pnas.0606877103; RA Cockman M.E., Lancaster D.E., Stolze I.P., Hewitson K.S., McDonough M.A., RA Coleman M.L., Coles C.H., Yu X., Hay R.T., Ley S.C., Pugh C.W., RA Oldham N.J., Masson N., Schofield C.J., Ratcliffe P.J.; RT "Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by RT the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor RT inhibiting HIF (FIH)."; RL Proc. Natl. Acad. Sci. U.S.A. 103:14767-14772(2006). RN [37] RP INTERACTION WITH RWDD3, SUMOYLATION, AND MUTAGENESIS OF LYS-21 AND LYS-22. RX PubMed=17956732; DOI=10.1016/j.cell.2007.07.044; RA Carbia-Nagashima A., Gerez J., Perez-Castro C., Paez-Pereda M., RA Silberstein S., Stalla G.K., Holsboer F., Arzt E.; RT "RSUME, a small RWD-containing protein, enhances SUMO conjugation and RT stabilizes HIF-1alpha during hypoxia."; RL Cell 131:309-323(2007). RN [38] RP INTERACTION WITH MEFV. RX PubMed=18577712; DOI=10.1182/blood-2008-01-134932; RA Chae J.J., Wood G., Richard K., Jaffe H., Colburn N.T., Masters S.L., RA Gumucio D.L., Shoham N.G., Kastner D.L.; RT "The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 RT and activates NF-kappaB through its N-terminal fragment."; RL Blood 112:1794-1803(2008). RN [39] RP UBIQUITINATION AT LYS-21 AND LYS-22. RX PubMed=20347421; DOI=10.1016/j.molcel.2010.02.025; RA Wu K., Kovacev J., Pan Z.Q.; RT "Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for RT polyubiquitination on a SCF substrate."; RL Mol. Cell 37:784-796(2010). RN [40] RP DEUBIQUITINATION BY PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS RP NSP2 PROTEIN. RX PubMed=20504922; DOI=10.1128/jvi.00217-10; RA Sun Z., Chen Z., Lawson S.R., Fang Y.; RT "The cysteine protease domain of porcine reproductive and respiratory RT syndrome virus nonstructural protein 2 possesses deubiquitinating and RT interferon antagonism functions."; RL J. Virol. 84:7832-7846(2010). RN [41] RP INTERACTION WITH RWDD3. RX PubMed=23469069; DOI=10.1371/journal.pone.0057795; RA Gerez J., Fuertes M., Tedesco L., Silberstein S., Sevlever G., RA Paez-Pereda M., Holsboer F., Turjanski A.G., Arzt E.; RT "In silico structural and functional characterization of the RSUME splice RT variants."; RL PLoS ONE 8:E57795-E57795(2013). RN [42] RP INTERACTION WITH DDRGK1. RX PubMed=23675531; DOI=10.1371/journal.pone.0064231; RA Xi P., Ding D., Zhou J., Wang M., Cong Y.S.; RT "DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha RT stability."; RL PLoS ONE 8:E64231-E64231(2013). RN [43] RP FUNCTION, AND DEUBIQUITINATION BY USP39. RX PubMed=36651806; DOI=10.4049/jimmunol.2200603; RA Quan J., Zhao X., Xiao Y., Wu H., Di Q., Wu Z., Chen X., Tang H., Zhao J., RA Guan Y., Xu Y., Chen W.; RT "USP39 Regulates NF-kappaB-Mediated Inflammatory Responses through RT Deubiquitinating K48-Linked IkappaBalpha."; RL J. Immunol. 210:640-652(2023). RN [44] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 70-282. RX PubMed=9865693; DOI=10.1016/s0092-8674(00)81698-0; RA Jacobs M.D., Harrison S.C.; RT "Structure of an IkappaBalpha/NF-kappaB complex."; RL Cell 95:749-758(1998). RN [45] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 73-302. RX PubMed=9865694; DOI=10.1016/s0092-8674(00)81699-2; RA Huxford T., Huang D.B., Malek S., Ghosh G.; RT "The crystal structure of the IkappaBalpha/NF-kappaB complex reveals RT mechanisms of NF-kappaB inactivation."; RL Cell 95:759-770(1998). RN [46] RP VARIANT EDAID2 ILE-32. RX PubMed=14523047; DOI=10.1172/jci18714; RA Courtois G., Smahi A., Reichenbach J., Doffinger R., Cancrini C., RA Bonnet M., Puel A., Chable-Bessia C., Yamaoka S., Feinberg J., RA Dupuis-Girod S., Bodemer C., Livadiotti S., Novelli F., Rossi P., RA Fischer A., Israel A., Munnich A., Le Deist F., Casanova J.L.; RT "A hypermorphic IkappaBalpha mutation is associated with autosomal dominant RT anhidrotic ectodermal dysplasia and T cell immunodeficiency."; RL J. Clin. Invest. 112:1108-1115(2003). RN [47] RP INVOLVEMENT IN EDAID2. RX PubMed=18412279; DOI=10.1002/humu.20740; RA Lopez-Granados E., Keenan J.E., Kinney M.C., Leo H., Jain N., Ma C.A., RA Quinones R., Gelfand E.W., Jain A.; RT "A novel mutation in NFKBIA/IKBA results in a degradation-resistant N- RT truncated protein and is associated with ectodermal dysplasia with RT immunodeficiency."; RL Hum. Mutat. 29:861-868(2008). CC -!- FUNCTION: Inhibits the activity of dimeric NF-kappa-B/REL complexes by CC trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by CC masking their nuclear localization signals (PubMed:1493333, CC PubMed:7479976, PubMed:36651806). On cellular stimulation by immune and CC pro-inflammatory responses, becomes phosphorylated promoting CC ubiquitination and degradation, enabling the dimeric RELA to CC translocate to the nucleus and activate transcription (PubMed:7796813, CC PubMed:7628694, PubMed:7878466, PubMed:7479976). CC {ECO:0000269|PubMed:1493333, ECO:0000269|PubMed:36651806, CC ECO:0000269|PubMed:7479976, ECO:0000269|PubMed:7628694, CC ECO:0000269|PubMed:7796813, ECO:0000269|PubMed:7878466}. CC -!- SUBUNIT: Interacts with RELA; the interaction requires the nuclear CC import signal (PubMed:1493333). Part of a 70-90 kDa complex at least CC consisting of CHUK, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14 CC (PubMed:9751059). Interacts with NKIRAS1 and NKIRAS2 (PubMed:10657303). CC Interacts with isoform 1 and isoform 2 of RWDD3; the interaction CC enhances sumoylation (PubMed:17956732, PubMed:23469069). Interacts with CC PRMT2 (PubMed:16648481). Interacts with PRKACA in platelets; this CC interaction is disrupted by thrombin and collagen (PubMed:20356841). CC Interacts with MEFV (PubMed:18577712). Interacts with DDRGK1; CC positively regulates NFKBIA phosphorylation and degradation CC (PubMed:23675531). {ECO:0000269|PubMed:10657303, CC ECO:0000269|PubMed:1493333, ECO:0000269|PubMed:16648481, CC ECO:0000269|PubMed:17956732, ECO:0000269|PubMed:18577712, CC ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:23469069, CC ECO:0000269|PubMed:23675531, ECO:0000269|PubMed:9751059}. CC -!- SUBUNIT: (Microbial infection) Interacts with HBV protein X. CC {ECO:0000269|PubMed:10454581}. CC -!- INTERACTION: CC P25963; O15111: CHUK; NbExp=15; IntAct=EBI-307386, EBI-81249; CC P25963; Q8N668: COMMD1; NbExp=3; IntAct=EBI-307386, EBI-1550112; CC P25963; P35221: CTNNA1; NbExp=5; IntAct=EBI-307386, EBI-701918; CC P25963; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-307386, EBI-744099; CC P25963; Q9UKB1: FBXW11; NbExp=2; IntAct=EBI-307386, EBI-355189; CC P25963; P25098: GRK2; NbExp=2; IntAct=EBI-307386, EBI-3904795; CC P25963; P34947: GRK5; NbExp=2; IntAct=EBI-307386, EBI-7149314; CC P25963; Q9NWT6: HIF1AN; NbExp=6; IntAct=EBI-307386, EBI-745632; CC P25963; O14920: IKBKB; NbExp=27; IntAct=EBI-307386, EBI-81266; CC P25963; Q9Y6K9: IKBKG; NbExp=6; IntAct=EBI-307386, EBI-81279; CC P25963; Q14511: NEDD9; NbExp=3; IntAct=EBI-307386, EBI-2108053; CC P25963; Q14511-2: NEDD9; NbExp=3; IntAct=EBI-307386, EBI-11746523; CC P25963; P19838: NFKB1; NbExp=8; IntAct=EBI-307386, EBI-300010; CC P25963; Q00653: NFKB2; NbExp=2; IntAct=EBI-307386, EBI-307326; CC P25963; P25963: NFKBIA; NbExp=2; IntAct=EBI-307386, EBI-307386; CC P25963; Q96HA1-2: POM121; NbExp=3; IntAct=EBI-307386, EBI-11956563; CC P25963; O43242: PSMD3; NbExp=3; IntAct=EBI-307386, EBI-357622; CC P25963; Q04864: REL; NbExp=3; IntAct=EBI-307386, EBI-307352; CC P25963; Q04206: RELA; NbExp=25; IntAct=EBI-307386, EBI-73886; CC P25963; Q04206-2: RELA; NbExp=2; IntAct=EBI-307386, EBI-289947; CC P25963; P23396: RPS3; NbExp=6; IntAct=EBI-307386, EBI-351193; CC P25963; P56279: TCL1A; NbExp=3; IntAct=EBI-307386, EBI-749995; CC P25963; P0CG48: UBC; NbExp=3; IntAct=EBI-307386, EBI-3390054; CC P25963; Q60680-2: Chuk; Xeno; NbExp=2; IntAct=EBI-307386, EBI-646264; CC P25963; Q9J0X9: UL54; Xeno; NbExp=3; IntAct=EBI-307386, EBI-7967856; CC P25963; P14340; Xeno; NbExp=2; IntAct=EBI-307386, EBI-465733; CC P25963; PRO_0000037965 [P14340]; Xeno; NbExp=2; IntAct=EBI-307386, EBI-9825968; CC P25963; PRO_0000038062 [P21530]; Xeno; NbExp=4; IntAct=EBI-307386, EBI-12558622; CC P25963; Q9E7P0; Xeno; NbExp=2; IntAct=EBI-307386, EBI-11361108; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10655476}. Nucleus CC {ECO:0000269|PubMed:10655476, ECO:0000269|PubMed:16648481, CC ECO:0000269|PubMed:9566872}. Note=Shuttles between the nucleus and the CC cytoplasm by a nuclear localization signal (NLS) and a CRM1-dependent CC nuclear export. {ECO:0000269|PubMed:10655476, CC ECO:0000269|PubMed:9566872}. CC -!- INDUCTION: Induced in adherent monocytes. {ECO:0000269|PubMed:1829648}. CC -!- PTM: Phosphorylated at Ser-32 and Ser-36 by IKKA/CHUK and IKKB/IKBKB; CC disables inhibition of NF-kappa-B DNA-binding activity (PubMed:7796813, CC PubMed:7628694, PubMed:7878466, PubMed:8631829, PubMed:9701247, CC PubMed:10329681, PubMed:10882136). Phosphorylation at positions 32 and CC 36 is prerequisite to recognition by the SCF(FBXW11) and SCF(BTRC) CC complexes, leading to polyubiquitination and subsequent degradation CC (PubMed:7628694, PubMed:8631829, PubMed:9701247, PubMed:10329681). CC Phosphorylated at Ser-32 in response to FK506 treatment: CC phosphorylation is independent of IKKA/CHUK and IKKB/IKBKB and promotes CC NFKBIA degradation, followed by NF-kappa-B activation CC (PubMed:10574930). Phosphorylated at Tyr-42: its effect is however CC unclear (PubMed:8797825, PubMed:8940099). According to a report, CC phosphorylation at Tyr-42 activates NF-kappa-B without triggering CC proteolytic degradation of NFKBIA (PubMed:8797825). According to CC another publication, phosphorylation at Tyr-42 inhibits NF-kappa-B CC activity by preventing phosphorylation at Ser-32 and Ser-36 and CC subsequent ubiquitination and degradation (PubMed:8940099). CC {ECO:0000269|PubMed:10329681, ECO:0000269|PubMed:10574930, CC ECO:0000269|PubMed:10882136, ECO:0000269|PubMed:7628694, CC ECO:0000269|PubMed:7796813, ECO:0000269|PubMed:7878466, CC ECO:0000269|PubMed:8631829, ECO:0000269|PubMed:8797825, CC ECO:0000269|PubMed:8940099, ECO:0000269|PubMed:9701247}. CC -!- PTM: Polyubiquitinated at Lys-21 and/or Lys-22 following CC phosphorylation at Ser-32 and Ser-36 (PubMed:7479976, PubMed:8631829, CC PubMed:9701247, PubMed:10329681, PubMed:20347421). Monoubiquitinated at CC Lys-21 and/or Lys-22 by UBE2D3 (PubMed:7479976, PubMed:10329681, CC PubMed:20347421). Ubiquitin chain elongation is then performed by CDC34 CC in cooperation with the SCF(FBXW11) E3 ligase complex, building CC ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin CC (PubMed:10437795, PubMed:20347421). The resulting polyubiquitination CC leads to protein degradation (PubMed:7628694, PubMed:7479976, CC PubMed:20347421). Also ubiquitinated by the SCF(BTRC) complex following CC stimulus-dependent phosphorylation at Ser-32 and Ser-36 CC (PubMed:10644755). Deubiquitinated by USP38, leading to NF-kappa-B CC inhibition (PubMed:36651806). {ECO:0000269|PubMed:10329681, CC ECO:0000269|PubMed:10437795, ECO:0000269|PubMed:10644755, CC ECO:0000269|PubMed:20347421, ECO:0000269|PubMed:36651806, CC ECO:0000269|PubMed:7479976, ECO:0000269|PubMed:7628694, CC ECO:0000269|PubMed:8631829, ECO:0000269|PubMed:9701247}. CC -!- PTM: Sumoylated; sumoylation requires the presence of the nuclear CC import signal. Sumoylation blocks ubiquitination and proteasome- CC mediated degradation of the protein thereby increasing the protein CC stability. {ECO:0000269|PubMed:11124955, ECO:0000269|PubMed:17956732, CC ECO:0000269|PubMed:20504922}. CC -!- PTM: Hydroxylated by HIF1AN. {ECO:0000269|PubMed:17003112}. CC -!- PTM: (Microbial infection) Deubiquitinated by porcine reproductive and CC respiratory syndrome virus Nsp2 protein, which thereby interferes with CC NFKBIA degradation and impairs subsequent NF-kappa-B activation. CC {ECO:0000269|PubMed:20504922}. CC -!- DISEASE: Ectodermal dysplasia and immunodeficiency 2 (EDAID2) CC [MIM:612132]: A form of ectoderma dysplasia, a heterogeneous group of CC disorders due to abnormal development of two or more ectodermal CC structures. This form of ectodermal dysplasia is associated with CC decreased production of pro-inflammatory cytokines and certain CC interferons, rendering patients susceptible to infection. EDAID2 CC inheritance is autosomal dominant. {ECO:0000269|PubMed:14523047, CC ECO:0000269|PubMed:18412279}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the NF-kappa-B inhibitor family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=NFKBIAbase; Note=NFKBIA mutation db; CC URL="http://structure.bmc.lu.se/idbase/NFKBIAbase/"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/nfkbia/"; 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; M69043; AAA16489.1; -; mRNA. DR EMBL; AJ249294; CAB65556.2; -; Genomic_DNA. DR EMBL; AJ249295; CAB65556.2; JOINED; Genomic_DNA. DR EMBL; AJ249283; CAB65556.2; JOINED; Genomic_DNA. DR EMBL; AJ249284; CAB65556.2; JOINED; Genomic_DNA. DR EMBL; AJ249285; CAB65556.2; JOINED; Genomic_DNA. DR EMBL; AJ249286; CAB65556.2; JOINED; Genomic_DNA. DR EMBL; AY033600; AAK51149.1; -; mRNA. DR EMBL; BT007091; AAP35754.1; -; mRNA. DR EMBL; AY496422; AAR29599.1; -; Genomic_DNA. DR EMBL; AK313421; BAG36213.1; -; mRNA. DR EMBL; AL133163; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471078; EAW65875.1; -; Genomic_DNA. DR EMBL; BC002601; AAH02601.1; -; mRNA. DR EMBL; BC004983; AAH04983.1; -; mRNA. DR CCDS; CCDS9656.1; -. DR PIR; A39935; A39935. DR RefSeq; NP_065390.1; NM_020529.2. DR PDB; 1IKN; X-ray; 2.30 A; D=67-302. DR PDB; 1NFI; X-ray; 2.70 A; E/F=70-282. DR PDB; 6TTU; EM; 3.70 A; I=21-41. DR PDB; 6Y1J; X-ray; 1.13 A; P=57-69. DR PDBsum; 1IKN; -. DR PDBsum; 1NFI; -. DR PDBsum; 6TTU; -. DR PDBsum; 6Y1J; -. DR AlphaFoldDB; P25963; -. DR BMRB; P25963; -. DR SMR; P25963; -. DR BioGRID; 110859; 213. DR CORUM; P25963; -. DR DIP; DIP-139N; -. DR ELM; P25963; -. DR IntAct; P25963; 95. DR MINT; P25963; -. DR STRING; 9606.ENSP00000216797; -. DR BindingDB; P25963; -. DR ChEMBL; CHEMBL2898; -. DR DrugBank; DB00945; Acetylsalicylic acid. DR DrugBank; DB06543; Astaxanthin. DR DrugBank; DB05983; Bardoxolone methyl. DR iPTMnet; P25963; -. DR MetOSite; P25963; -. DR PhosphoSitePlus; P25963; -. DR BioMuta; NFKBIA; -. DR DMDM; 126682; -. DR EPD; P25963; -. DR jPOST; P25963; -. DR MassIVE; P25963; -. DR MaxQB; P25963; -. DR PaxDb; 9606-ENSP00000216797; -. DR PeptideAtlas; P25963; -. DR ProteomicsDB; 54304; -. DR Pumba; P25963; -. DR Antibodypedia; 3541; 2269 antibodies from 49 providers. DR DNASU; 4792; -. DR Ensembl; ENST00000216797.10; ENSP00000216797.6; ENSG00000100906.12. DR GeneID; 4792; -. DR KEGG; hsa:4792; -. DR MANE-Select; ENST00000216797.10; ENSP00000216797.6; NM_020529.3; NP_065390.1. DR UCSC; uc001wtf.5; human. DR AGR; HGNC:7797; -. DR CTD; 4792; -. DR DisGeNET; 4792; -. DR GeneCards; NFKBIA; -. DR HGNC; HGNC:7797; NFKBIA. DR HPA; ENSG00000100906; Tissue enhanced (bone). DR MalaCards; NFKBIA; -. DR MIM; 164008; gene. DR MIM; 612132; phenotype. DR neXtProt; NX_P25963; -. DR OpenTargets; ENSG00000100906; -. DR Orphanet; 251579; Giant cell glioblastoma. DR Orphanet; 251576; Gliosarcoma. DR Orphanet; 98813; Hypohidrotic ectodermal dysplasia with immunodeficiency. DR Orphanet; 150; Nasopharyngeal carcinoma. DR PharmGKB; PA31601; -. DR VEuPathDB; HostDB:ENSG00000100906; -. DR eggNOG; KOG0504; Eukaryota. DR GeneTree; ENSGT00940000162733; -. DR InParanoid; P25963; -. DR OMA; EIRIQPQ; -. DR OrthoDB; 621606at2759; -. DR PhylomeDB; P25963; -. DR TreeFam; TF320166; -. DR PathwayCommons; P25963; -. DR Reactome; R-HSA-1169091; Activation of NF-kappaB in B cells. DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1. DR Reactome; R-HSA-202424; Downstream TCR signaling. DR Reactome; R-HSA-209560; NF-kB is activated and signals survival. DR Reactome; R-HSA-2871837; FCERI mediated NF-kB activation. DR Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation. DR Reactome; R-HSA-4755510; SUMOylation of immune response proteins. DR Reactome; R-HSA-5603029; IkBA variant leads to EDA-ID. DR Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-933542; TRAF6 mediated NF-kB activation. DR Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses. DR SABIO-RK; P25963; -. DR SignaLink; P25963; -. DR SIGNOR; P25963; -. DR BioGRID-ORCS; 4792; 28 hits in 1172 CRISPR screens. DR ChiTaRS; NFKBIA; human. DR EvolutionaryTrace; P25963; -. DR GeneWiki; I%CE%BAB%CE%B1; -. DR GenomeRNAi; 4792; -. DR Pharos; P25963; Tchem. DR PRO; PR:P25963; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; P25963; Protein. DR Bgee; ENSG00000100906; Expressed in vena cava and 215 other cell types or tissues. DR ExpressionAtlas; P25963; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0033256; C:I-kappaB/NF-kappaB complex; TAS:BHF-UCL. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0140313; F:molecular sequestering activity; IDA:UniProt. DR GO; GO:0051059; F:NF-kappaB binding; IDA:UniProtKB. DR GO; GO:0008139; F:nuclear localization sequence binding; IPI:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProtKB. DR GO; GO:0140416; F:transcription regulator inhibitor activity; IEA:Ensembl. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0050853; P:B cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0007249; P:canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:0070417; P:cellular response to cold; NAS:BHF-UCL. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IBA:GO_Central. DR GO; GO:0007253; P:cytoplasmic sequestering of NF-kappaB; IMP:BHF-UCL. DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:ARUK-UCL. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:0010888; P:negative regulation of lipid storage; IMP:BHF-UCL. DR GO; GO:0010745; P:negative regulation of macrophage derived foam cell differentiation; IMP:BHF-UCL. DR GO; GO:0045638; P:negative regulation of myeloid cell differentiation; IEA:Ensembl. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:MGI. DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IEA:Ensembl. DR GO; GO:0038061; P:non-canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:0007219; P:Notch signaling pathway; IEA:Ensembl. DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl. DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl. DR GO; GO:0010875; P:positive regulation of cholesterol efflux; IMP:BHF-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:CAFA. DR GO; GO:0051247; P:positive regulation of protein metabolic process; IMP:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ARUK-UCL. DR GO; GO:0060261; P:positive regulation of transcription initiation by RNA polymerase II; IEA:Ensembl. DR GO; GO:0006606; P:protein import into nucleus; IEA:Ensembl. DR GO; GO:0042127; P:regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl. DR GO; GO:0032495; P:response to muramyl dipeptide; IEA:Ensembl. DR GO; GO:0035994; P:response to muscle stretch; IEA:Ensembl. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:CAFA. DR DisProt; DP00468; -. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR IDEAL; IID00654; -. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR PANTHER; PTHR46680; NF-KAPPA-B INHIBITOR ALPHA; 1. DR PANTHER; PTHR46680:SF1; NF-KAPPA-B INHIBITOR ALPHA; 1. DR Pfam; PF12796; Ank_2; 1. DR Pfam; PF13857; Ank_5; 1. DR PRINTS; PR01415; ANKYRIN. DR SMART; SM00248; ANK; 5. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 3. DR Genevisible; P25963; HS. PE 1: Evidence at protein level; KW 3D-structure; ANK repeat; Cytoplasm; Disease variant; Ectodermal dysplasia; KW Host-virus interaction; Hydroxylation; Isopeptide bond; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; Ubl conjugation. FT CHAIN 1..317 FT /note="NF-kappa-B inhibitor alpha" FT /id="PRO_0000066999" FT REPEAT 73..103 FT /note="ANK 1" FT REPEAT 110..139 FT /note="ANK 2" FT REPEAT 143..172 FT /note="ANK 3" FT REPEAT 182..211 FT /note="ANK 4" FT REPEAT 216..245 FT /note="ANK 5" FT REGION 1..39 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 30..36 FT /note="Destruction motif" FT /evidence="ECO:0000269|PubMed:8657102" FT MOTIF 45..54 FT /note="Nuclear export signal" FT /evidence="ECO:0000269|PubMed:10655476" FT MOTIF 110..120 FT /note="Nuclear import signal" FT /evidence="ECO:0000269|PubMed:9566872" FT COMPBIAS 11..39 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 32 FT /note="Phosphoserine; by IKKA and IKKE" FT /evidence="ECO:0000269|PubMed:10329681, FT ECO:0000269|PubMed:10574930, ECO:0000269|PubMed:10882136, FT ECO:0000269|PubMed:7628694, ECO:0000269|PubMed:7796813, FT ECO:0000269|PubMed:7878466, ECO:0000269|PubMed:8631829" FT MOD_RES 36 FT /note="Phosphoserine; by IKKA, IKKB, IKKE and TBK1" FT /evidence="ECO:0000269|PubMed:10329681, FT ECO:0000269|PubMed:10882136, ECO:0000269|PubMed:7628694, FT ECO:0000269|PubMed:7796813, ECO:0000269|PubMed:7878466, FT ECO:0000269|PubMed:8631829" FT MOD_RES 42 FT /note="Phosphotyrosine; by Tyr-kinases" FT /evidence="ECO:0000269|PubMed:8797825, FT ECO:0000269|PubMed:8940099" FT MOD_RES 210 FT /note="(3S)-3-hydroxyasparagine; by HIF1AN; partial" FT /evidence="ECO:0000269|PubMed:17003112" FT MOD_RES 244 FT /note="(3S)-3-hydroxyasparagine; by HIF1AN; partial" FT /evidence="ECO:0000269|PubMed:17003112" FT MOD_RES 283 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:8622692, FT ECO:0000269|PubMed:8657113" FT MOD_RES 288 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:8622692" FT MOD_RES 291 FT /note="Phosphothreonine; by CK2" FT /evidence="ECO:0000269|PubMed:8622692, FT ECO:0000269|PubMed:8657113" FT MOD_RES 293 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:8622692" FT MOD_RES 299 FT /note="Phosphothreonine; by CK2" FT /evidence="ECO:0000269|PubMed:8657113" FT CROSSLNK 21 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000269|PubMed:11124955" FT CROSSLNK 21 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:10574930, FT ECO:0000269|PubMed:20347421, ECO:0000269|PubMed:7479976" FT CROSSLNK 22 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:10574930, FT ECO:0000269|PubMed:20347421, ECO:0000269|PubMed:7479976" FT VARIANT 32 FT /note="S -> I (in EDAID2; dbSNP:rs28933100)" FT /evidence="ECO:0000269|PubMed:14523047" FT /id="VAR_034871" FT MUTAGEN 21 FT /note="K->R: Little change in Tax-stimulated FT transactivation. No sumoylation. Greatly reduced Tax- or FT cytokine-stimulated transactivation and decrease in FT ubiquitination and degradation; when associated with R-22. FT Does not affect activation by FK506." FT /evidence="ECO:0000269|PubMed:11124955, FT ECO:0000269|PubMed:17956732, ECO:0000269|PubMed:7479976, FT ECO:0000269|PubMed:8657102" FT MUTAGEN 22 FT /note="K->R: Little change in Tax-stimulated FT transactivation. No sumoylation. Greatly reduced Tax- or FT cytokine-stimulated transactivation and decrease in FT ubiquitination and degradation; when associated with R-21. FT Does not affect activation by FK506." FT /evidence="ECO:0000269|PubMed:11124955, FT ECO:0000269|PubMed:17956732, ECO:0000269|PubMed:7479976, FT ECO:0000269|PubMed:8657102" FT MUTAGEN 31 FT /note="D->A: Loss of phosphorylation; when associated with FT A-35." FT /evidence="ECO:0000269|PubMed:8657102" FT MUTAGEN 32 FT /note="S->A: Loss of phosphorylation, ubiquitination and FT degradation; when associated with A-36. Abolished FT activation by FK506." FT /evidence="ECO:0000269|PubMed:10329681, FT ECO:0000269|PubMed:10574930, ECO:0000269|PubMed:7628694, FT ECO:0000269|PubMed:7796813, ECO:0000269|PubMed:7878466, FT ECO:0000269|PubMed:8631829, ECO:0000269|PubMed:8657102" FT MUTAGEN 32 FT /note="S->E: Mimics phosphorylation; promoting FT ubiquitination and degradation; when associated with E-36." FT /evidence="ECO:0000269|PubMed:7628694, FT ECO:0000269|PubMed:7796813" FT MUTAGEN 32 FT /note="S->T: Decrease in phosphorylation and degradation; FT when associated with T-36." FT /evidence="ECO:0000269|PubMed:10329681, FT ECO:0000269|PubMed:8657102" FT MUTAGEN 35 FT /note="D->A: Loss in phosphorylation; when associated with FT A-31." FT /evidence="ECO:0000269|PubMed:8657102" FT MUTAGEN 35 FT /note="D->G: No change neither in phosphorylation, nor on FT degradation." FT /evidence="ECO:0000269|PubMed:8657102" FT MUTAGEN 36 FT /note="S->A: Loss of phosphorylation, ubiquitination, and FT degradation; when associated with A-32. Does not affect FT activation by FK506." FT /evidence="ECO:0000269|PubMed:10329681, FT ECO:0000269|PubMed:7628694, ECO:0000269|PubMed:7796813, FT ECO:0000269|PubMed:7878466, ECO:0000269|PubMed:8631829, FT ECO:0000269|PubMed:8657102" FT MUTAGEN 36 FT /note="S->E: Mimics phosphorylation; promoting FT ubiquitination and degradation; when associated with E-32." FT /evidence="ECO:0000269|PubMed:7628694, FT ECO:0000269|PubMed:7796813" FT MUTAGEN 36 FT /note="S->T: Decrease in phosphorylation and degradation; FT when associated with T-32." FT /evidence="ECO:0000269|PubMed:10329681, FT ECO:0000269|PubMed:8657102" FT MUTAGEN 38 FT /note="K->R: No change in Tax-stimulated transactivation. FT No change in Tax-stimulated transactivation; when FT associated with R-47." FT /evidence="ECO:0000269|PubMed:7479976" FT MUTAGEN 42 FT /note="Y->F: No phosphorylation." FT /evidence="ECO:0000269|PubMed:8797825" FT MUTAGEN 45..52 FT /note="MVKELQEI->AAKEAQEA: No nuclear export." FT /evidence="ECO:0000269|PubMed:10655476" FT MUTAGEN 47 FT /note="K->R: Little change in Tax-stimulated FT transactivation. No change in Tax-stimulated FT transactivation; when associated with R-38." FT /evidence="ECO:0000269|PubMed:7479976" FT MUTAGEN 115..120 FT /note="LHLAVI->AHAAVA: Greatly reduced nuclear FT localization. Great reduction in its ability to inhibit DNA FT binding of RELA." FT /evidence="ECO:0000269|PubMed:9566872" FT MUTAGEN 210 FT /note="N->A: Almost abolished ability to inhibit FT NF-kappa-BDNA-binding activity; when associated with FT A-244." FT /evidence="ECO:0000269|PubMed:17003112" FT MUTAGEN 234 FT /note="S->A: No inducible ubiquitination nor protein FT degradation." FT /evidence="ECO:0000269|PubMed:8657102" FT MUTAGEN 244 FT /note="N->A: Almost abolished ability to inhibit FT NF-kappa-BDNA-binding activity; when associated with FT A-210." FT /evidence="ECO:0000269|PubMed:17003112" FT MUTAGEN 262 FT /note="S->A: No inducible ubiquitination nor protein FT degradation." FT /evidence="ECO:0000269|PubMed:8657102" FT MUTAGEN 263 FT /note="T->A: No inducible ubiquitination nor protein FT degradation." FT /evidence="ECO:0000269|PubMed:8657102" FT TURN 72..74 FT /evidence="ECO:0007829|PDB:1NFI" FT HELIX 79..83 FT /evidence="ECO:0007829|PDB:1IKN" FT STRAND 87..91 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 101..104 FT /evidence="ECO:0007829|PDB:1NFI" FT HELIX 114..120 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 124..128 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 147..154 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 157..165 FT /evidence="ECO:0007829|PDB:1IKN" FT TURN 167..170 FT /evidence="ECO:0007829|PDB:1IKN" FT STRAND 171..173 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 175..177 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 186..192 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 196..205 FT /evidence="ECO:0007829|PDB:1IKN" FT TURN 214..216 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 220..226 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 230..237 FT /evidence="ECO:0007829|PDB:1IKN" FT TURN 238..240 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 253..256 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 263..270 FT /evidence="ECO:0007829|PDB:1IKN" FT HELIX 275..277 FT /evidence="ECO:0007829|PDB:1IKN" FT TURN 285..287 FT /evidence="ECO:0007829|PDB:1IKN" SQ SEQUENCE 317 AA; 35609 MW; 088B313226786395 CRC64; MFQAAERPQE WAMEGPRDGL KKERLLDDRH DSGLDSMKDE EYEQMVKELQ EIRLEPQEVP RGSEPWKQQL TEDGDSFLHL AIIHEEKALT MEVIRQVKGD LAFLNFQNNL QQTPLHLAVI TNQPEIAEAL LGAGCDPELR DFRGNTPLHL ACEQGCLASV GVLTQSCTTP HLHSILKATN YNGHTCLHLA SIHGYLGIVE LLVSLGADVN AQEPCNGRTA LHLAVDLQNP DLVSLLLKCG ADVNRVTYQG YSPYQLTWGR PSTRIQQQLG QLTLENLQML PESEDEESYD TESEFTEFTE DELPYDDCVF GGQRLTL //