ID NF2L2_HUMAN Reviewed; 605 AA. AC Q16236; B2RBU2; B4E338; E9PGJ7; Q53RW6; Q59HH2; Q96F71; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2002, sequence version 3. DT 02-OCT-2024, entry version 222. DE RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|PubMed:11035812}; DE Short=NF-E2-related factor 2 {ECO:0000303|PubMed:11035812}; DE Short=NFE2-related factor 2 {ECO:0000303|PubMed:11035812}; DE Short=Nrf-2 {ECO:0000303|PubMed:11256947}; DE AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919}; GN Name=NFE2L2 {ECO:0000303|PubMed:29018201, ECO:0000312|HGNC:HGNC:7782}; GN Synonyms=NRF2 {ECO:0000303|PubMed:33009401, ECO:0000303|PubMed:7937919}; 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 [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Tongue, and Uterus; 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Myeloid leukemia cell; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-202 (ISOFORM 1). RC TISSUE=Melanoma; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-605 (ISOFORM 1), FUNCTION, AND TISSUE RP SPECIFICITY. RC TISSUE=Fetal liver; RX PubMed=7937919; DOI=10.1073/pnas.91.21.9926; RA Moi P., Chan K., Asunis I., Cao A., Kan Y.W.; RT "Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine RT zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat RT of the beta-globin locus control region."; RL Proc. Natl. Acad. Sci. U.S.A. 91:9926-9930(1994). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION BY PKC. RX PubMed=11035812; DOI=10.1073/pnas.220418997; RA Huang H.-C., Nguyen T., Pickett C.B.; RT "Regulation of the antioxidant response element by protein kinase C- RT mediated phosphorylation of NF-E2-related factor 2."; RL Proc. Natl. Acad. Sci. U.S.A. 97:12475-12480(2000). RN [9] RP INTERACTION WITH PMF1. RX PubMed=11256947; DOI=10.1042/0264-6021:3550045; RA Wang Y., Devereux W., Stewart T.M., Casero R.A. Jr.; RT "Characterization of the interaction between the transcription factors RT human polyamine modulated factor (PMF-1) and NF-E2-related factor 2 (Nrf-2) RT in the transcriptional regulation of the spermidine/spermine N1- RT acetyltransferase (SSAT) gene."; RL Biochem. J. 355:45-49(2001). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KEAP1, UBIQUITINATION, RP ETGE MOTIF, DOMAIN, AND MUTAGENESIS OF 79-GLU--GLU-82 AND GLU-82. RX PubMed=15601839; DOI=10.1128/mcb.25.1.162-171.2005; RA Furukawa M., Xiong Y.; RT "BTB protein Keap1 targets antioxidant transcription factor Nrf2 for RT ubiquitination by the Cullin 3-Roc1 ligase."; RL Mol. Cell. Biol. 25:162-171(2005). RN [11] RP UBIQUITINATION. RX PubMed=15983046; DOI=10.1074/jbc.m501279200; RA Zhang D.D., Lo S.C., Sun Z., Habib G.M., Lieberman M.W., Hannink M.; RT "Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, RT targets Keap1 for degradation by a proteasome-independent pathway."; RL J. Biol. Chem. 280:30091-30099(2005). RN [12] RP FUNCTION, AND UBIQUITINATION. RX PubMed=19489739; DOI=10.1042/bj20090471; RA Eggler A.L., Small E., Hannink M., Mesecar A.D.; RT "Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) RT activation are dependent on the partial molar volume at position 151 of RT Keap1."; RL Biochem. J. 422:171-180(2009). RN [13] RP INTERACTION WITH PGAM5 AND KEAP1. RX PubMed=18387606; DOI=10.1016/j.yexcr.2008.02.014; RA Lo S.-C., Hannink M.; RT "PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to RT mitochondria."; RL Exp. Cell Res. 314:1789-1803(2008). RN [14] RP INDUCTION. RX PubMed=19424503; DOI=10.1371/journal.pone.0005492; RA Wang X.J., Zhang D.D.; RT "Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational RT level."; RL PLoS ONE 4:E5492-E5492(2009). RN [15] RP FUNCTION. RX PubMed=20452972; DOI=10.1074/jbc.m110.118976; RA Jain A., Lamark T., Sjoettem E., Larsen K.B., Awuh J.A., Oevervatn A., RA McMahon M., Hayes J.D., Johansen T.; RT "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a RT positive feedback loop by inducing antioxidant response element-driven gene RT transcription."; RL J. Biol. Chem. 285:22576-22591(2010). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-215, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [17] RP INTERACTION WITH EEF1D. RX PubMed=21597468; DOI=10.1038/embor.2011.82; RA Kaitsuka T., Tomizawa K., Matsushita M.; RT "Transformation of eEF1Bdelta into heat-shock response transcription factor RT by alternative splicing."; RL EMBO Rep. 12:673-681(2011). RN [18] RP ACETYLATION AT LYS-596 AND LYS-599, DEACETYLATION BY SIRT1, AND SUBCELLULAR RP LOCATION. RX PubMed=21196497; DOI=10.1074/jbc.m110.208173; RA Kawai Y., Garduno L., Theodore M., Yang J., Arinze I.J.; RT "Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor RT erythroid 2-related factor 2) regulates its transcriptional activity and RT nucleocytoplasmic localization."; RL J. Biol. Chem. 286:7629-7640(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-215, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [20] RP INTERACTION WITH HERPES VIRUS 8 PROTEIN LANA1 (MICROBIAL INFECTION), AND RP SUBCELLULAR LOCATION. RX PubMed=25995248; DOI=10.1128/jvi.00895-15; RA Gjyshi O., Roy A., Dutta S., Veettil M.V., Dutta D., Chandran B.; RT "Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus RT Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene RT Repression."; RL J. Virol. 89:7874-7892(2015). RN [21] RP INTERACTION WITH MOTS-C, AND SUBCELLULAR LOCATION. RX PubMed=29983246; DOI=10.1016/j.cmet.2018.06.008; RA Kim K.H., Son J.M., Benayoun B.A., Lee C.; RT "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to RT Regulate Nuclear Gene Expression in Response to Metabolic Stress."; RL Cell Metab. 28:516-524(2018). RN [22] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=29590092; DOI=10.1038/nature25986; RA Mills E.L., Ryan D.G., Prag H.A., Dikovskaya D., Menon D., Zaslona Z., RA Jedrychowski M.P., Costa A.S.H., Higgins M., Hams E., Szpyt J., RA Runtsch M.C., King M.S., McGouran J.F., Fischer R., Kessler B.M., RA McGettrick A.F., Hughes M.M., Carroll R.G., Booty L.M., Knatko E.V., RA Meakin P.J., Ashford M.L.J., Modis L.K., Brunori G., Sevin D.C., RA Fallon P.G., Caldwell S.T., Kunji E.R.S., Chouchani E.T., Frezza C., RA Dinkova-Kostova A.T., Hartley R.C., Murphy M.P., O'Neill L.A.; RT "Itaconate is an anti-inflammatory metabolite that activates Nrf2 via RT alkylation of KEAP1."; RL Nature 556:113-117(2018). RN [23] RP FUNCTION, GLYCATION AT LYS-462; LYS-472; LYS-487; ARG-499; ARG-569 AND RP LYS-574, AND MUTAGENESIS OF LYS-462; LYS-472; LYS-487; ARG-499; ARG-569 AND RP ARG-587. RX PubMed=31398338; DOI=10.1016/j.cell.2019.07.031; RA Sanghvi V.R., Leibold J., Mina M., Mohan P., Berishaj M., Li Z., RA Miele M.M., Lailler N., Zhao C., de Stanchina E., Viale A., Akkari L., RA Lowe S.W., Ciriello G., Hendrickson R.C., Wendel H.G.; RT "The oncogenic action of NRF2 depends on de-glycation by fructosamine-3- RT kinase."; RL Cell 178:807-819(2019). RN [24] RP REVIEW. RX PubMed=28842501; DOI=10.1074/jbc.r117.800169; RA Suzuki T., Yamamoto M.; RT "Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 RT system during cellular stress."; RL J. Biol. Chem. 292:16817-16824(2017). RN [25] RP FUNCTION. RX PubMed=30158636; DOI=10.1038/s41467-018-05861-7; RA Olagnier D., Brandtoft A.M., Gunderstofte C., Villadsen N.L., Krapp C., RA Thielke A.L., Laustsen A., Peri S., Hansen A.L., Bonefeld L., Thyrsted J., RA Bruun V., Iversen M.B., Lin L., Artegoitia V.M., Su C., Yang L., Lin R., RA Balachandran S., Luo Y., Nyegaard M., Marrero B., Goldbach-Mansky R., RA Motwani M., Ryan D.G., Fitzgerald K.A., O'Neill L.A., Hollensen A.K., RA Damgaard C.K., de Paoli F.V., Bertram H.C., Jakobsen M.R., Poulsen T.B., RA Holm C.K.; RT "Nrf2 negatively regulates STING indicating a link between antiviral RT sensing and metabolic reprogramming."; RL Nat. Commun. 9:3506-3506(2018). RN [26] RP FUNCTION, ACTIVITY REGULATION (MICROBIAL INFECTION), AND ACTIVITY RP REGULATION. RX PubMed=33009401; DOI=10.1038/s41467-020-18764-3; RA Olagnier D., Farahani E., Thyrsted J., Blay-Cadanet J., Herengt A., RA Idorn M., Hait A., Hernaez B., Knudsen A., Iversen M.B., Schilling M., RA Joergensen S.E., Thomsen M., Reinert L.S., Lappe M., Hoang H.D., RA Gilchrist V.H., Hansen A.L., Ottosen R., Nielsen C.G., Moeller C., RA van der Horst D., Peri S., Balachandran S., Huang J., Jakobsen M., RA Svenningsen E.B., Poulsen T.B., Bartsch L., Thielke A.L., Luo Y., Alain T., RA Rehwinkel J., Alcami A., Hiscott J., Mogensen T.H., Paludan S.R., RA Holm C.K.; RT "SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral RT and anti-inflammatory activity of 4-octyl-itaconate and dimethyl RT fumarate."; RL Nat. Commun. 11:4938-4938(2020). RN [27] RP ERRATUM OF PUBMED:33009401. RX PubMed=33087717; DOI=10.1038/s41467-020-19363-y; RA Olagnier D., Farahani E., Thyrsted J., Blay-Cadanet J., Herengt A., RA Idorn M., Hait A., Hernaez B., Knudsen A., Iversen M.B., Schilling M., RA Joergensen S.E., Thomsen M., Reinert L.S., Lappe M., Hoang H.D., RA Gilchrist V.H., Hansen A.L., Ottosen R., Nielsen C.G., Moeller C., RA van der Horst D., Peri S., Balachandran S., Huang J., Jakobsen M., RA Svenningsen E.B., Poulsen T.B., Bartsch L., Thielke A.L., Luo Y., Alain T., RA Rehwinkel J., Alcami A., Hiscott J., Mogensen T.H., Paludan S.R., RA Holm C.K.; RT "Author Correction: SARS-CoV2-mediated suppression of NRF2-signaling RT reveals potent antiviral and anti-inflammatory activity of 4-octyl- RT itaconate and dimethyl fumarate."; RL Nat. Commun. 11:5419-5419(2020). RN [28] RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 69-84 IN COMPLEX WITH KEAP1, AND RP MUTAGENESIS OF THR-80. RX PubMed=16888629; DOI=10.1038/sj.emboj.7601243; RA Lo S.-C., Li X., Henzl M.T., Beamer L.J., Hannink M.; RT "Structure of the Keap1:Nrf2 interface provides mechanistic insight into RT Nrf2 signaling."; RL EMBO J. 25:3605-3617(2006). RN [29] RP INVOLVEMENT IN IMDDHH, VARIANTS IMDDHH ARG-31; LYS-79; LYS-80 AND SER-81, RP CHARACTERIZATION OF VARIANT IMDDHH LYS-80, AND FUNCTION. RX PubMed=29018201; DOI=10.1038/s41467-017-00932-7; RA Huppke P., Weissbach S., Church J.A., Schnur R., Krusen M., RA Dreha-Kulaczewski S., Kuehn-Velten W.N., Wolf A., Huppke B., Millan F., RA Begtrup A., Almusafri F., Thiele H., Altmueller J., Nuernberg P., RA Mueller M., Gaertner J.; RT "Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem RT disorder."; RL Nat. Commun. 8:818-818(2017). CC -!- FUNCTION: Transcription factor that plays a key role in the response to CC oxidative stress: binds to antioxidant response (ARE) elements present CC in the promoter region of many cytoprotective genes, such as phase 2 CC detoxifying enzymes, and promotes their expression, thereby CC neutralizing reactive electrophiles (PubMed:11035812, PubMed:19489739, CC PubMed:29018201, PubMed:31398338). In normal conditions, ubiquitinated CC and degraded in the cytoplasm by the BCR(KEAP1) complex CC (PubMed:11035812, PubMed:15601839, PubMed:29018201). In response to CC oxidative stress, electrophile metabolites inhibit activity of the CC BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, CC heterodimerization with one of the small Maf proteins and binding to CC ARE elements of cytoprotective target genes (PubMed:19489739, CC PubMed:29590092). The NFE2L2/NRF2 pathway is also activated in response CC to selective autophagy: autophagy promotes interaction between KEAP1 CC and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, CC leading to NFE2L2/NRF2 nuclear accumulation and expression of CC cytoprotective genes (PubMed:20452972). May also be involved in the CC transcriptional activation of genes of the beta-globin cluster by CC mediating enhancer activity of hypersensitive site 2 of the beta-globin CC locus control region (PubMed:7937919). Also plays an important role in CC the regulation of the innate immune response and antiviral cytosolic CC DNA sensing. It is a critical regulator of the innate immune response CC and survival during sepsis by maintaining redox homeostasis and CC restraint of the dysregulation of pro-inflammatory signaling pathways CC like MyD88-dependent and -independent and TNF-alpha signaling (By CC similarity). Suppresses macrophage inflammatory response by blocking CC pro-inflammatory cytokine transcription and the induction of IL6 (By CC similarity). Binds to the proximity of pro-inflammatory genes in CC macrophages and inhibits RNA Pol II recruitment. The inhibition is CC independent of the NRF2-binding motif and reactive oxygen species level CC (By similarity). Represses antiviral cytosolic DNA sensing by CC suppressing the expression of the adapter protein STING1 and decreasing CC responsiveness to STING1 agonists while increasing susceptibility to CC infection with DNA viruses (PubMed:30158636). Once activated, limits CC the release of pro-inflammatory cytokines in response to human CC coronavirus SARS-CoV-2 infection and to virus-derived ligands through a CC mechanism that involves inhibition of IRF3 dimerization. Also inhibits CC both SARS-CoV-2 replication, as well as the replication of several CC other pathogenic viruses including Herpes Simplex Virus-1 and-2, CC Vaccinia virus, and Zika virus through a type I interferon (IFN)- CC independent mechanism (PubMed:33009401). {ECO:0000250|UniProtKB:Q60795, CC ECO:0000269|PubMed:11035812, ECO:0000269|PubMed:15601839, CC ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:20452972, CC ECO:0000269|PubMed:29018201, ECO:0000269|PubMed:29590092, CC ECO:0000269|PubMed:30158636, ECO:0000269|PubMed:31398338, CC ECO:0000269|PubMed:33009401, ECO:0000269|PubMed:7937919}. CC -!- ACTIVITY REGULATION: Activated by cell derived metabolites including CC itaconate and fumarate. {ECO:0000269|PubMed:29590092, CC ECO:0000269|PubMed:33009401}. CC -!- ACTIVITY REGULATION: (Microbial infection) Transcription factor CC activity on antioxidant target genes is significantly inhibited by SARS CC coronavirus-2/SARS-COV-2. {ECO:0000269|PubMed:29018201}. CC -!- SUBUNIT: Heterodimer; heterodimerizes with small Maf proteins (By CC similarity). Interacts (via the bZIP domain) with MAFG and MAFK; CC required for binding to antioxidant response elements (AREs) on DNA (By CC similarity). Interacts with KEAP1; the interaction is direct and CC promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex CC (PubMed:15601839, PubMed:16888629). Forms a ternary complex with PGAM5 CC and KEAP1 (PubMed:18387606). Interacts with EEF1D at heat shock CC promoter elements (HSE) (PubMed:21597468). Interacts via its leucine- CC zipper domain with the coiled-coil domain of PMF1 (PubMed:11256947). CC Interacts with CHD6; involved in activation of the transcription (By CC similarity). Interacts with ESRRB; represses NFE2L2 transcriptional CC activity (By similarity). Interacts with MOTS-c, a peptide produced by CC the mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in CC the nucleus following metabolic stress (PubMed:29983246). CC {ECO:0000250|UniProtKB:O54968, ECO:0000250|UniProtKB:Q60795, CC ECO:0000269|PubMed:11256947, ECO:0000269|PubMed:15601839, CC ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:18387606, CC ECO:0000269|PubMed:21597468, ECO:0000269|PubMed:29983246}. CC -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8 protein CC LANA1. {ECO:0000269|PubMed:25995248}. CC -!- INTERACTION: CC Q16236; P27695: APEX1; NbExp=3; IntAct=EBI-2007911, EBI-1048805; CC Q16236; P53365: ARFIP2; NbExp=2; IntAct=EBI-2007911, EBI-638194; CC Q16236; O15144: ARPC2; NbExp=5; IntAct=EBI-2007911, EBI-352356; CC Q16236; P18847: ATF3; NbExp=5; IntAct=EBI-2007911, EBI-712767; CC Q16236; P18848: ATF4; NbExp=8; IntAct=EBI-2007911, EBI-492498; CC Q16236; Q9ULD4: BRPF3; NbExp=3; IntAct=EBI-2007911, EBI-1753470; CC Q16236; Q9Y297: BTRC; NbExp=2; IntAct=EBI-2007911, EBI-307461; CC Q16236; P55210: CASP7; NbExp=2; IntAct=EBI-2007911, EBI-523958; CC Q16236; P53567: CEBPG; NbExp=5; IntAct=EBI-2007911, EBI-740209; CC Q16236; Q96G23: CERS2; NbExp=2; IntAct=EBI-2007911, EBI-1057080; CC Q16236; Q6V702: CFAP299; NbExp=3; IntAct=EBI-2007911, EBI-25429087; CC Q16236; Q9UBW8: COPS7A; NbExp=2; IntAct=EBI-2007911, EBI-712982; CC Q16236; O60519: CREBL2; NbExp=5; IntAct=EBI-2007911, EBI-2872455; CC Q16236; Q9NS37: CREBZF; NbExp=5; IntAct=EBI-2007911, EBI-632965; CC Q16236; P35638: DDIT3; NbExp=5; IntAct=EBI-2007911, EBI-742651; CC Q16236; O75822: EIF3J; NbExp=5; IntAct=EBI-2007911, EBI-366647; CC Q16236; P78545: ELF3; NbExp=5; IntAct=EBI-2007911, EBI-1057285; CC Q16236; P19419: ELK1; NbExp=5; IntAct=EBI-2007911, EBI-726632; CC Q16236; P15036: ETS2; NbExp=2; IntAct=EBI-2007911, EBI-1646991; CC Q16236; P50549: ETV1; NbExp=4; IntAct=EBI-2007911, EBI-3905068; CC Q16236; P43268: ETV4; NbExp=6; IntAct=EBI-2007911, EBI-6447147; CC Q16236; P41212: ETV6; NbExp=5; IntAct=EBI-2007911, EBI-1372759; CC Q16236; Q9UKB1: FBXW11; NbExp=2; IntAct=EBI-2007911, EBI-355189; CC Q16236; P53539: FOSB; NbExp=6; IntAct=EBI-2007911, EBI-2806743; CC Q16236; P15408: FOSL2; NbExp=6; IntAct=EBI-2007911, EBI-3893419; CC Q16236; P15976: GATA1; NbExp=2; IntAct=EBI-2007911, EBI-3909284; CC Q16236; P62993: GRB2; NbExp=2; IntAct=EBI-2007911, EBI-401755; CC Q16236; P10914: IRF1; NbExp=3; IntAct=EBI-2007911, EBI-1055781; CC Q16236; P05412: JUN; NbExp=2; IntAct=EBI-2007911, EBI-852823; CC Q16236; O60341: KDM1A; NbExp=5; IntAct=EBI-2007911, EBI-710124; CC Q16236; Q14145: KEAP1; NbExp=38; IntAct=EBI-2007911, EBI-751001; CC Q16236; P52292: KPNA2; NbExp=4; IntAct=EBI-2007911, EBI-349938; CC Q16236; O00629: KPNA4; NbExp=4; IntAct=EBI-2007911, EBI-396343; CC Q16236; Q9UJU2: LEF1; NbExp=3; IntAct=EBI-2007911, EBI-926131; CC Q16236; Q9ULX9: MAFF; NbExp=6; IntAct=EBI-2007911, EBI-721128; CC Q16236; O15525: MAFG; NbExp=16; IntAct=EBI-2007911, EBI-713514; CC Q16236; O60675: MAFK; NbExp=7; IntAct=EBI-2007911, EBI-2559512; CC Q16236; P52564: MAP2K6; NbExp=5; IntAct=EBI-2007911, EBI-448135; CC Q16236; P41227: NAA10; NbExp=4; IntAct=EBI-2007911, EBI-747693; CC Q16236; O94916: NFAT5; NbExp=4; IntAct=EBI-2007911, EBI-308320; CC Q16236; Q6P1K2: PMF1; NbExp=2; IntAct=EBI-2007911, EBI-713832; CC Q16236; P10276: RARA; NbExp=2; IntAct=EBI-2007911, EBI-413374; CC Q16236; Q04864: REL; NbExp=5; IntAct=EBI-2007911, EBI-307352; CC Q16236; Q04206: RELA; NbExp=5; IntAct=EBI-2007911, EBI-73886; CC Q16236; Q13342: SP140; NbExp=4; IntAct=EBI-2007911, EBI-2865100; CC Q16236; P40763: STAT3; NbExp=5; IntAct=EBI-2007911, EBI-518675; CC Q16236; O75478: TADA2A; NbExp=2; IntAct=EBI-2007911, EBI-742268; CC Q16236; P20226: TBP; NbExp=5; IntAct=EBI-2007911, EBI-355371; CC Q16236; Q10587: TEF; NbExp=5; IntAct=EBI-2007911, EBI-2796967; CC Q16236; P13805: TNNT1; NbExp=4; IntAct=EBI-2007911, EBI-726527; CC Q16236; P13805-3: TNNT1; NbExp=3; IntAct=EBI-2007911, EBI-12151635; CC Q16236; Q9BTA9: WAC; NbExp=3; IntAct=EBI-2007911, EBI-749118; CC Q16236; Q60953: Pml; Xeno; NbExp=2; IntAct=EBI-2007911, EBI-3895605; CC Q16236; P11416: Rara; Xeno; NbExp=2; IntAct=EBI-2007911, EBI-346736; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:11035812, CC ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:21196497}. Nucleus CC {ECO:0000255|PROSITE-ProRule:PRU00978, ECO:0000269|PubMed:11035812, CC ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:21196497, CC ECO:0000269|PubMed:29983246}. Note=Cytosolic under unstressed CC conditions: ubiquitinated and degraded by the BCR(KEAP1) E3 ubiquitin CC ligase complex (PubMed:15601839, PubMed:21196497). Translocates into CC the nucleus upon induction by electrophilic agents that inactivate the CC BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:21196497). CC {ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:21196497}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q16236-1; Sequence=Displayed; CC Name=2; CC IsoId=Q16236-2; Sequence=VSP_025045; CC Name=3; CC IsoId=Q16236-3; Sequence=VSP_025045, VSP_046168; CC -!- TISSUE SPECIFICITY: Widely expressed. Highest expression in adult CC muscle, kidney, lung, liver and in fetal muscle. CC {ECO:0000269|PubMed:7937919}. CC -!- INDUCTION: Down-regulated by ENC1 via a proteasomal ubiquitin- CC independent protein catabolic process. {ECO:0000269|PubMed:19424503}. CC -!- DOMAIN: The ETGE motif, and to a lower extent the DLG motif, mediate CC interaction with KEAP1. {ECO:0000269|PubMed:15601839}. CC -!- PTM: Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin CC ligase complex leading to its degradation (PubMed:15601839, CC PubMed:15983046, PubMed:19489739). In response to oxidative stress, CC electrophile metabolites, such as sulforaphane, modify KEAP1, leading CC to inhibit activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 CC nuclear accumulation and activity (PubMed:19489739, PubMed:29590092). CC In response to autophagy, the BCR(KEAP1) complex is inactivated (By CC similarity). {ECO:0000250|UniProtKB:Q60795, CC ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15983046, CC ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:29590092}. CC -!- PTM: Phosphorylation of Ser-40 by PKC in response to oxidative stress CC dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its CC translocation into the nucleus. {ECO:0000250|UniProtKB:O54968}. CC -!- PTM: Acetylation at Lys-596 and Lys-599 increases nuclear localization CC whereas deacetylation by SIRT1 enhances cytoplasmic presence. CC {ECO:0000269|PubMed:21196497}. CC -!- PTM: Glycation impairs transcription factor activity by preventing CC heterodimerization with small Maf proteins (PubMed:31398338). CC Deglycation by FN3K restores activity (PubMed:31398338). CC {ECO:0000269|PubMed:31398338}. CC -!- DISEASE: Immunodeficiency, developmental delay, and hypohomocysteinemia CC (IMDDHH) [MIM:617744]: An early onset multisystem disorder CC characterized by immunodeficiency, recurrent infections, developmental CC delay, poor growth, intellectual disability, and hypohomocysteinemia. CC Some patients manifest congenital cardiac defects. IMDDHH inheritance CC pattern is autosomal dominant. {ECO:0000269|PubMed:29018201}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB32188.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAD92023.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; 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; AK304555; BAG65350.1; -; mRNA. DR EMBL; AK314816; BAG37339.1; -; mRNA. DR EMBL; AB208786; BAD92023.1; ALT_INIT; mRNA. DR EMBL; AC019080; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC079305; AAY14710.1; -; Genomic_DNA. DR EMBL; CH471058; EAX11062.1; -; Genomic_DNA. DR EMBL; BC011558; AAH11558.1; -; mRNA. DR EMBL; AL135266; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; S74017; AAB32188.1; ALT_INIT; mRNA. DR CCDS; CCDS42782.1; -. [Q16236-1] DR CCDS; CCDS46457.1; -. [Q16236-2] DR CCDS; CCDS46458.1; -. [Q16236-3] DR RefSeq; NP_001138884.1; NM_001145412.3. [Q16236-2] DR RefSeq; NP_001138885.1; NM_001145413.3. [Q16236-3] DR RefSeq; NP_001300829.1; NM_001313900.1. [Q16236-2] DR RefSeq; NP_001300830.1; NM_001313901.1. [Q16236-2] DR RefSeq; NP_006155.2; NM_006164.4. [Q16236-1] DR PDB; 2FLU; X-ray; 1.50 A; P=69-84. DR PDB; 2LZ1; NMR; -; A=445-523. DR PDB; 3ZGC; X-ray; 2.20 A; C=76-82. DR PDB; 4IFL; X-ray; 1.80 A; P=69-84. DR PDB; 5WFV; X-ray; 1.91 A; P=76-84. DR PDB; 6T7V; X-ray; 2.60 A; I=76-84. DR PDB; 7K28; X-ray; 2.15 A; P=77-84. DR PDB; 7K29; X-ray; 2.20 A; P=76-84. DR PDB; 7K2A; X-ray; 1.90 A; P=76-83. DR PDB; 7K2B; X-ray; 2.31 A; P=77-83. DR PDB; 7K2C; X-ray; 2.11 A; P=77-82. DR PDB; 7K2D; X-ray; 2.21 A; P=77-82. DR PDB; 7K2E; X-ray; 2.03 A; P=77-82. DR PDB; 7K2K; X-ray; 1.98 A; P=77-82. DR PDB; 7O7B; NMR; -; A=445-523. DR PDB; 7X5E; X-ray; 2.30 A; B/F=452-560. DR PDB; 7X5F; X-ray; 2.60 A; B/F=452-560. DR PDB; 7X5G; X-ray; 2.30 A; B/F=452-560. DR PDB; 8EJR; X-ray; 2.08 A; C=76-82. DR PDB; 8EJS; X-ray; 2.82 A; C=76-82. DR PDBsum; 2FLU; -. DR PDBsum; 2LZ1; -. DR PDBsum; 3ZGC; -. DR PDBsum; 4IFL; -. DR PDBsum; 5WFV; -. DR PDBsum; 6T7V; -. DR PDBsum; 7K28; -. DR PDBsum; 7K29; -. DR PDBsum; 7K2A; -. DR PDBsum; 7K2B; -. DR PDBsum; 7K2C; -. DR PDBsum; 7K2D; -. DR PDBsum; 7K2E; -. DR PDBsum; 7K2K; -. DR PDBsum; 7O7B; -. DR PDBsum; 7X5E; -. DR PDBsum; 7X5F; -. DR PDBsum; 7X5G; -. DR PDBsum; 8EJR; -. DR PDBsum; 8EJS; -. DR AlphaFoldDB; Q16236; -. DR SMR; Q16236; -. DR BioGRID; 110852; 157. DR ComplexPortal; CPX-6570; bZIP transcription factor complex, ATF4-NFE2L2. DR CORUM; Q16236; -. DR DIP; DIP-29971N; -. DR ELM; Q16236; -. DR IntAct; Q16236; 130. DR MINT; Q16236; -. DR STRING; 9606.ENSP00000380252; -. DR BindingDB; Q16236; -. DR ChEMBL; CHEMBL1075094; -. DR DrugCentral; Q16236; -. DR GlyCosmos; Q16236; 6 sites, No reported glycans. DR GlyGen; Q16236; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q16236; -. DR PhosphoSitePlus; Q16236; -. DR BioMuta; NFE2L2; -. DR DMDM; 25453452; -. DR jPOST; Q16236; -. DR MassIVE; Q16236; -. DR PaxDb; 9606-ENSP00000380252; -. DR PeptideAtlas; Q16236; -. DR ProteomicsDB; 20333; -. DR ProteomicsDB; 60843; -. [Q16236-1] DR ProteomicsDB; 60844; -. [Q16236-2] DR Antibodypedia; 903; 1013 antibodies from 46 providers. DR DNASU; 4780; -. DR Ensembl; ENST00000397062.8; ENSP00000380252.3; ENSG00000116044.17. [Q16236-1] DR Ensembl; ENST00000397063.9; ENSP00000380253.4; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000421929.6; ENSP00000412191.2; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000446151.6; ENSP00000411575.2; ENSG00000116044.17. [Q16236-3] DR Ensembl; ENST00000448782.6; ENSP00000400073.2; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000464747.5; ENSP00000467401.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699328.1; ENSP00000514303.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699330.1; ENSP00000514304.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699343.1; ENSP00000514318.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699351.1; ENSP00000514325.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699408.1; ENSP00000514369.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699409.1; ENSP00000514370.1; ENSG00000116044.17. [Q16236-2] DR Ensembl; ENST00000699434.1; ENSP00000514386.1; ENSG00000116044.17. [Q16236-2] DR GeneID; 4780; -. DR KEGG; hsa:4780; -. DR MANE-Select; ENST00000397062.8; ENSP00000380252.3; NM_006164.5; NP_006155.2. DR UCSC; uc002ulg.6; human. [Q16236-1] DR AGR; HGNC:7782; -. DR CTD; 4780; -. DR DisGeNET; 4780; -. DR GeneCards; NFE2L2; -. DR HGNC; HGNC:7782; NFE2L2. DR HPA; ENSG00000116044; Low tissue specificity. DR MalaCards; NFE2L2; -. DR MIM; 600492; gene. DR MIM; 617744; phenotype. DR neXtProt; NX_Q16236; -. DR OpenTargets; ENSG00000116044; -. DR Orphanet; 619979; Developmental delay-immunodeficiency-leukoencephalopathy-hypohomocysteinemia syndrome. DR PharmGKB; PA31588; -. DR VEuPathDB; HostDB:ENSG00000116044; -. DR eggNOG; KOG3863; Eukaryota. DR GeneTree; ENSGT00950000182892; -. DR HOGENOM; CLU_498373_0_0_1; -. DR InParanoid; Q16236; -. DR OMA; DMEEMDQ; -. DR OrthoDB; 382726at2759; -. DR PhylomeDB; Q16236; -. DR TreeFam; TF326681; -. DR PathwayCommons; Q16236; -. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9707587; Regulation of HMOX1 expression and activity. DR Reactome; R-HSA-9707616; Heme signaling. DR Reactome; R-HSA-9755511; KEAP1-NFE2L2 pathway. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR Reactome; R-HSA-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2. DR Reactome; R-HSA-9818025; NFE2L2 regulating TCA cycle genes. DR Reactome; R-HSA-9818026; NFE2L2 regulating inflammation associated genes. DR Reactome; R-HSA-9818027; NFE2L2 regulating anti-oxidant/detoxification enzymes. DR Reactome; R-HSA-9818028; NFE2L2 regulates pentose phosphate pathway genes. DR Reactome; R-HSA-9818030; NFE2L2 regulating tumorigenic genes. DR Reactome; R-HSA-9818032; NFE2L2 regulating MDR associated enzymes. DR Reactome; R-HSA-9818035; NFE2L2 regulating ER-stress associated genes. DR Reactome; R-HSA-9818749; Regulation of NFE2L2 gene expression. DR SignaLink; Q16236; -. DR SIGNOR; Q16236; -. DR BioGRID-ORCS; 4780; 95 hits in 1196 CRISPR screens. DR ChiTaRS; NFE2L2; human. DR EvolutionaryTrace; Q16236; -. DR GeneWiki; NFE2L2; -. DR GenomeRNAi; 4780; -. DR Pharos; Q16236; Tchem. DR PRO; PR:Q16236; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q16236; protein. DR Bgee; ENSG00000116044; Expressed in epithelium of nasopharynx and 214 other cell types or tissues. DR ExpressionAtlas; Q16236; baseline and differential. DR GO; GO:0005813; C:centrosome; IDA:HPA. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0016592; C:mediator complex; EXP:DisProt. DR GO; GO:0043228; C:non-membrane-bounded organelle; IDA:DisProt. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0032993; C:protein-DNA complex; ISS:ParkinsonsUK-UCL. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IPI:ComplexPortal. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IMP:ParkinsonsUK-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:DisProt. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL. DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB. DR GO; GO:0001221; F:transcription coregulator binding; IEA:Ensembl. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:DisProt. DR GO; GO:0046223; P:aflatoxin catabolic process; IEA:Ensembl. DR GO; GO:0045454; P:cell redox homeostasis; IMP:UniProtKB. DR GO; GO:1904385; P:cellular response to angiotensin; IEA:Ensembl. DR GO; GO:0071280; P:cellular response to copper ion; IEA:Ensembl. DR GO; GO:0071498; P:cellular response to fluid shear stress; IDA:UniProtKB. DR GO; GO:0042149; P:cellular response to glucose starvation; IEA:Ensembl. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IMP:BHF-UCL. DR GO; GO:0071456; P:cellular response to hypoxia; IMP:BHF-UCL. DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; IMP:BHF-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IMP:BHF-UCL. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISS:ParkinsonsUK-UCL. DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl. DR GO; GO:0140467; P:integrated stress response signaling; NAS:ComplexPortal. DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl. DR GO; GO:1900038; P:negative regulation of cellular response to hypoxia; IEA:Ensembl. DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IMP:BHF-UCL. DR GO; GO:0110076; P:negative regulation of ferroptosis; IMP:UniProtKB. DR GO; GO:1902037; P:negative regulation of hematopoietic stem cell differentiation; IEA:Ensembl. DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; IMP:BHF-UCL. DR GO; GO:1904753; P:negative regulation of vascular associated smooth muscle cell migration; IEA:Ensembl. DR GO; GO:0036499; P:PERK-mediated unfolded protein response; ISS:ParkinsonsUK-UCL. DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl. DR GO; GO:0030194; P:positive regulation of blood coagulation; IEA:Ensembl. DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IEA:Ensembl. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:DisProt. DR GO; GO:1904294; P:positive regulation of ERAD pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:CACAO. DR GO; GO:0046326; P:positive regulation of glucose import; IEA:Ensembl. DR GO; GO:1903788; P:positive regulation of glutathione biosynthetic process; IEA:Ensembl. DR GO; GO:0010976; P:positive regulation of neuron projection development; IEA:Ensembl. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL. DR GO; GO:2000060; P:positive regulation of ubiquitin-dependent protein catabolic process; TAS:ParkinsonsUK-UCL. DR GO; GO:0010499; P:proteasomal ubiquitin-independent protein catabolic process; IDA:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:1900407; P:regulation of cellular response to oxidative stress; EXP:DisProt. DR GO; GO:0045995; P:regulation of embryonic development; IEA:Ensembl. DR GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB. DR GO; GO:2000121; P:regulation of removal of superoxide radicals; IEA:Ensembl. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IDA:UniProt. DR CDD; cd14720; bZIP_NFE2-like; 1. DR CDD; cd22249; UDM1_RNF168_RNF169-like; 1. DR DisProt; DP01115; -. DR Gene3D; 1.10.880.10; Transcription factor, Skn-1-like, DNA-binding domain; 1. DR IDEAL; IID00213; -. DR InterPro; IPR004827; bZIP. DR InterPro; IPR004826; bZIP_Maf. DR InterPro; IPR046347; bZIP_sf. DR InterPro; IPR047167; NFE2-like. DR InterPro; IPR008917; TF_DNA-bd_sf. DR PANTHER; PTHR24411; NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR; 1. DR PANTHER; PTHR24411:SF3; NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2; 1. DR Pfam; PF03131; bZIP_Maf; 1. DR SMART; SM00338; BRLZ; 1. DR SUPFAM; SSF47454; A DNA-binding domain in eukaryotic transcription factors; 1. DR SUPFAM; SSF57959; Leucine zipper domain; 1. DR PROSITE; PS50217; BZIP; 1. DR PROSITE; PS00036; BZIP_BASIC; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activator; Alternative splicing; Cytoplasm; KW Disease variant; DNA-binding; Glycation; Glycoprotein; KW Host-virus interaction; Nucleus; Phosphoprotein; Proteomics identification; KW Reference proteome; Transcription; Transcription regulation; KW Ubl conjugation. FT CHAIN 1..605 FT /note="Nuclear factor erythroid 2-related factor 2" FT /id="PRO_0000076449" FT DOMAIN 497..560 FT /note="bZIP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" FT REGION 334..449 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 499..518 FT /note="Basic motif" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" FT REGION 522..529 FT /note="Leucine-zipper" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" FT REGION 571..605 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 591..596 FT /note="Mediates interaction with CHD6 and is necessary to FT activate transcription" FT /evidence="ECO:0000250|UniProtKB:O54968" FT MOTIF 29..31 FT /note="DLG motif" FT /evidence="ECO:0000250|UniProtKB:Q60795" FT MOTIF 79..82 FT /note="ETGE motif" FT /evidence="ECO:0000250|UniProtKB:Q60795" FT COMPBIAS 334..371 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 388..420 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 421..449 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 40 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000250|UniProtKB:O54968" FT MOD_RES 215 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 596 FT /note="N6-acetyllysine; by CREBBP" FT /evidence="ECO:0000269|PubMed:21196497" FT MOD_RES 599 FT /note="N6-acetyllysine; by CREBBP" FT /evidence="ECO:0000269|PubMed:21196497" FT CARBOHYD 462 FT /note="N-linked (Glc) (glycation) lysine" FT /evidence="ECO:0000269|PubMed:31398338" FT CARBOHYD 472 FT /note="N-linked (Glc) (glycation) lysine" FT /evidence="ECO:0000269|PubMed:31398338" FT CARBOHYD 487 FT /note="N-linked (Glc) (glycation) lysine" FT /evidence="ECO:0000269|PubMed:31398338" FT CARBOHYD 499 FT /note="N-linked (Glc) (glycation) arginine" FT /evidence="ECO:0000305|PubMed:31398338" FT CARBOHYD 569 FT /note="N-linked (Glc) (glycation) arginine" FT /evidence="ECO:0000305|PubMed:31398338" FT CARBOHYD 574 FT /note="N-linked (Glc) (glycation) lysine" FT /evidence="ECO:0000269|PubMed:31398338" FT VAR_SEQ 1..16 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.2" FT /id="VSP_025045" FT VAR_SEQ 135..141 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_046168" FT VARIANT 31 FT /note="G -> R (in IMDDHH; dbSNP:rs1553488015)" FT /evidence="ECO:0000269|PubMed:29018201" FT /id="VAR_080492" FT VARIANT 43 FT /note="R -> Q (in dbSNP:rs35248500)" FT /id="VAR_032110" FT VARIANT 79 FT /note="E -> K (in IMDDHH; dbSNP:rs1057519922)" FT /evidence="ECO:0000269|PubMed:29018201" FT /id="VAR_080493" FT VARIANT 80 FT /note="T -> K (in IMDDHH; increased protein abundance; FT increased positive regulation of transcription of target FT genes; changed cell redox homeostasis; dbSNP:rs1553487947)" FT /evidence="ECO:0000269|PubMed:29018201" FT /id="VAR_080494" FT VARIANT 81 FT /note="G -> S (in IMDDHH; dbSNP:rs1553487942)" FT /evidence="ECO:0000269|PubMed:29018201" FT /id="VAR_080495" FT VARIANT 99 FT /note="S -> P (in dbSNP:rs5031039)" FT /id="VAR_020322" FT VARIANT 268 FT /note="V -> M (in dbSNP:rs34154613)" FT /id="VAR_032111" FT MUTAGEN 79..82 FT /note="Missing: Abolished interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:15601839" FT MUTAGEN 80 FT /note="T->A: Loss of interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:16888629" FT MUTAGEN 82 FT /note="E->G: Abolished interaction with KEAP1." FT /evidence="ECO:0000269|PubMed:15601839" FT MUTAGEN 462 FT /note="K->A: Loss of function; when associated with A-472; FT A-487; A-499; A-569 and A-587." FT /evidence="ECO:0000269|PubMed:31398338" FT MUTAGEN 472 FT /note="K->A: Loss of function; when associated with A-462; FT A-487; A-499; A-569 and A-587." FT /evidence="ECO:0000269|PubMed:31398338" FT MUTAGEN 487 FT /note="K->A: Loss of function; when associated with A-462; FT A-472; A-499; A-569 and A-587." FT /evidence="ECO:0000269|PubMed:31398338" FT MUTAGEN 499 FT /note="R->A: Loss of function; when associated with A-462; FT A-472; A-487; A-569 and A-587." FT /evidence="ECO:0000269|PubMed:31398338" FT MUTAGEN 569 FT /note="R->A: Loss of function; when associated with A-462; FT A-472; A-487; A-499 and A-587." FT /evidence="ECO:0000269|PubMed:31398338" FT MUTAGEN 587 FT /note="R->A: Loss of function; when associated with A-462; FT A-472; A-487; A-499 and A-569." FT /evidence="ECO:0000269|PubMed:31398338" FT CONFLICT 72 FT /note="A -> T (in Ref. 7; AAB32188)" FT /evidence="ECO:0000305" FT CONFLICT 92 FT /note="I -> T (in Ref. 7; AAB32188)" FT /evidence="ECO:0000305" FT CONFLICT 178 FT /note="D -> Y (in Ref. 3; AL135266)" FT /evidence="ECO:0000305" FT CONFLICT 521 FT /note="N -> D (in Ref. 1; BAG65350)" FT /evidence="ECO:0000305" FT TURN 78..80 FT /evidence="ECO:0007829|PDB:2FLU" FT STRAND 449..455 FT /evidence="ECO:0007829|PDB:7O7B" FT HELIX 456..463 FT /evidence="ECO:0007829|PDB:7X5E" FT HELIX 470..475 FT /evidence="ECO:0007829|PDB:7X5E" FT HELIX 478..485 FT /evidence="ECO:0007829|PDB:7X5E" FT HELIX 492..556 FT /evidence="ECO:0007829|PDB:7X5E" SQ SEQUENCE 605 AA; 67827 MW; 99FAFD811B6C1416 CRC64; MMDLELPPPG LPSQQDMDLI DILWRQDIDL GVSREVFDFS QRRKEYELEK QKKLEKERQE QLQKEQEKAF FAQLQLDEET GEFLPIQPAQ HIQSETSGSA NYSQVAHIPK SDALYFDDCM QLLAQTFPFV DDNEVSSATF QSLVPDIPGH IESPVFIATN QAQSPETSVA QVAPVDLDGM QQDIEQVWEE LLSIPELQCL NIENDKLVET TMVPSPEAKL TEVDNYHFYS SIPSMEKEVG NCSPHFLNAF EDSFSSILST EDPNQLTVNS LNSDATVNTD FGDEFYSAFI AEPSISNSMP SPATLSHSLS ELLNGPIDVS DLSLCKAFNQ NHPESTAEFN DSDSGISLNT SPSVASPEHS VESSSYGDTL LGLSDSEVEE LDSAPGSVKQ NGPKTPVHSS GDMVQPLSPS QGQSTHVHDA QCENTPEKEL PVSPGHRKTP FTKDKHSSRL EAHLTRDELR AKALHIPFPV EKIINLPVVD FNEMMSKEQF NEAQLALIRD IRRRGKNKVA AQNCRKRKLE NIVELEQDLD HLKDEKEKLL KEKGENDKSL HLLKKQLSTL YLEVFSMLRD EDGKPYSPSE YSLQQTRDGN VFLVPKSKKP DVKKN //