NF2L2_HUMAN
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 03-AUG-2022, entry version 210.
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=HEBP1;
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:16888629, PubMed:15601839). 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=34; 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=3; IntAct=EBI-2007911, EBI-721128;
CC Q16236; O15525: MAFG; NbExp=12; IntAct=EBI-2007911, EBI-713514;
CC Q16236; O60675: MAFK; NbExp=6; IntAct=EBI-2007911, EBI-2559512;
CC Q16236; P52564: MAP2K6; NbExp=5; IntAct=EBI-2007911, EBI-448135;
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};
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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 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 AlphaFoldDB; Q16236; -.
DR SMR; Q16236; -.
DR BioGRID; 110852; 139.
DR ComplexPortal; CPX-6570; bZIP transcription factor complex, ATF4-NFE2L2.
DR CORUM; Q16236; -.
DR DIP; DIP-29971N; -.
DR ELM; Q16236; -.
DR IntAct; Q16236; 93.
DR MINT; Q16236; -.
DR STRING; 9606.ENSP00000380252; -.
DR BindingDB; Q16236; -.
DR ChEMBL; CHEMBL1075094; -.
DR GlyGen; Q16236; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q16236; -.
DR PhosphoSitePlus; Q16236; -.
DR BioMuta; NFE2L2; -.
DR DMDM; 25453452; -.
DR EPD; Q16236; -.
DR jPOST; Q16236; -.
DR MassIVE; Q16236; -.
DR MaxQB; Q16236; -.
DR PaxDb; Q16236; -.
DR PeptideAtlas; Q16236; -.
DR PRIDE; Q16236; -.
DR ProteomicsDB; 20333; -.
DR ProteomicsDB; 60843; -. [Q16236-1]
DR ProteomicsDB; 60844; -. [Q16236-2]
DR Antibodypedia; 903; 895 antibodies from 46 providers.
DR DNASU; 4780; -.
DR Ensembl; ENST00000397062.8; ENSP00000380252.3; ENSG00000116044.16. [Q16236-1]
DR Ensembl; ENST00000397063.8; ENSP00000380253.4; ENSG00000116044.16. [Q16236-2]
DR Ensembl; ENST00000446151.6; ENSP00000411575.2; ENSG00000116044.16. [Q16236-3]
DR Ensembl; ENST00000464747.5; ENSP00000467401.1; ENSG00000116044.16. [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 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 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; PMDLYSL; -.
DR OrthoDB; 1095280at2759; -.
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 SignaLink; Q16236; -.
DR SIGNOR; Q16236; -.
DR BioGRID-ORCS; 4780; 92 hits in 1112 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 212 other tissues.
DR ExpressionAtlas; Q16236; baseline and differential.
DR Genevisible; Q16236; HS.
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: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; IEA:Ensembl.
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: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:0046223; P:aflatoxin catabolic process; IEA:Ensembl.
DR GO; GO:0007568; P:aging; 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: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; IC:ComplexPortal.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IMP:BHF-UCL.
DR GO; GO:1902037; P:negative regulation of hematopoietic stem cell differentiation; IEA:Ensembl.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; IGI:ParkinsonsUK-UCL.
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:1903071; P:positive regulation of ER-associated ubiquitin-dependent protein catabolic process; 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:0061419; P:positive regulation of transcription from RNA polymerase II promoter in response to hypoxia; IMP:BHF-UCL.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; IEA:Ensembl.
DR GO; GO:0036003; P:positive regulation of transcription from RNA polymerase II promoter in response to stress; IMP:BHF-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: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:0010226; P:response to lithium ion; IEA:Ensembl.
DR DisProt; DP01115; -.
DR IDEAL; IID00213; -.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR004826; bZIP_Maf.
DR InterPro; IPR046347; bZIP_sf.
DR InterPro; IPR029845; Nrf2.
DR InterPro; IPR008917; TF_DNA-bd_sf.
DR PANTHER; PTHR24411:SF3; PTHR24411:SF3; 1.
DR Pfam; PF03131; bZIP_Maf; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR SUPFAM; SSF57959; SSF57959; 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; Reference proteome;
KW Transcription; Transcription regulation; 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..464
FT /evidence="ECO:0007829|PDB:2LZ1"
FT HELIX 470..475
FT /evidence="ECO:0007829|PDB:2LZ1"
FT HELIX 478..487
FT /evidence="ECO:0007829|PDB:2LZ1"
FT HELIX 492..504
FT /evidence="ECO:0007829|PDB:2LZ1"
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
