NF2L2_MOUSE
ID NF2L2_MOUSE Reviewed; 597 AA.
AC Q60795; Q3UQK0;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 2.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|PubMed:9240432};
DE Short=NF-E2-related factor 2 {ECO:0000303|PubMed:9240432};
DE Short=NFE2-related factor 2 {ECO:0000303|PubMed:9240432};
DE AltName: Full=Nuclear factor, erythroid derived 2, like 2;
GN Name=Nfe2l2 {ECO:0000312|MGI:MGI:108420};
GN Synonyms=Nrf2 {ECO:0000303|PubMed:8943040, ECO:0000303|PubMed:9240432};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/SvJ; TISSUE=Lung;
RX PubMed=8943040; DOI=10.1073/pnas.93.24.13943;
RA Chan K., Lu R., Chang J.C., Kan Y.W.;
RT "NRF2, a member of the NFE2 family of transcription factors, is not
RT essential for murine erythropoiesis, growth, and development.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:13943-13948(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryonic lung;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Czech II; TISSUE=Mammary gland;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 17-597.
RC STRAIN=C57BL/6J; TISSUE=Erythroblast;
RX PubMed=7726861; DOI=10.1006/bbrc.1995.1467;
RA Chui D.H.K., Tang W., Orkin S.H.;
RT "cDNA cloning of murine Nrf 2 gene, coding for a p45 NF-E2 related
RT transcription factor.";
RL Biochem. Biophys. Res. Commun. 209:40-46(1995).
RN [6]
RP FUNCTION, INTERACTION WITH MAFK, AND DISRUPTION PHENOTYPE.
RX PubMed=9240432; DOI=10.1006/bbrc.1997.6943;
RA Itoh K., Chiba T., Takahashi S., Ishii T., Igarashi K., Katoh Y., Oyake T.,
RA Hayashi N., Satoh K., Hatayama I., Yamamoto M., Nabeshima Y.;
RT "An Nrf2/small Maf heterodimer mediates the induction of phase II
RT detoxifying enzyme genes through antioxidant response elements.";
RL Biochem. Biophys. Res. Commun. 236:313-322(1997).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH KEAP1.
RX PubMed=9887101; DOI=10.1101/gad.13.17.2328;
RA Itoh K., Wakabayashi N., Katoh Y., Ishii T., Igarashi K., Engel J.D.,
RA Yamamoto M.;
RT "Keap1 represses nuclear activation of antioxidant responsive elements by
RT Nrf2 through binding to the amino-terminal Neh2 domain.";
RL Genes Dev. 13:76-86(1999).
RN [8]
RP INTERACTION WITH PMF1.
RX PubMed=11583586; DOI=10.1042/0264-6021:3590387;
RA Wang Y., Devereux W., Woster P.M., Casero R.A. Jr.;
RT "Cloning and characterization of the mouse polyamine-modulated factor-1
RT (mPMF-1) gene: an alternatively spliced homologue of the human
RT transcription factor.";
RL Biochem. J. 359:387-392(2001).
RN [9]
RP DISRUPTION PHENOTYPE.
RX PubMed=11248092; DOI=10.1073/pnas.051618798;
RA Ramos-Gomez M., Kwak M.K., Dolan P.M., Itoh K., Yamamoto M., Talalay P.,
RA Kensler T.W.;
RT "Sensitivity to carcinogenesis is increased and chemoprotective efficacy of
RT enzyme inducers is lost in nrf2 transcription factor-deficient mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:3410-3415(2001).
RN [10]
RP DISRUPTION PHENOTYPE.
RX PubMed=12032331; DOI=10.1073/pnas.112203099;
RA Fahey J.W., Haristoy X., Dolan P.M., Kensler T.W., Scholtus I.,
RA Stephenson K.K., Talalay P., Lozniewski A.;
RT "Sulforaphane inhibits extracellular, intracellular, and antibiotic-
RT resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-
RT induced stomach tumors.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:7610-7615(2002).
RN [11]
RP DISRUPTION PHENOTYPE.
RX PubMed=12968018; DOI=10.1074/jbc.m308439200;
RA Leung L., Kwong M., Hou S., Lee C., Chan J.Y.;
RT "Deficiency of the Nrf1 and Nrf2 transcription factors results in early
RT embryonic lethality and severe oxidative stress.";
RL J. Biol. Chem. 278:48021-48029(2003).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=14517554; DOI=10.1038/ng1248;
RA Wakabayashi N., Itoh K., Wakabayashi J., Motohashi H., Noda S.,
RA Takahashi S., Imakado S., Kotsuji T., Otsuka F., Roop D.R., Harada T.,
RA Engel J.D., Yamamoto M.;
RT "Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2
RT activation.";
RL Nat. Genet. 35:238-245(2003).
RN [13]
RP FUNCTION, INTERACTION WITH KEAP1, UBIQUITINATION, ETGE MOTIF, DOMAIN, AND
RP MUTAGENESIS OF 79-GLU--GLU-82.
RX PubMed=15282312; DOI=10.1128/mcb.24.16.7130-7139.2004;
RA Kobayashi A., Kang M.I., Okawa H., Ohtsuji M., Zenke Y., Chiba T.,
RA Igarashi K., Yamamoto M.;
RT "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3
RT ligase to regulate proteasomal degradation of Nrf2.";
RL Mol. Cell. Biol. 24:7130-7139(2004).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KEAP1, AND UBIQUITINATION.
RX PubMed=15367669; DOI=10.1128/mcb.24.19.8477-8486.2004;
RA Cullinan S.B., Gordan J.D., Jin J., Harper J.W., Diehl J.A.;
RT "The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3
RT ligase: oxidative stress sensing by a Cul3-Keap1 ligase.";
RL Mol. Cell. Biol. 24:8477-8486(2004).
RN [15]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KEAP1, UBIQUITINATION,
RP DOMAIN, AND ETGE AND DLG MOTIF.
RX PubMed=15581590; DOI=10.1016/j.abb.2004.10.012;
RA Katoh Y., Iida K., Kang M.I., Kobayashi A., Mizukami M., Tong K.I.,
RA McMahon M., Hayes J.D., Itoh K., Yamamoto M.;
RT "Evolutionary conserved N-terminal domain of Nrf2 is essential for the
RT Keap1-mediated degradation of the protein by proteasome.";
RL Arch. Biochem. Biophys. 433:342-350(2005).
RN [16]
RP INTERACTION WITH KEAP1, UBIQUITINATION, DOMAIN, ETGE AND DLG MOTIF, AND
RP MUTAGENESIS OF 18-ASP--LEU-23; 29-ASP--GLY-31 AND 79-GLU--GLU-82.
RX PubMed=16790436; DOI=10.1074/jbc.m601119200;
RA McMahon M., Thomas N., Itoh K., Yamamoto M., Hayes J.D.;
RT "Dimerization of substrate adaptors can facilitate cullin-mediated
RT ubiquitylation of proteins by a 'tethering' mechanism: a two-site
RT interaction model for the Nrf2-Keap1 complex.";
RL J. Biol. Chem. 281:24756-24768(2006).
RN [17]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=16585964; DOI=10.1172/jci25790;
RA Thimmulappa R.K., Lee H., Rangasamy T., Reddy S.P., Yamamoto M.,
RA Kensler T.W., Biswal S.;
RT "Nrf2 is a critical regulator of the innate immune response and survival
RT during experimental sepsis.";
RL J. Clin. Invest. 116:984-995(2006).
RN [18]
RP INTERACTION WITH KEAP1, UBIQUITINATION, DOMAIN, DLG MOTIF, AND MUTAGENESIS
RP OF 79-GLU--GLU-82.
RX PubMed=16581765; DOI=10.1128/mcb.26.8.2887-2900.2006;
RA Tong K.I., Katoh Y., Kusunoki H., Itoh K., Tanaka T., Yamamoto M.;
RT "Keap1 recruits Neh2 through binding to ETGE and DLG motifs:
RT characterization of the two-site molecular recognition model.";
RL Mol. Cell. Biol. 26:2887-2900(2006).
RN [19]
RP INTERACTION WITH ESRRB.
RX PubMed=17920186; DOI=10.1016/j.mce.2007.08.011;
RA Zhou W., Lo S.C., Liu J.H., Hannink M., Lubahn D.B.;
RT "ERRbeta: a potent inhibitor of Nrf2 transcriptional activity.";
RL Mol. Cell. Endocrinol. 278:52-62(2007).
RN [20]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20498371; DOI=10.1074/jbc.m110.145441;
RA Fujii S., Sawa T., Ihara H., Tong K.I., Ida T., Okamoto T., Ahtesham A.K.,
RA Ishima Y., Motohashi H., Yamamoto M., Akaike T.;
RT "The critical role of nitric oxide signaling, via protein S-guanylation and
RT nitrated cyclic GMP, in the antioxidant adaptive response.";
RL J. Biol. Chem. 285:23970-23984(2010).
RN [21]
RP FUNCTION, AND UBIQUITINATION.
RX PubMed=20421418; DOI=10.1128/mcb.00248-10;
RA Lau A., Wang X.J., Zhao F., Villeneuve N.F., Wu T., Jiang T., Sun Z.,
RA White E., Zhang D.D.;
RT "A noncanonical mechanism of Nrf2 activation by autophagy deficiency:
RT direct interaction between Keap1 and p62.";
RL Mol. Cell. Biol. 30:3275-3285(2010).
RN [22]
RP FUNCTION.
RX PubMed=20173742; DOI=10.1038/ncb2021;
RA Komatsu M., Kurokawa H., Waguri S., Taguchi K., Kobayashi A., Ichimura Y.,
RA Sou Y.S., Ueno I., Sakamoto A., Tong K.I., Kim M., Nishito Y., Iemura S.,
RA Natsume T., Ueno T., Kominami E., Motohashi H., Tanaka K., Yamamoto M.;
RT "The selective autophagy substrate p62 activates the stress responsive
RT transcription factor Nrf2 through inactivation of Keap1.";
RL Nat. Cell Biol. 12:213-223(2010).
RN [23]
RP FUNCTION.
RX PubMed=27211851; DOI=10.1038/ncomms11624;
RA Kobayashi E.H., Suzuki T., Funayama R., Nagashima T., Hayashi M.,
RA Sekine H., Tanaka N., Moriguchi T., Motohashi H., Nakayama K., Yamamoto M.;
RT "Nrf2 suppresses macrophage inflammatory response by blocking
RT proinflammatory cytokine transcription.";
RL Nat. Commun. 7:11624-11624(2016).
RN [24]
RP GLYCATION, FUNCTION, AND INTERACTION WITH MAFG.
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 [25]
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 [26]
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 76-84 IN COMPLEX WITH KEAP1.
RX PubMed=16507366; DOI=10.1016/j.molcel.2006.01.013;
RA Padmanabhan B., Tong K.I., Ohta T., Nakamura Y., Scharlock M., Ohtsuji M.,
RA Kang M., Kobayashi A., Yokoyama S., Yamamoto M.;
RT "Structural basis for defects of Keap1 activity provoked by its point
RT mutations in lung cancer.";
RL Mol. Cell 21:689-700(2006).
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:9240432, PubMed:9887101,
CC PubMed:12032331, PubMed:14517554, PubMed:31398338). In normal
CC conditions, ubiquitinated and degraded in the cytoplasm by the
CC BCR(KEAP1) complex (PubMed:15282312, PubMed:15367669, PubMed:15581590).
CC In response to oxidative stress, electrophile metabolites inhibit
CC activity of the BCR(KEAP1) complex, promoting nuclear accumulation of
CC NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and
CC binding to ARE elements of cytoprotective target genes
CC (PubMed:12032331). The NFE2L2/NRF2 pathway is also activated in
CC response to selective autophagy: autophagy promotes interaction between
CC KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1)
CC complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of
CC cytoprotective genes (PubMed:20421418, PubMed:20173742). May also be
CC involved in the transcriptional activation of genes of the beta-globin
CC cluster by mediating enhancer activity of hypersensitive site 2 of the
CC beta-globin locus control region (By similarity). Also plays an
CC important role in the regulation of the innate immune response. It is a
CC critical regulator of the innate immune response and survival during
CC sepsis by maintaining redox homeostasis and restraint of the
CC dysregulation of pro-inflammatory signaling pathways like MyD88-
CC dependent and -independent and TNF-alpha signaling (PubMed:16585964).
CC Suppresses macrophage inflammatory response by blocking pro-
CC inflammatory cytokine transcription and the induction of IL6
CC (PubMed:27211851). 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 (PubMed:27211851). 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 (By similarity).
CC {ECO:0000250|UniProtKB:Q16236, ECO:0000269|PubMed:12032331,
CC ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:15282312,
CC ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590,
CC ECO:0000269|PubMed:16585964, ECO:0000269|PubMed:20173742,
CC ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:27211851,
CC ECO:0000269|PubMed:31398338, ECO:0000269|PubMed:9240432,
CC ECO:0000269|PubMed:9887101}.
CC -!- SUBUNIT: Heterodimer; heterodimerizes with small Maf proteins
CC (PubMed:9240432). Interacts (via the bZIP domain) with MAFG and MAFK;
CC required for binding to antioxidant response elements (AREs) on DNA
CC (PubMed:9240432, PubMed:31398338). Interacts with KEAP1; the
CC interaction is direct and promotes ubiquitination by the BCR(KEAP1) E3
CC ubiquitin ligase complex (PubMed:9887101, PubMed:15282312,
CC PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:16581765,
CC PubMed:16507366). Forms a ternary complex with PGAM5 and KEAP1 (By
CC similarity). Interacts with EEF1D at heat shock promoter elements (HSE)
CC (By similarity). Interacts via its leucine-zipper domain with the
CC coiled-coil domain of PMF1 (PubMed:11583586). Interacts with CHD6;
CC involved in activation of the transcription (By similarity). Interacts
CC with ESRRB; represses NFE2L2 transcriptional activity
CC (PubMed:17920186). Interacts with MOTS-c, a peptide produced by the
CC mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in the
CC nucleus following metabolic stress (By similarity).
CC {ECO:0000250|UniProtKB:O54968, ECO:0000250|UniProtKB:Q16236,
CC ECO:0000269|PubMed:11583586, ECO:0000269|PubMed:15282312,
CC ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590,
CC ECO:0000269|PubMed:16507366, ECO:0000269|PubMed:16581765,
CC ECO:0000269|PubMed:16790436, ECO:0000269|PubMed:17920186,
CC ECO:0000269|PubMed:31398338, ECO:0000269|PubMed:9240432,
CC ECO:0000269|PubMed:9887101}.
CC -!- INTERACTION:
CC Q60795; Q8BWG8: Arrb1; NbExp=4; IntAct=EBI-642563, EBI-641778;
CC Q60795; Q9Z2X8: Keap1; NbExp=23; IntAct=EBI-642563, EBI-647110;
CC Q60795; P97474: Pitx2; NbExp=2; IntAct=EBI-642563, EBI-1175125;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:15367669,
CC ECO:0000269|PubMed:9887101}. Nucleus {ECO:0000255|PROSITE-
CC ProRule:PRU00978, ECO:0000269|PubMed:12032331,
CC ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:9887101}.
CC Note=Cytosolic under unstressed conditions: ubiquitinated and degraded
CC by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:15367669).
CC Translocates into the nucleus upon induction by electrophilic agents
CC that inactivate the BCR(KEAP1) E3 ubiquitin ligase complex
CC (PubMed:14517554). {ECO:0000269|PubMed:14517554,
CC ECO:0000269|PubMed:15367669}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Highest expression in liver,
CC skeletal muscle, luminal cells of the stomach and intestine, lining of
CC the bronchi and alveoli, and in renal tubules; followed by heart,
CC spleen, testis and brain.
CC -!- DOMAIN: The ETGE motif, and to a lower extent the DLG motif, mediate
CC interaction with KEAP1. {ECO:0000269|PubMed:15282312,
CC ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:16581765,
CC ECO:0000269|PubMed:16790436}.
CC -!- PTM: Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin
CC ligase complex leading to its degradation (PubMed:15282312,
CC PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:20421418). In
CC response to oxidative stress, electrophile metabolites, such as
CC sulforaphane, modify KEAP1, leading to inhibit activity of the
CC BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and
CC activity (PubMed:15367669). In response to autophagy, the BCR(KEAP1)
CC complex is inactivated (PubMed:20421418). {ECO:0000269|PubMed:15282312,
CC ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590,
CC ECO:0000269|PubMed:16790436, ECO:0000269|PubMed:20421418}.
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-588 and Lys-591 increases nuclear localization
CC whereas deacetylation by SIRT1 enhances cytoplasmic presence.
CC {ECO:0000250|UniProtKB:Q16236}.
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 -!- DISRUPTION PHENOTYPE: Mice are viable and fertile but have low and
CC uninducible phase 2 detoxifying enzymes, are much more susceptible to
CC carcinogens and the toxicity of oxygen and electrophiles and cannot be
CC protected by inducers (PubMed:9240432, PubMed:11248092,
CC PubMed:12032331). Mutant mice show an increased mortality during LPS
CC and cecal ligation and puncture-induced septic shock compared to wild-
CC types. They show greater pulmonary inflammation and greater TNF
CC secretion upon LPS administration (PubMed:16585964). Mice lacking both
CC Nfe2l2/Nrf2 and Keap1 reverse the hyperkeratosis phenotype observed in
CC Keap1 knockout: mice and are healthy and viable in normal conditions
CC (PubMed:14517554). Mice lacking both Nfe2l1 and Nfe2l2 die early
CC between embryonic days 9 and 10 and exhibit extensive apoptosis due to
CC marked oxidative stress in cells that is indicated by elevated
CC intracellular reactive oxygen species levels and cell death
CC (PubMed:12968018). {ECO:0000269|PubMed:11248092,
CC ECO:0000269|PubMed:12032331, ECO:0000269|PubMed:12968018,
CC ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:16585964,
CC ECO:0000269|PubMed:9240432}.
CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
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DR EMBL; U70475; AAC52983.1; -; Genomic_DNA.
DR EMBL; U70474; AAC52983.1; JOINED; Genomic_DNA.
DR EMBL; AK142347; BAE25040.1; -; mRNA.
DR EMBL; AL772404; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC026943; AAH26943.1; -; mRNA.
DR EMBL; U20532; AAA68291.1; -; mRNA.
DR CCDS; CCDS16150.1; -.
DR PIR; I49261; I49261.
DR RefSeq; NP_035032.1; NM_010902.4.
DR PDB; 1X2R; X-ray; 1.70 A; B=76-84.
DR PDB; 2DYH; X-ray; 1.90 A; B=22-36.
DR PDB; 3WN7; X-ray; 1.57 A; B/M=17-51.
DR PDB; 7ECA; X-ray; 2.00 A; B=65-89.
DR PDBsum; 1X2R; -.
DR PDBsum; 2DYH; -.
DR PDBsum; 3WN7; -.
DR PDBsum; 7ECA; -.
DR AlphaFoldDB; Q60795; -.
DR SMR; Q60795; -.
DR BioGRID; 201744; 25.
DR CORUM; Q60795; -.
DR DIP; DIP-49666N; -.
DR ELM; Q60795; -.
DR IntAct; Q60795; 5.
DR MINT; Q60795; -.
DR STRING; 10090.ENSMUSP00000099733; -.
DR BindingDB; Q60795; -.
DR ChEMBL; CHEMBL1075148; -.
DR iPTMnet; Q60795; -.
DR PhosphoSitePlus; Q60795; -.
DR PaxDb; Q60795; -.
DR PRIDE; Q60795; -.
DR ProteomicsDB; 287396; -.
DR Antibodypedia; 903; 895 antibodies from 46 providers.
DR DNASU; 18024; -.
DR Ensembl; ENSMUST00000102672; ENSMUSP00000099733; ENSMUSG00000015839.
DR GeneID; 18024; -.
DR KEGG; mmu:18024; -.
DR UCSC; uc008keq.1; mouse.
DR CTD; 4780; -.
DR MGI; MGI:108420; Nfe2l2.
DR VEuPathDB; HostDB:ENSMUSG00000015839; -.
DR eggNOG; KOG3863; Eukaryota.
DR GeneTree; ENSGT00950000182892; -.
DR HOGENOM; CLU_498373_0_0_1; -.
DR InParanoid; Q60795; -.
DR OMA; PMDLYSL; -.
DR OrthoDB; 1095280at2759; -.
DR PhylomeDB; Q60795; -.
DR TreeFam; TF326681; -.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-9755511; KEAP1-NFE2L2 pathway.
DR Reactome; R-MMU-9759194; Nuclear events mediated by NFE2L2.
DR Reactome; R-MMU-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2.
DR BioGRID-ORCS; 18024; 8 hits in 80 CRISPR screens.
DR ChiTaRS; Nfe2l2; mouse.
DR EvolutionaryTrace; Q60795; -.
DR PRO; PR:Q60795; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q60795; protein.
DR Bgee; ENSMUSG00000015839; Expressed in urinary bladder urothelium and 268 other tissues.
DR Genevisible; Q60795; MM.
DR GO; GO:0005813; C:centrosome; ISO:MGI.
DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0032993; C:protein-DNA complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:MGI.
DR GO; GO:0005667; C:transcription regulator complex; TAS:ParkinsonsUK-UCL.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
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; IBA:GO_Central.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB.
DR GO; GO:0046223; P:aflatoxin catabolic process; ISO:MGI.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0045454; P:cell redox homeostasis; IMP:ParkinsonsUK-UCL.
DR GO; GO:1904385; P:cellular response to angiotensin; ISO:MGI.
DR GO; GO:0071280; P:cellular response to copper ion; IMP:MGI.
DR GO; GO:0071498; P:cellular response to fluid shear stress; ISS:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISO:MGI.
DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; ISO:MGI.
DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISO:MGI.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IMP:MGI.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:MGI.
DR GO; GO:0006954; P:inflammatory response; IMP:MGI.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; ISO:MGI.
DR GO; GO:0060548; P:negative regulation of cell death; ISO:MGI.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; ISO:MGI.
DR GO; GO:1902037; P:negative regulation of hematopoietic stem cell differentiation; IMP:CACAO.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; ISO:MGI.
DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:1904753; P:negative regulation of vascular associated smooth muscle cell migration; ISO:MGI.
DR GO; GO:0036499; P:PERK-mediated unfolded protein response; IDA:ParkinsonsUK-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:MGI.
DR GO; GO:0030194; P:positive regulation of blood coagulation; IMP:BHF-UCL.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; ISO:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ParkinsonsUK-UCL.
DR GO; GO:0046326; P:positive regulation of glucose import; IDA:CACAO.
DR GO; GO:1903788; P:positive regulation of glutathione biosynthetic process; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0061419; P:positive regulation of transcription from RNA polymerase II promoter in response to hypoxia; ISO:MGI.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; ISO:MGI.
DR GO; GO:0036003; P:positive regulation of transcription from RNA polymerase II promoter in response to stress; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0010499; P:proteasomal ubiquitin-independent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0045995; P:regulation of embryonic development; IGI:MGI.
DR GO; GO:0045088; P:regulation of innate immune response; IMP:UniProtKB.
DR GO; GO:2000121; P:regulation of removal of superoxide radicals; IMP:BHF-UCL.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010226; P:response to lithium ion; IEA:Ensembl.
DR DisProt; DP00968; -.
DR IDEAL; IID50024; -.
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; Cytoplasm; DNA-binding; Glycation;
KW Glycoprotein; Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..597
FT /note="Nuclear factor erythroid 2-related factor 2"
FT /id="PRO_0000076450"
FT DOMAIN 489..552
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 327..440
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 491..510
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 514..521
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 563..597
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 583..588
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:0000305|PubMed:15581590,
FT ECO:0000305|PubMed:16581765, ECO:0000305|PubMed:16790436"
FT MOTIF 79..82
FT /note="ETGE motif"
FT /evidence="ECO:0000305|PubMed:15282312,
FT ECO:0000305|PubMed:16581765, ECO:0000305|PubMed:16790436"
FT COMPBIAS 331..351
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 393..423
FT /note="Polar 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 207
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MOD_RES 588
FT /note="N6-acetyllysine; by CREBBP"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MOD_RES 591
FT /note="N6-acetyllysine; by CREBBP"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 454
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 464
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 479
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 491
FT /note="N-linked (Glc) (glycation) arginine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 561
FT /note="N-linked (Glc) (glycation) arginine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 566
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MUTAGEN 18..23
FT /note="DLIDIL->ALIDIA: Does not affect ubiquitination and
FT degradation by the BCR(KEAP1) complex in the cytoplasm."
FT /evidence="ECO:0000269|PubMed:16790436"
FT MUTAGEN 19..23
FT /note="LIDIL->AIDIA: Abolished ubiquitination and
FT degradation by the BCR(KEAP1) complex in the cytoplasm;
FT when associated with A-30."
FT /evidence="ECO:0000269|PubMed:15581590"
FT MUTAGEN 29..31
FT /note="DLG->AGE: Abolished ubiquitination and degradation
FT by the BCR(KEAP1) complex in the cytoplasm."
FT /evidence="ECO:0000269|PubMed:16790436"
FT MUTAGEN 30
FT /note="L->A: Abolished ubiquitination and degradation by
FT the BCR(KEAP1) complex in the cytoplasm; when associated
FT with 19-A--A-23."
FT /evidence="ECO:0000269|PubMed:15581590"
FT MUTAGEN 79..82
FT /note="Missing: Abolished interaction with KEAP1."
FT /evidence="ECO:0000269|PubMed:15282312,
FT ECO:0000269|PubMed:16581765, ECO:0000269|PubMed:16790436"
FT HELIX 19..25
FT /evidence="ECO:0007829|PDB:3WN7"
FT HELIX 28..30
FT /evidence="ECO:0007829|PDB:3WN7"
FT HELIX 34..37
FT /evidence="ECO:0007829|PDB:3WN7"
FT TURN 78..80
FT /evidence="ECO:0007829|PDB:1X2R"
SQ SEQUENCE 597 AA; 66901 MW; 6128707C82CAE239 CRC64;
MMDLELPPPG LQSQQDMDLI DILWRQDIDL GVSREVFDFS QRQKDYELEK QKKLEKERQE
QLQKEQEKAF FAQFQLDEET GEFLPIQPAQ HIQTDTSGSA SYSQVAHIPK QDALYFEDCM
QLLAETFPFV DDHESLALDI PSHAESSVFT APHQAQSLNS SLEAAMTDLS SIEQDMEQVW
QELFSIPELQ CLNTENKQLA DTTAVPSPEA TLTEMDSNYH FYSSISSLEK EVGNCGPHFL
HGFEDSFSSI LSTDDASQLT SLDSNPTLNT DFGDEFYSAF IAEPSDGGSM PSSAAISQSL
SELLDGTIEG CDLSLCKAFN PKHAEGTMEF NDSDSGISLN TSPSRASPEH SVESSIYGDP
PPGFSDSEME ELDSAPGSVK QNGPKAQPAH SPGDTVQPLS PAQGHSAPMR ESQCENTTKK
EVPVSPGHQK APFTKDKHSS RLEAHLTRDE LRAKALHIPF PVEKIINLPV DDFNEMMSKE
QFNEAQLALI RDIRRRGKNK VAAQNCRKRK LENIVELEQD LGHLKDEREK LLREKGENDR
NLHLLKRRLS TLYLEVFSML RDEDGKPYSP SEYSLQQTRD GNVFLVPKSK KPDTKKN
