NF2L1_MOUSE
ID NF2L1_MOUSE Reviewed; 741 AA.
AC Q61985; E9Q038; O70234;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 29-MAY-2013, sequence version 2.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Endoplasmic reticulum membrane sensor NFE2L1 {ECO:0000305};
DE AltName: Full=Locus control region-factor 1 {ECO:0000303|PubMed:9087432};
DE Short=LCR-F1 {ECO:0000303|PubMed:9087432};
DE AltName: Full=Nuclear factor erythroid 2-related factor 1 {ECO:0000305};
DE Short=NF-E2-related factor 1 {ECO:0000303|PubMed:9580677};
DE Short=NFE2-related factor 1 {ECO:0000303|PubMed:9580677};
DE AltName: Full=Nuclear factor, erythroid derived 2, like 1;
DE Contains:
DE RecName: Full=Transcription factor NRF1 {ECO:0000305};
GN Name=Nfe2l1 {ECO:0000303|PubMed:7759107, ECO:0000312|MGI:MGI:99421};
GN Synonyms=Nrf1 {ECO:0000303|PubMed:9580677};
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 [MRNA] (ISOFORM 1).
RC TISSUE=Embryo;
RX PubMed=7759107; DOI=10.1016/0888-7543(95)80015-e;
RA McKie J., Johnstone K., Mattei M.-G., Scambler P.;
RT "Cloning and mapping of murine Nfe2l1.";
RL Genomics 25:716-719(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 3), FUNCTION, AND
RP PHOSPHORYLATION BY CKII.
RX PubMed=9580677; DOI=10.1093/nar/26.10.2291;
RA Prieschl E.E., Novotny V., Csonga R., Jaksche D., Elbe-Buerger A.,
RA Thumb W., Auer M., Stingl G., Baumruker T.;
RT "A novel splice variant of the transcription factor Nrf1 interacts with the
RT TNFalpha promoter and stimulates transcription.";
RL Nucleic Acids Res. 26:2291-2297(1998).
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 DISRUPTION PHENOTYPE.
RX PubMed=9087432; DOI=10.1101/gad.11.6.786;
RA Farmer S.C., Sun C.W., Winnier G.E., Hogan B.L., Townes T.M.;
RT "The bZIP transcription factor LCR-F1 is essential for mesoderm formation
RT in mouse development.";
RL Genes Dev. 11:786-798(1997).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9501099; DOI=10.1093/emboj/17.6.1779;
RA Chan J.Y., Kwong M., Lu R., Chang J., Wang B., Yen T.S., Kan Y.W.;
RT "Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-
RT 1, results in anemia and embryonic lethality in mice.";
RL EMBO J. 17:1779-1787(1998).
RN [6]
RP FUNCTION, AND DNA-BINDING.
RX PubMed=10601325; DOI=10.1074/jbc.274.52.37491;
RA Kwong M., Kan Y.W., Chan J.Y.;
RT "The CNC basic leucine zipper factor, Nrf1, is essential for cell survival
RT in response to oxidative stress-inducing agents. Role for Nrf1 in gamma-
RT gcs(l) and gss expression in mouse fibroblasts.";
RL J. Biol. Chem. 274:37491-37498(1999).
RN [7]
RP FUNCTION, DNA-BINDING, AND INTERACTION WITH MAFG.
RX PubMed=11342101; DOI=10.1016/s0167-4781(00)00276-1;
RA Myhrstad M.C., Husberg C., Murphy P., Nordstroem O., Blomhoff R.,
RA Moskaug J.O., Kolstoe A.B.;
RT "TCF11/Nrf1 overexpression increases the intracellular glutathione level
RT and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy
RT subunit promoter.";
RL Biochim. Biophys. Acta 1517:212-219(2001).
RN [8]
RP FUNCTION, AND 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 [9]
RP FUNCTION.
RX PubMed=12808106; DOI=10.1128/mcb.23.13.4673-4686.2003;
RA Chen L., Kwong M., Lu R., Ginzinger D., Lee C., Leung L., Chan J.Y.;
RT "Nrf1 is critical for redox balance and survival of liver cells during
RT development.";
RL Mol. Cell. Biol. 23:4673-4686(2003).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15738389; DOI=10.1073/pnas.0500660102;
RA Xu Z., Chen L., Leung L., Yen T.S., Lee C., Chan J.Y.;
RT "Liver-specific inactivation of the Nrf1 gene in adult mouse leads to
RT nonalcoholic steatohepatitis and hepatic neoplasia.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:4120-4125(2005).
RN [11]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16872277; DOI=10.1042/bj20060725;
RA Zhang Y., Crouch D.H., Yamamoto M., Hayes J.D.;
RT "Negative regulation of the Nrf1 transcription factor by its N-terminal
RT domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the
RT endoplasmic reticulum.";
RL Biochem. J. 399:373-385(2006).
RN [12]
RP SUBCELLULAR LOCATION, AND GLYCOSYLATION.
RX PubMed=17705787; DOI=10.1042/bj20070761;
RA Zhang Y., Lucocq J.M., Yamamoto M., Hayes J.D.;
RT "The NHB1 (N-terminal homology box 1) sequence in transcription factor Nrf1
RT is required to anchor it to the endoplasmic reticulum and also to enable
RT its asparagine-glycosylation.";
RL Biochem. J. 408:161-172(2007).
RN [13]
RP FUNCTION.
RX PubMed=17510056; DOI=10.1074/jbc.m702614200;
RA Xing W., Singgih A., Kapoor A., Alarcon C.M., Baylink D.J., Mohan S.;
RT "Nuclear factor-E2-related factor-1 mediates ascorbic acid induction of
RT osterix expression via interaction with antioxidant-responsive element in
RT bone cells.";
RL J. Biol. Chem. 282:22052-22061(2007).
RN [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18826952; DOI=10.1074/jbc.m804597200;
RA Ohtsuji M., Katsuoka F., Kobayashi A., Aburatani H., Hayes J.D.,
RA Yamamoto M.;
RT "Nrf1 and Nrf2 play distinct roles in activation of antioxidant response
RT element-dependent genes.";
RL J. Biol. Chem. 283:33554-33562(2008).
RN [15]
RP SUBCELLULAR LOCATION, GLYCOSYLATION, AND SUBUNIT.
RX PubMed=18990090; DOI=10.1042/bj20081575;
RA Zhang Y., Lucocq J.M., Hayes J.D.;
RT "The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor
RT that is activated by t-butyl hydroquinone but not by endoplasmic reticulum
RT stressors.";
RL Biochem. J. 418:293-310(2009).
RN [16]
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=20629635; DOI=10.1042/bj20100471;
RA Zhang Y., Hayes J.D.;
RT "Identification of topological determinants in the N-terminal domain of
RT transcription factor Nrf1 that control its orientation in the endoplasmic
RT reticulum membrane.";
RL Biochem. J. 430:497-510(2010).
RN [17]
RP FUNCTION.
RX PubMed=20385086; DOI=10.1016/j.molcel.2010.02.029;
RA Radhakrishnan S.K., Lee C.S., Young P., Beskow A., Chan J.Y.,
RA Deshaies R.J.;
RT "Transcription factor Nrf1 mediates the proteasome recovery pathway after
RT proteasome inhibition in mammalian cells.";
RL Mol. Cell 38:17-28(2010).
RN [18]
RP DISRUPTION PHENOTYPE.
RX PubMed=21554501; DOI=10.1111/j.1365-2443.2011.01522.x;
RA Kobayashi A., Tsukide T., Miyasaka T., Morita T., Mizoroki T., Saito Y.,
RA Ihara Y., Takashima A., Noguchi N., Fukamizu A., Hirotsu Y., Ohtsuji M.,
RA Katsuoka F., Yamamoto M.;
RT "Central nervous system-specific deletion of transcription factor Nrf1
RT causes progressive motor neuronal dysfunction.";
RL Genes Cells 16:692-703(2011).
RN [19]
RP UBIQUITINATION, INTERACTION WITH FBXW7, AND MUTAGENESIS OF
RP 350-SER--GLU-354.
RX PubMed=21953459; DOI=10.1074/jbc.m111.253807;
RA Biswas M., Phan D., Watanabe M., Chan J.Y.;
RT "The Fbw7 tumor suppressor regulates nuclear factor E2-related factor 1
RT transcription factor turnover through proteasome-mediated proteolysis.";
RL J. Biol. Chem. 286:39282-39289(2011).
RN [20]
RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, INTERACTION WITH BTRC AND
RP SYVN1, AND MUTAGENESIS OF 448-SER--SER-451.
RX PubMed=21911472; DOI=10.1128/mcb.05663-11;
RA Tsuchiya Y., Morita T., Kim M., Iemura S., Natsume T., Yamamoto M.,
RA Kobayashi A.;
RT "Dual regulation of the transcriptional activity of Nrf1 by beta-TrCP- and
RT Hrd1-dependent degradation mechanisms.";
RL Mol. Cell. Biol. 31:4500-4512(2011).
RN [21]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21536885; DOI=10.1073/pnas.1019209108;
RA Lee C.S., Lee C., Hu T., Nguyen J.M., Zhang J., Martin M.V., Vawter M.P.,
RA Huang E.J., Chan J.Y.;
RT "Loss of nuclear factor E2-related factor 1 in the brain leads to
RT dysregulation of proteasome gene expression and neurodegeneration.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:8408-8413(2011).
RN [22]
RP FUNCTION.
RX PubMed=22586274; DOI=10.1128/mcb.06706-11;
RA Hirotsu Y., Hataya N., Katsuoka F., Yamamoto M.;
RT "NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid
RT metabolism through regulation of the Lipin1 and PGC-1beta genes.";
RL Mol. Cell. Biol. 32:2760-2770(2012).
RN [23]
RP ALTERNATIVE PROMOTER USAGE, IDENTIFICATION OF ISOFORM 2, FUNCTION,
RP INTERACTION WITH MAFG, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=23144760; DOI=10.1371/journal.pone.0048404;
RA Kwong E.K., Kim K.M., Penalosa P.J., Chan J.Y.;
RT "Characterization of Nrf1b, a novel isoform of the nuclear factor-
RT erythroid-2 related transcription factor-1 that activates antioxidant
RT response element-regulated genes.";
RL PLoS ONE 7:E48404-E48404(2012).
RN [24]
RP FUNCTION, PHOSPHORYLATION AT SER-497, AND MUTAGENESIS OF SER-496; SER-497;
RP SER-499 AND THR-501.
RX PubMed=23816881; DOI=10.1128/mcb.01271-12;
RA Tsuchiya Y., Taniguchi H., Ito Y., Morita T., Karim M.R., Ohtake N.,
RA Fukagai K., Ito T., Okamuro S., Iemura S., Natsume T., Nishida E.,
RA Kobayashi A.;
RT "The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated
RT proteins by regulating proteasome gene expression.";
RL Mol. Cell. Biol. 33:3461-3472(2013).
RN [25]
RP FUNCTION.
RX PubMed=25041126; DOI=10.1111/gtc.12165;
RA Hirotsu Y., Higashi C., Fukutomi T., Katsuoka F., Tsujita T., Yagishita Y.,
RA Matsuyama Y., Motohashi H., Uruno A., Yamamoto M.;
RT "Transcription factor NF-E2-related factor 1 impairs glucose metabolism in
RT mice.";
RL Genes Cells 19:650-665(2014).
RN [26]
RP SUBCELLULAR LOCATION.
RX PubMed=26268886; DOI=10.1038/srep12983;
RA Zhang Y., Li S., Xiang Y., Qiu L., Zhao H., Hayes J.D.;
RT "The selective post-translational processing of transcription factor Nrf1
RT yields distinct isoforms that dictate its ability to differentially
RT regulate gene expression.";
RL Sci. Rep. 5:12983-12983(2015).
RN [27]
RP REVIEW.
RX PubMed=26947393; DOI=10.1016/j.gene.2016.03.002;
RA Kim H.M., Han J.W., Chan J.Y.;
RT "Nuclear factor erythroid-2 like 1 (NFE2L1): structure, function and
RT regulation.";
RL Gene 584:17-25(2016).
RN [28]
RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, DOMAIN,
RP CHOLESTEROL-BINDING, AND DISRUPTION PHENOTYPE.
RX PubMed=29149604; DOI=10.1016/j.cell.2017.10.003;
RA Widenmaier S.B., Snyder N.A., Nguyen T.B., Arduini A., Lee G.Y.,
RA Arruda A.P., Saksi J., Bartelt A., Hotamisligil G.S.;
RT "NRF1 is an ER membrane sensor that is central to cholesterol
RT homeostasis.";
RL Cell 171:1094-1109(2017).
CC -!- FUNCTION: [Endoplasmic reticulum membrane sensor NFE2L1]: Endoplasmic
CC reticulum membrane sensor that translocates into the nucleus in
CC response to various stresses to act as a transcription factor
CC (PubMed:20385086, PubMed:21536885, PubMed:23816881, PubMed:29149604).
CC Constitutes a precursor of the transcription factor NRF1. Able to
CC detect various cellular stresses, such as cholesterol excess, oxidative
CC stress or proteasome inhibition (PubMed:20385086, PubMed:21536885,
CC PubMed:23816881, PubMed:29149604). In response to stress, it is
CC released from the endoplasmic reticulum membrane following cleavage by
CC the protease DDI2 and translocates into the nucleus to form the
CC transcription factor NRF1 (PubMed:29149604). Acts as a key sensor of
CC cholesterol excess: in excess cholesterol conditions, the endoplasmic
CC reticulum membrane form of the protein directly binds cholesterol via
CC its CRAC motif, preventing cleavage and release of the transcription
CC factor NRF1, thereby allowing expression of genes promoting cholesterol
CC removal, such as CD36 (PubMed:29149604). Involved in proteasome
CC homeostasis: in response to proteasome inhibition, it is released from
CC the endoplasmic reticulum membrane, translocates to the nucleus and
CC activates expression of genes encoding proteasome subunits
CC (PubMed:20385086, PubMed:21536885, PubMed:23816881).
CC {ECO:0000269|PubMed:20385086, ECO:0000269|PubMed:21536885,
CC ECO:0000269|PubMed:23816881, ECO:0000269|PubMed:29149604}.
CC -!- FUNCTION: [Transcription factor NRF1]: CNC-type bZIP family
CC transcription factor that translocates to the nucleus and regulates
CC expression of target genes in response to various stresses
CC (PubMed:10601325, PubMed:11342101, PubMed:23144760, PubMed:16872277,
CC PubMed:21911472, PubMed:23816881, PubMed:29149604). Heterodimerizes
CC with small-Maf proteins (MAFF, MAFG or MAFK) and binds DNA motifs
CC including the antioxidant response elements (AREs), which regulate
CC expression of genes involved in oxidative stress response
CC (PubMed:12808106, PubMed:15738389, PubMed:23144760, PubMed:16872277,
CC PubMed:21911472, PubMed:23816881). Activates or represses expression of
CC target genes, depending on the context (PubMed:12808106,
CC PubMed:15738389, PubMed:23144760, PubMed:16872277, PubMed:21911472,
CC PubMed:23816881). Plays a key role in cholesterol homeostasis by acting
CC as a sensor of cholesterol excess: in low cholesterol conditions,
CC translocates into the nucleus and represses expression of genes
CC involved in defense against cholesterol excess, such as CD36
CC (PubMed:29149604). In excess cholesterol conditions, the endoplasmic
CC reticulum membrane form of the protein directly binds cholesterol via
CC its CRAC motif, preventing cleavage and release of the transcription
CC factor NRF1, thereby allowing expression of genes promoting cholesterol
CC removal (PubMed:29149604). Critical for redox balance in response to
CC oxidative stress: acts by binding the AREs motifs on promoters and
CC mediating activation of oxidative stress response genes, such as GCLC,
CC GCLM, GSS, MT1 and MT2 (PubMed:10601325, PubMed:11342101,
CC PubMed:12968018, PubMed:15738389, PubMed:18826952). Plays an essential
CC role during fetal liver hematopoiesis: probably has a protective
CC function against oxidative stress and is involved in lipid homeostasis
CC in the liver (PubMed:9501099, PubMed:12808106, PubMed:15738389,
CC PubMed:18826952, PubMed:22586274). Involved in proteasome homeostasis:
CC in response to proteasome inhibition, mediates the 'bounce-back' of
CC proteasome subunits by translocating into the nucleus and activating
CC expression of genes encoding proteasome subunits (PubMed:20385086,
CC PubMed:21536885, PubMed:23816881). Also involved in regulating glucose
CC flux (PubMed:25041126). Together with CEBPB; represses expression of
CC DSPP during odontoblast differentiation (By similarity). In response to
CC ascorbic acid induction, activates expression of SP7/Osterix in
CC osteoblasts (PubMed:17510056). {ECO:0000250|UniProtKB:Q14494,
CC ECO:0000269|PubMed:10601325, ECO:0000269|PubMed:11342101,
CC ECO:0000269|PubMed:12808106, ECO:0000269|PubMed:12968018,
CC ECO:0000269|PubMed:15738389, ECO:0000269|PubMed:16872277,
CC ECO:0000269|PubMed:17510056, ECO:0000269|PubMed:18826952,
CC ECO:0000269|PubMed:20385086, ECO:0000269|PubMed:21536885,
CC ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:22586274,
CC ECO:0000269|PubMed:23144760, ECO:0000269|PubMed:23816881,
CC ECO:0000269|PubMed:25041126, ECO:0000269|PubMed:29149604,
CC ECO:0000269|PubMed:9501099}.
CC -!- FUNCTION: [Isoform 2]: Transcription factor that binds the antioxidant
CC response elements (ARE) consensus sequence on promoters and activates
CC their expression. {ECO:0000269|PubMed:23144760,
CC ECO:0000269|PubMed:9580677}.
CC -!- FUNCTION: [Isoform 3]: Transcription factor that binds the extended
CC kappa 3 site of the TNF-alpha promoter after Fc gamma RIII stimulation
CC and participates in the induction of this cytokine (PubMed:9580677).
CC {ECO:0000269|PubMed:9580677}.
CC -!- SUBUNIT: Interacts with KEAP1. {ECO:0000250|UniProtKB:Q14494}.
CC -!- SUBUNIT: [Endoplasmic reticulum membrane sensor NFE2L1]: Interacts (via
CC CPD region) with FBXW7; leading to its ubiquitination and degradation
CC (PubMed:21953459). Interacts with SYVN1/HRD1; leading to its
CC ubiquitination and degradation (PubMed:21911472). Interacts (when
CC ubiquitinated) with DDI2; leading to its cleavage (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:21911472,
CC ECO:0000269|PubMed:21953459}.
CC -!- SUBUNIT: [Transcription factor NRF1]: Interacts (via the bZIP domain)
CC with small MAF protein (MAFF, MAFG or MAFK); required for binding to
CC antioxidant response elements (AREs) on DNA (PubMed:11342101,
CC PubMed:18990090, PubMed:23144760). Interacts (via Destruction motif)
CC with BTRC; leading to its ubiquitination and degradation
CC (PubMed:21911472). Interacts with CEBPB; the heterodimer represses
CC expression of DSPP during odontoblast differentiation (By similarity).
CC Interacts with MOTS-c, a peptide produced by the mitochondrially
CC encoded 12S rRNA MT-RNR1 (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:11342101,
CC ECO:0000269|PubMed:18990090, ECO:0000269|PubMed:21911472,
CC ECO:0000269|PubMed:23144760}.
CC -!- SUBCELLULAR LOCATION: [Endoplasmic reticulum membrane sensor NFE2L1]:
CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:16872277,
CC ECO:0000269|PubMed:17705787, ECO:0000269|PubMed:18990090,
CC ECO:0000269|PubMed:20629635, ECO:0000269|PubMed:21911472,
CC ECO:0000269|PubMed:29149604}; Single-pass type II membrane protein
CC {ECO:0000250|UniProtKB:Q14494}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:16872277, ECO:0000269|PubMed:17705787,
CC ECO:0000269|PubMed:18990090, ECO:0000269|PubMed:20629635,
CC ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:29149604}; Single-pass
CC type III membrane protein {ECO:0000250|UniProtKB:Q14494}. Note=In
CC normal conditions, probably has a single-pass type II membrane protein
CC topology, with the DNA-binding domain facing the endoplasmic reticulum
CC lumen (By similarity). Following cellular stress, it is rapidly and
CC efficiently retrotranslocated to the cytosolic side of the membrane, a
CC process dependent on p97/VCP, to have a single-pass type III membrane
CC protein topology with the major part of the protein facing the cytosol
CC (By similarity). Retrotranslocated proteins are normally rapidly
CC degraded by the proteasome and active species do not accumulate (By
CC similarity). However, retrotranslocated protein NFE2L1 escapes
CC degradation and is cleaved at Leu-104 by DDI2, releasing the protein
CC from the endoplasmic reticulum membrane and forming the transcription
CC factor NRF1 that translocates into the nucleus (By similarity).
CC {ECO:0000250|UniProtKB:Q14494}.
CC -!- SUBCELLULAR LOCATION: [Transcription factor NRF1]: Nucleus
CC {ECO:0000255|PROSITE-ProRule:PRU00978, ECO:0000269|PubMed:21911472,
CC ECO:0000269|PubMed:23144760, ECO:0000269|PubMed:29149604}.
CC Note=Translocates into the nucleus following cleavage of Endoplasmic
CC reticulum membrane sensor NFE2L1 by aspartyl protease DDI2.
CC {ECO:0000305|PubMed:29149604}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000269|PubMed:23144760}. Nucleus {ECO:0000269|PubMed:23144760}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Long {ECO:0000303|PubMed:9580677}, Nrf1a
CC {ECO:0000303|PubMed:23144760};
CC IsoId=Q61985-1; Sequence=Displayed;
CC Name=2; Synonyms=Nrf1b {ECO:0000303|PubMed:23144760};
CC IsoId=Q61985-3; Sequence=VSP_000580, VSP_046524;
CC Name=3; Synonyms=Short {ECO:0000303|PubMed:9580677};
CC IsoId=Q61985-2; Sequence=VSP_000580, VSP_046523, VSP_000581;
CC -!- TISSUE SPECIFICITY: Isoform 1: Widely expressed including kidney, brown
CC fat, white fat, large intestine, small intestine, stomach, lung, brain
CC and liver (PubMed:23144760). Isoform 1: Expressed in mouse embryonic
CC fibroblasts (MEF) (PubMed:23144760). Isoform 2: Widely expressed
CC including kidney, brown fat, white fat, large intestine, small
CC intestine, stomach, lung, brain and liver (PubMed:23144760). Isoform 2:
CC levels in white fat, lung and liver are increased compared to isoform 1
CC (at protein level) (PubMed:23144760). Isoform 2: levels are elevated in
CC brown fat and brain, but are reduced in liver compared to isoform 1
CC levels (PubMed:23144760). Isoform 2: Expressed in mouse embryonic
CC fibroblasts (MEF) (PubMed:23144760). {ECO:0000269|PubMed:23144760}.
CC -!- DOMAIN: The cholesterol recognition/amino acid consensus (CRAC) region
CC directly binds cholesterol, as well as campesterol and 27-
CC hydroxycholesterol (PubMed:29149604). Has much lower affinity for
CC epicholesterol (PubMed:29149604). {ECO:0000269|PubMed:29149604}.
CC -!- PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: Cleaved at Leu-104
CC by the aspartyl protease DDI2 following retrotranslocation, releasing
CC the protein from the endoplasmic reticulum membrane and forming the
CC transcription factor NRF1 that translocates into the nucleus.
CC Ubiquitination is prerequisite for cleavage by aspartyl protease DDI2.
CC {ECO:0000250|UniProtKB:Q14494}.
CC -!- PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: N-glycosylated in
CC normal conditions, when it has a single-pass type II membrane protein
CC topology, with the DNA-binding domain facing the endoplasmic reticulum
CC lumen (PubMed:17705787, PubMed:18990090). Deglycosylated during
CC retrotranslocation to the cytosolic side of the membrane, to have a
CC single-pass type III membrane protein topology with the major part of
CC the protein facing the cytosol (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:17705787,
CC ECO:0000269|PubMed:18990090}.
CC -!- PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: Ubiquitinated by
CC the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by
CC the proteasome (PubMed:21953459, PubMed:21911472). Ubiquitinated during
CC retrotranslocation to the cytosolic side of the membrane:
CC ubiquitination does not lead to degradation and is required for
CC processing by the aspartyl protease DDI2 and subsequent release from
CC the endoplasmic reticulum membrane (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:21911472,
CC ECO:0000269|PubMed:21953459}.
CC -!- PTM: [Transcription factor NRF1]: Phosphorylation by CK2 at Ser-497
CC inhibits transcription factor activity, possibly by affecting DNA-
CC binding activity (PubMed:9580677, PubMed:23816881). Phosphorylation at
CC Ser-568 is required for interaction with CEBPB (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:23816881,
CC ECO:0000269|PubMed:9580677}.
CC -!- PTM: [Transcription factor NRF1]: Ubiquitinated by the SCF(BTRC)
CC complex in the nucleus, leading to its degradation by the proteasome.
CC {ECO:0000269|PubMed:21911472}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality: embryos progress normally to
CC the late egg cylinder stage at approximately 6.5 days post coitus
CC (dpc), but development is arrested before 7.5 dpc (PubMed:9087432,
CC PubMed:9501099). Mutant embryos fail to form a primitive streak and
CC lack detectable mesoderm (PubMed:9087432). Homozygous embryos suffer
CC from anemia as a result of abnormal fetal liver erythropoiesis
CC (PubMed:9501099). No defect in globin gene expression are detected;
CC abnormal red cell production being the result of a defect in the fetal
CC liver microenvironment specific for erythroid cells (PubMed:9501099).
CC Mice lacking both Nfe2l1 and Nfe2l2 die early between embryonic days 9
CC and 10 and exhibit extensive apoptosis due to marked oxidative stress
CC in cells that is indicated by elevated intracellular reactive oxygen
CC species levels and cell death (PubMed:12968018). Conditional knockout
CC mice lacking Nfe2l1 in the liver do not show any liver damage when they
CC are maintained in an unstressed condition (PubMed:15738389). In
CC oxidative stress condition, they develop hepatic cancer following
CC steatosis, apoptosis, necrosis, inflammation, and fibrosis
CC (PubMed:15738389). Hepatocyte-specific deletion causes liver damage
CC resembling the human disease non-alcoholic steatohepatitis
CC (PubMed:18826952). Liver of conditional knockout mice lacking Nfe2l1
CC show massive hepatic cholesterol accumulation and damage due to
CC inability to mediate response to cholesterol excess (PubMed:29149604).
CC Conditional knockout mice lacking Nfe2l1 in the brain show proteasome
CC impairment and progressive degeneration in cortical neurons
CC (PubMed:21554501, PubMed:21536885). {ECO:0000269|PubMed:12968018,
CC ECO:0000269|PubMed:15738389, ECO:0000269|PubMed:18826952,
CC ECO:0000269|PubMed:21536885, ECO:0000269|PubMed:21554501,
CC ECO:0000269|PubMed:29149604, ECO:0000269|PubMed:9087432,
CC ECO:0000269|PubMed:9501099}.
CC -!- MISCELLANEOUS: [Isoform 1]: Produced by alternative promoter usage.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative promoter usage.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing of isoform
CC 1. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
CC -!- CAUTION: [Endoplasmic reticulum membrane sensor NFE2L1]: Its topology
CC is subject to discussion. According to some groups, it has a single-
CC pass type II membrane protein in normal conditions and is
CC retrotranslocated into a single-pass type III membrane protein in
CC response to stress. According to other reports, it is integrated into
CC the endoplasmic reticulum membrane via multiple membrane-spanning
CC alpha-helices (PubMed:20629635, PubMed:26268886).
CC {ECO:0000269|PubMed:20629635, ECO:0000269|PubMed:26268886}.
CC -!- CAUTION: [Endoplasmic reticulum membrane sensor NFE2L1]: Was initially
CC thought to be either inactive as transcription factor or to repress
CC transcriptional activation mediated by other isoforms (PubMed:9580677).
CC The presence of the transmembrane region at the N-terminus may explain
CC the inability to observe transcription factor activity.
CC {ECO:0000269|PubMed:9580677}.
CC ---------------------------------------------------------------------------
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DR EMBL; X78709; CAA55362.1; -; mRNA.
DR EMBL; AF015881; AAC40108.1; -; Genomic_DNA.
DR EMBL; AL596384; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS25304.1; -. [Q61985-1]
DR CCDS; CCDS48894.1; -. [Q61985-3]
DR PIR; I48694; I48694.
DR RefSeq; NP_001123922.1; NM_001130450.1. [Q61985-1]
DR RefSeq; NP_032712.2; NM_008686.3. [Q61985-1]
DR AlphaFoldDB; Q61985; -.
DR SMR; Q61985; -.
DR STRING; 10090.ENSMUSP00000103286; -.
DR GlyGen; Q61985; 3 sites.
DR iPTMnet; Q61985; -.
DR PhosphoSitePlus; Q61985; -.
DR MaxQB; Q61985; -.
DR PaxDb; Q61985; -.
DR PRIDE; Q61985; -.
DR ProteomicsDB; 287393; -. [Q61985-1]
DR ProteomicsDB; 287394; -. [Q61985-3]
DR ProteomicsDB; 287395; -. [Q61985-2]
DR Antibodypedia; 30234; 252 antibodies from 32 providers.
DR DNASU; 18023; -.
DR Ensembl; ENSMUST00000081775; ENSMUSP00000080467; ENSMUSG00000038615. [Q61985-1]
DR Ensembl; ENSMUST00000107657; ENSMUSP00000103284; ENSMUSG00000038615. [Q61985-1]
DR Ensembl; ENSMUST00000107658; ENSMUSP00000103285; ENSMUSG00000038615. [Q61985-1]
DR Ensembl; ENSMUST00000167110; ENSMUSP00000127804; ENSMUSG00000038615. [Q61985-3]
DR Ensembl; ENSMUST00000167149; ENSMUSP00000128527; ENSMUSG00000038615. [Q61985-1]
DR GeneID; 18023; -.
DR KEGG; mmu:18023; -.
DR UCSC; uc007lcq.2; mouse. [Q61985-1]
DR UCSC; uc011ydl.1; mouse. [Q61985-3]
DR CTD; 4779; -.
DR MGI; MGI:99421; Nfe2l1.
DR VEuPathDB; HostDB:ENSMUSG00000038615; -.
DR eggNOG; KOG3863; Eukaryota.
DR GeneTree; ENSGT00950000182892; -.
DR HOGENOM; CLU_024173_1_0_1; -.
DR InParanoid; Q61985; -.
DR OMA; LQAMDVN; -.
DR BioGRID-ORCS; 18023; 4 hits in 76 CRISPR screens.
DR ChiTaRS; Nfe2l1; mouse.
DR PRO; PR:Q61985; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q61985; protein.
DR Bgee; ENSMUSG00000038615; Expressed in hindlimb stylopod muscle and 267 other tissues.
DR ExpressionAtlas; Q61985; baseline and differential.
DR Genevisible; Q61985; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:MGI.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:CAFA.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:MGI.
DR GO; GO:0015485; F:cholesterol binding; IDA:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:1990841; F:promoter-specific chromatin binding; IDA:MGI.
DR GO; GO:0019904; F:protein domain specific binding; IPI:CAFA.
DR GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:CAFA.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:UniProtKB.
DR GO; GO:0019725; P:cellular homeostasis; IMP:MGI.
DR GO; GO:0071397; P:cellular response to cholesterol; IDA:UniProtKB.
DR GO; GO:0070417; P:cellular response to cold; IMP:MGI.
DR GO; GO:0071280; P:cellular response to copper ion; IMP:MGI.
DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; IDA:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0042883; P:cysteine transport; IMP:MGI.
DR GO; GO:0030218; P:erythrocyte differentiation; IMP:MGI.
DR GO; GO:0006002; P:fructose 6-phosphate metabolic process; IMP:MGI.
DR GO; GO:0021781; P:glial cell fate commitment; IDA:MGI.
DR GO; GO:0051156; P:glucose 6-phosphate metabolic process; IMP:MGI.
DR GO; GO:0006749; P:glutathione metabolic process; IMP:MGI.
DR GO; GO:0055088; P:lipid homeostasis; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0097201; P:negative regulation of transcription from RNA polymerase II promoter in response to stress; IDA:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0036003; P:positive regulation of transcription from RNA polymerase II promoter in response to stress; IDA:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IMP:MGI.
DR GO; GO:0019217; P:regulation of fatty acid metabolic process; IMP:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0010906; P:regulation of glucose metabolic process; IMP:MGI.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:MGI.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IMP:MGI.
DR GO; GO:0007088; P:regulation of mitotic nuclear division; IMP:MGI.
DR GO; GO:1903353; P:regulation of nucleus organization; IMP:MGI.
DR GO; GO:1901329; P:regulation of odontoblast differentiation; ISS:UniProtKB.
DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IMP:MGI.
DR GO; GO:1905897; P:regulation of response to endoplasmic reticulum stress; IMP:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:MGI.
DR GO; GO:0021522; P:spinal cord motor neuron differentiation; IMP:MGI.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR004826; bZIP_Maf.
DR InterPro; IPR029847; NFE2L1.
DR InterPro; IPR008917; TF_DNA-bd_sf.
DR PANTHER; PTHR24411:SF31; PTHR24411:SF31; 1.
DR Pfam; PF03131; bZIP_Maf; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW Activator; Alternative promoter usage; Alternative splicing;
KW Cholesterol metabolism; Cytoplasm; DNA-binding; Endoplasmic reticulum;
KW Glycoprotein; Lipid metabolism; Lipid-binding; Membrane; Nucleus;
KW Phosphoprotein; Reference proteome; Repressor; Signal-anchor;
KW Steroid metabolism; Sterol metabolism; Transcription;
KW Transcription regulation; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1..741
FT /note="Endoplasmic reticulum membrane sensor NFE2L1"
FT /id="PRO_0000076448"
FT CHAIN 104..741
FT /note="Transcription factor NRF1"
FT /evidence="ECO:0000250|UniProtKB:Q14494"
FT /id="PRO_0000443104"
FT TRANSMEM 7..24
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT DOMAIN 623..686
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 108..148
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 191..199
FT /note="Cholesterol recognition/amino acid consensus (CRAC)
FT region"
FT /evidence="ECO:0000269|PubMed:29149604"
FT REGION 198..220
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 350..354
FT /note="CPD"
FT /evidence="ECO:0000269|PubMed:21953459"
FT REGION 441..501
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 551..582
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 625..644
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 651..665
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 722..741
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 447..451
FT /note="Destruction motif"
FT /evidence="ECO:0000269|PubMed:21911472"
FT MOTIF 730..737
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 112..141
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 441..495
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 567..582
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 103..104
FT /note="Cleavage; by DDI2"
FT /evidence="ECO:0000250|UniProtKB:Q14494"
FT MOD_RES 497
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000269|PubMed:23816881"
FT MOD_RES 568
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14494"
FT CARBOHYD 319
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 331
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 394
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..158
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_000580"
FT VAR_SEQ 159..291
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_046523"
FT VAR_SEQ 159..170
FT /note="VAPPVSGDLTKE -> MGWESRLTAASA (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_046524"
FT VAR_SEQ 447..583
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_000581"
FT MUTAGEN 350..354
FT /note="Missing: Abolishes interaction with FBXW7."
FT /evidence="ECO:0000269|PubMed:21953459"
FT MUTAGEN 448..451
FT /note="SGLS->AGLA: Abolishes ubiquitination and degradation
FT by the SCF(BTRC) complex."
FT /evidence="ECO:0000269|PubMed:21911472"
FT MUTAGEN 496
FT /note="S->A: Does not affect phosphorylation by CK2."
FT /evidence="ECO:0000269|PubMed:23816881"
FT MUTAGEN 497
FT /note="S->A: Abolishes phosphorylation by CK2."
FT /evidence="ECO:0000269|PubMed:23816881"
FT MUTAGEN 499
FT /note="S->A: Does not affect phosphorylation by CK2."
FT /evidence="ECO:0000269|PubMed:23816881"
FT MUTAGEN 501
FT /note="T->A: Does not affect phosphorylation by CK2."
FT /evidence="ECO:0000269|PubMed:23816881"
FT CONFLICT 318
FT /note="T -> S (in Ref. 1; CAA55362)"
FT /evidence="ECO:0000305"
FT CONFLICT 387
FT /note="L -> P (in Ref. 1; CAA55362)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 741 AA; 81575 MW; DDB267F32CD2A92C CRC64;
MLSLKKYLTE GLLQFTILLS LIGVRVDVDT YLTSQLPPLR EIILGPSSAY TQTQFHNLRN
TLDGYGIHPK SIDLDNYFTA RRLLSQVRAL DRFQVPTTEV NAWLVHRDPE GSVSGSQPNS
GLALESSSGL QDVTGPDNGV RESETEQGFG EDLEDLGAVA PPVSGDLTKE DIDLIDILWR
QDIDLGAGRE VFDYSHRQKE QDVDKELQDG REREDTWSGE GAEALARDLL VDGETGESFP
AQFPADVSSI PEAVPSESES PALQNSLLSP LLTGTESPFD LEQQWQDLMS IMEMQAMEVN
TSASEILYNA PPGDPLSTNY SLAPNTPINQ NVSLHQASLG GCSQDFSLFS PEVESLPVAS
SSTLLPLVPS NSTSLNSTFG STNLAGLFFP SQLNGTANDT SGPELPDPLG GLLDEAMLDE
ISLMDLAIEE GFNPVQASQL EEEFDSDSGL SLDSSHSPSS LSSSEGSSSS SSSSSSSSAS
SSASSSFSEE GAVGYSSDSE TLDLEEAEGA VGYQPEYSKF CRMSYQDPSQ LSCLPYLEHV
GHNHTYNMAP SALDSADLPP PSTLKKGSKE KQADFLDKQM SRDEHRARAM KIPFTNDKII
NLPVEEFNEL LSKYQLSEAQ LSLIRDIRRR GKNKMAAQNC RKRKLDTILN LERDVEDLQR
DKARLLREKV EFLRSLRQMK QKVQSLYQEV FGRLRDEHGR PYSPSQYALQ YAGDGSVLLI
PRTMADQQAR RQERKPKDRR K
