NF2L2_RAT
ID NF2L2_RAT Reviewed; 604 AA.
AC O54968; Q6P7C8;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 2.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|PubMed:12198130};
DE Short=NF-E2-related factor 2 {ECO:0000303|PubMed:12198130};
DE Short=NFE2-related factor 2 {ECO:0000303|PubMed:12198130};
DE AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000250|UniProtKB:Q16236};
GN Name=Nfe2l2 {ECO:0000312|RGD:620360};
GN Synonyms=Nrf2 {ECO:0000303|PubMed:12198130};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC STRAIN=Wistar; TISSUE=Liver;
RA Sakai M., Ito M., Sasaki K., Nishi S.;
RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Prostate;
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 [3]
RP PHOSPHORYLATION AT SER-40, AND MUTAGENESIS OF SER-40.
RX PubMed=12198130; DOI=10.1074/jbc.m206911200;
RA Huang H.-C., Nguyen T., Pickett C.B.;
RT "Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates
RT antioxidant response element-mediated transcription.";
RL J. Biol. Chem. 277:42769-42774(2002).
RN [4]
RP FUNCTION, INTERACTION WITH CHD6 AND MAFK, SUBCELLULAR LOCATION, AND REGION.
RX PubMed=16314513; DOI=10.1128/mcb.25.24.10895-10906.2005;
RA Nioi P., Nguyen T., Sherratt P.J., Pickett C.B.;
RT "The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional
RT activation.";
RL Mol. Cell. Biol. 25:10895-10906(2005).
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:16314513). In normal
CC conditions, ubiquitinated and degraded in the cytoplasm by the
CC BCR(KEAP1) complex. In response to oxidative stress, electrophile
CC metabolites inhibit activity of the BCR(KEAP1) complex, promoting
CC nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the
CC small Maf proteins and binding to ARE elements of cytoprotective target
CC genes. The NFE2L2/NRF2 pathway is also activated in response to
CC selective autophagy: autophagy promotes interaction between KEAP1 and
CC SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex,
CC leading to NFE2L2/NRF2 nuclear accumulation and expression of
CC cytoprotective genes (By similarity). 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 (By similarity). Also plays an important role in
CC the regulation of the innate immune response. It is a critical
CC regulator of the innate immune response and survival during sepsis by
CC maintaining redox homeostasis and restraint of the dysregulation of
CC pro-inflammatory signaling pathways like MyD88-dependent and
CC -independent and TNF-alpha signaling. Suppresses macrophage
CC inflammatory response by blocking pro-inflammatory cytokine
CC transcription and the induction of IL6. Binds to the proximity of pro-
CC inflammatory genes in macrophages and inhibits RNA Pol II recruitment.
CC The inhibition is independent of the Nrf2-binding motif and reactive
CC oxygen species level (By similarity). Represses antiviral cytosolic DNA
CC sensing by suppressing the expression of the adapter protein STING1 and
CC decreasing responsiveness to STING1 agonists while increasing
CC susceptibility to infection with DNA viruses (By similarity).
CC {ECO:0000250|UniProtKB:Q16236, ECO:0000250|UniProtKB:Q60795,
CC ECO:0000269|PubMed:16314513}.
CC -!- SUBUNIT: Heterodimer; heterodimerizes with small Maf proteins
CC (PubMed:16314513). Interacts (via the bZIP domain) with MAFG and MAFK;
CC required for binding to antioxidant response elements (AREs) on DNA
CC (PubMed:16314513). Interacts with KEAP1; the interaction is direct and
CC promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex
CC (By similarity). Forms a ternary complex with PGAM5 and KEAP1.
CC Interacts with EEF1D at heat shock promoter elements (HSE) (By
CC similarity). Interacts via its leucine-zipper domain with the coiled-
CC coil domain of PMF1 (By similarity). Interacts with CHD6; involved in
CC activation of the transcription (PubMed:16314513). Interacts with
CC ESRRB; represses NFE2L2 transcriptional activity (By similarity).
CC Interacts with MOTS-c, a peptide produced by the mitochondrially
CC encoded 12S rRNA MT-RNR1; the interaction occurs in the nucleus
CC following metabolic stress (By similarity).
CC {ECO:0000250|UniProtKB:Q16236, ECO:0000250|UniProtKB:Q60795,
CC ECO:0000269|PubMed:16314513}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q60795}. Nucleus {ECO:0000255|PROSITE-
CC ProRule:PRU00978, ECO:0000269|PubMed:16314513}. Note=Cytosolic under
CC unstressed conditions: ubiquitinated and degraded by the BCR(KEAP1) E3
CC ubiquitin ligase complex. Translocates into the nucleus upon induction
CC by electrophilic agents that inactivate the BCR(KEAP1) E3 ubiquitin
CC ligase complex. {ECO:0000250|UniProtKB:Q60795}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O54968-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O54968-2; Sequence=VSP_025046;
CC -!- DOMAIN: The ETGE motif, and to a lower extent the DLG motif, mediate
CC interaction with KEAP1. {ECO:0000250|UniProtKB:Q60795}.
CC -!- PTM: Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin
CC ligase complex leading to its degradation. In response to oxidative
CC stress, electrophile metabolites, such as sulforaphane, modify KEAP1,
CC leading to inhibit activity of the BCR(KEAP1) complex, promoting
CC NFE2L2/NRF2 nuclear accumulation and activity. In response to
CC autophagy, the BCR(KEAP1) complex is inactivated.
CC {ECO:0000250|UniProtKB:Q60795}.
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:0000269|PubMed:12198130}.
CC -!- PTM: Acetylation at Lys-595 and Lys-598 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. Deglycation by FN3K
CC restores activity. {ECO:0000250|UniProtKB:Q16236}.
CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF037350; AAB92256.1; -; mRNA.
DR EMBL; BC061724; AAH61724.1; -; mRNA.
DR RefSeq; NP_113977.1; NM_031789.2. [O54968-2]
DR RefSeq; XP_006234458.1; XM_006234396.3. [O54968-1]
DR AlphaFoldDB; O54968; -.
DR SMR; O54968; -.
DR BioGRID; 249784; 2.
DR STRING; 10116.ENSRNOP00000002114; -.
DR ChEMBL; CHEMBL1075141; -.
DR iPTMnet; O54968; -.
DR PhosphoSitePlus; O54968; -.
DR PaxDb; O54968; -.
DR Ensembl; ENSRNOT00000002114; ENSRNOP00000002114; ENSRNOG00000001548. [O54968-1]
DR GeneID; 83619; -.
DR KEGG; rno:83619; -.
DR UCSC; RGD:620360; rat. [O54968-1]
DR CTD; 4780; -.
DR RGD; 620360; Nfe2l2.
DR eggNOG; KOG3863; Eukaryota.
DR GeneTree; ENSGT00950000182892; -.
DR InParanoid; O54968; -.
DR OMA; PMDLYSL; -.
DR OrthoDB; 1095280at2759; -.
DR PhylomeDB; O54968; -.
DR Reactome; R-RNO-8951664; Neddylation.
DR Reactome; R-RNO-9755511; KEAP1-NFE2L2 pathway.
DR Reactome; R-RNO-9759194; Nuclear events mediated by NFE2L2.
DR Reactome; R-RNO-9762114; GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2.
DR PRO; PR:O54968; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000001548; Expressed in stomach and 20 other tissues.
DR GO; GO:0005813; C:centrosome; IEA:Ensembl.
DR GO; GO:0000785; C:chromatin; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0032993; C:protein-DNA complex; ISO:RGD.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS: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:RGD.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0001221; F:transcription coregulator binding; IPI:UniProtKB.
DR GO; GO:0046223; P:aflatoxin catabolic process; IMP:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0045454; P:cell redox homeostasis; ISS:UniProtKB.
DR GO; GO:1904385; P:cellular response to angiotensin; IDA:RGD.
DR GO; GO:0071280; P:cellular response to copper ion; ISO:RGD.
DR GO; GO:0071498; P:cellular response to fluid shear stress; ISS:UniProtKB.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISO:RGD.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISO:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:RGD.
DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; ISO:RGD.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEP:RGD.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; ISO:RGD.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; ISO:RGD.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:RGD.
DR GO; GO:0060548; P:negative regulation of cell death; IMP:RGD.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; ISO:RGD.
DR GO; GO:1902037; P:negative regulation of hematopoietic stem cell differentiation; ISO:RGD.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; ISO:RGD.
DR GO; GO:1902176; P:negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:1904753; P:negative regulation of vascular associated smooth muscle cell migration; IMP:RGD.
DR GO; GO:0036499; P:PERK-mediated unfolded protein response; ISO:RGD.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:RGD.
DR GO; GO:0030194; P:positive regulation of blood coagulation; ISO:RGD.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:RGD.
DR GO; GO:0046326; P:positive regulation of glucose import; ISO:RGD.
DR GO; GO:1903788; P:positive regulation of glutathione biosynthetic process; ISO:RGD.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0061419; P:positive regulation of transcription from RNA polymerase II promoter in response to hypoxia; ISO:RGD.
DR GO; GO:0036091; P:positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress; IMP:UniProtKB.
DR GO; GO:0036003; P:positive regulation of transcription from RNA polymerase II promoter in response to stress; ISO:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:2000121; P:regulation of removal of superoxide radicals; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISO:RGD.
DR GO; GO:0010226; P:response to lithium ion; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
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 Acetylation; Activator; Alternative splicing; Cytoplasm; DNA-binding;
KW Glycation; Glycoprotein; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..604
FT /note="Nuclear factor erythroid 2-related factor 2"
FT /id="PRO_0000076451"
FT DOMAIN 496..559
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 334..447
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 498..517
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 521..528
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 570..604
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 590..595
FT /note="Mediates interaction with CHD6 and is necessary to
FT activate transcription"
FT /evidence="ECO:0000269|PubMed:16314513"
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..358
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 387..430
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 40
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000269|PubMed:12198130"
FT MOD_RES 214
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MOD_RES 595
FT /note="N6-acetyllysine; by CREBBP"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MOD_RES 598
FT /note="N6-acetyllysine; by CREBBP"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 461
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 471
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 486
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 498
FT /note="N-linked (Glc) (glycation) arginine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 568
FT /note="N-linked (Glc) (glycation) arginine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 573
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT VAR_SEQ 135..141
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_025046"
FT MUTAGEN 40
FT /note="S->A: Fails to dissociate from KEAP1 after PKC
FT activation."
FT /evidence="ECO:0000269|PubMed:12198130"
SQ SEQUENCE 604 AA; 67703 MW; A07478F07F0C90B2 CRC64;
MMDLELPPPG LQSQQDMDLI DILWRQDIDL GVSREVFDFS QRQKDYELEK QKKLEKERQE
QLQKEQEKAF FAQLQLDEET GEFLPIQPAQ HIQTDTSGSV SYSQVAHIPK QDALYFEDCM
QLLAETFPFV DDHEVSSPTF QSLALDIPSH VESSVFTTPD QAQSLDSSLE TAMTDLSSIQ
QDMEQVWQEL FSIPELQCLN TENKQQAETT TVPSPEATLT EMDSNYHFYS SIPSLEKEVD
SCSPHFLHGF EDSFSSILST DDASQLNSLD SNPTLNTDFG DEFYSAFLAE PSGGGSMPSS
AAISQSLSEL LGGPIEGCDL SLCKAFNQKH TEGTVEFNDS DSGISLNTSP SRASPEHSVE
SSIYGDPPPG FSDSEMEELD SAPGSVKQNG PKAQPTHSSG DTVQPLSPAQ GHSAAVHESQ
CENTTKKEVP VSPGHQKVPF TKDKHSSRLE AHLTRDELRA KALHIPFPVE KIINLPVDDF
NEMMSKEQFN EAQLALIRDI RRRGKNKVAA QNCRKRKLEN IVELEQDLGH LKDEREKLLR
EKGENDRNLH LLKRKLSTLY LEVFSMLRDE DGKPYSPSEY SLQQTRDGNV FLVPKSKKPD
TKKN
