UniProtKB - Q60795 (NF2L2_MOUSE)
Nuclear factor erythroid 2-related factor 2
Nfe2l2
Functioni
Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles (PubMed:9240432, PubMed:9887101, PubMed:12032331, PubMed:14517554, PubMed:31398338).
In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex (PubMed:15282312, PubMed:15367669, PubMed:15581590).
In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes (PubMed:12032331).
The NFE2L2/NRF2 pathway is also activated in response to selective autophagy: autophagy promotes interaction between KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of cytoprotective genes (PubMed:20421418, PubMed:20173742).
May also be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region (By similarity).
Plays also an important role in the regulation of the innate immune response. It is a critical regulator of the innate immune response and survival during sepsis by maintaining redox homeostasis and restraint of the dysregulation of proinflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling (PubMed:16585964).
Suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription and the induction of IL6 (PubMed:27211851).
Binds to the proximity of proinflammatory genes in macrophages and inhibits RNA Pol II recruitment. The inhibition is independent of the Nrf2-binding motif and reactive oxygen species level (PubMed:27211851).
Represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists while increasing susceptibility to infection with DNA viruses (By similarity).
By similarity12 PublicationsGO - Molecular functioni
- DNA binding Source: MGI
- DNA-binding transcription activator activity, RNA polymerase II-specific Source: NTNU_SB
- DNA-binding transcription factor activity Source: UniProtKB
- DNA-binding transcription factor activity, RNA polymerase II-specific Source: GO_Central
- protein domain specific binding Source: MGI
- RNA polymerase II cis-regulatory region sequence-specific DNA binding Source: NTNU_SB
- RNA polymerase II-specific DNA-binding transcription factor binding Source: MGI
- sequence-specific DNA binding Source: UniProtKB
- transcription cis-regulatory region binding Source: UniProtKB
- transcription coregulator binding Source: MGI
- transcription factor binding Source: UniProtKB
GO - Biological processi
- aflatoxin catabolic process Source: MGI
- aging Source: Ensembl
- cell redox homeostasis Source: ParkinsonsUK-UCL
- cellular response to angiotensin Source: MGI
- cellular response to copper ion Source: MGI
- cellular response to fluid shear stress Source: UniProtKB
- cellular response to glucose starvation Source: ParkinsonsUK-UCL
- cellular response to hydrogen peroxide Source: MGI
- cellular response to laminar fluid shear stress Source: MGI
- cellular response to oxidative stress Source: UniProtKB
- cellular response to tumor necrosis factor Source: MGI
- cellular response to xenobiotic stimulus Source: MGI
- endoplasmic reticulum unfolded protein response Source: MGI
- inflammatory response Source: MGI
- negative regulation of cardiac muscle cell apoptotic process Source: MGI
- negative regulation of cell death Source: MGI
- negative regulation of endothelial cell apoptotic process Source: MGI
- negative regulation of hematopoietic stem cell differentiation Source: CACAO
- negative regulation of hydrogen peroxide-induced cell death Source: MGI
- negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway Source: MGI
- negative regulation of vascular associated smooth muscle cell migration Source: MGI
- PERK-mediated unfolded protein response Source: ParkinsonsUK-UCL
- positive regulation of angiogenesis Source: MGI
- positive regulation of blood coagulation Source: BHF-UCL
- positive regulation of blood vessel endothelial cell migration Source: MGI
- positive regulation of gene expression Source: ParkinsonsUK-UCL
- positive regulation of glucose import Source: CACAO
- positive regulation of glutathione biosynthetic process Source: ParkinsonsUK-UCL
- positive regulation of neuron projection development Source: MGI
- positive regulation of reactive oxygen species metabolic process Source: BHF-UCL
- positive regulation of transcription, DNA-templated Source: MGI
- positive regulation of transcription by RNA polymerase II Source: NTNU_SB
- positive regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: MGI
- positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: MGI
- positive regulation of transcription from RNA polymerase II promoter in response to stress Source: MGI
- proteasomal ubiquitin-independent protein catabolic process Source: UniProtKB
- proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
- protein ubiquitination Source: UniProtKB
- regulation of embryonic development Source: MGI
- regulation of innate immune response Source: UniProtKB
- regulation of removal of superoxide radicals Source: BHF-UCL
- regulation of transcription, DNA-templated Source: MGI
- regulation of transcription by RNA polymerase II Source: GO_Central
- response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
- response to lithium ion Source: Ensembl
Keywordsi
Molecular function | Activator, DNA-binding |
Biological process | Transcription, Transcription regulation |
Enzyme and pathway databases
Reactomei | R-MMU-8932339, ROS sensing by NFE2L2 |
Names & Taxonomyi
Protein namesi | Recommended name: Nuclear factor erythroid 2-related factor 21 PublicationShort name: NF-E2-related factor 21 Publication Short name: NFE2-related factor 21 Publication Alternative name(s): Nuclear factor, erythroid derived 2, like 2 |
Gene namesi | |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:108420, Nfe2l2 |
VEuPathDBi | HostDB:ENSMUSG00000015839 |
Subcellular locationi
Cytoplasm and Cytosol
- cytosol 2 Publications
Nucleus
- Nucleus PROSITE-ProRule annotation3 Publications
Note: Cytosolic under unstressed conditions: ubiquitinated and degraded by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:15367669). Translocates into the nucleus upon induction by electrophilic agents that inactivate the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:14517554).2 Publications
Cytoskeleton
- centrosome Source: MGI
Cytosol
- cytosol Source: BHF-UCL
Golgi apparatus
- Golgi apparatus Source: MGI
Nucleus
- nucleoplasm Source: MGI
- nucleus Source: UniProtKB
- RNA polymerase II transcription regulator complex Source: Ensembl
Plasma Membrane
- plasma membrane Source: MGI
Other locations
- chromatin Source: BHF-UCL
- cytoplasm Source: UniProtKB
- protein-DNA complex Source: ParkinsonsUK-UCL
- transcription regulator complex Source: ParkinsonsUK-UCL
Keywords - Cellular componenti
Cytoplasm, NucleusPathology & Biotechi
Disruption phenotypei
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 18 – 23 | DLIDIL → ALIDIA: Does not affect ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm. 1 Publication | 6 | |
Mutagenesisi | 19 – 23 | LIDIL → AIDIA: Abolished ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm; when associated with A-30. 1 Publication | 5 | |
Mutagenesisi | 29 – 31 | DLG → AGE: Abolished ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm. 1 Publication | 3 | |
Mutagenesisi | 30 | L → A: Abolished ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm; when associated with 19-A--A-23. 1 Publication | 1 | |
Mutagenesisi | 79 – 82 | Missing : Abolished interaction with KEAP1. 3 Publications | 4 |
Chemistry databases
ChEMBLi | CHEMBL1075148 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000076450 | 1 – 597 | Nuclear factor erythroid 2-related factor 2Add BLAST | 597 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 40 | Phosphoserine; by PKCBy similarity | 1 | |
Modified residuei | 207 | PhosphoserineBy similarity | 1 | |
Glycosylationi | 454 | N-linked (Glc) (glycation) lysineBy similarity | 1 | |
Glycosylationi | 464 | N-linked (Glc) (glycation) lysineBy similarity | 1 | |
Glycosylationi | 479 | N-linked (Glc) (glycation) lysineBy similarity | 1 | |
Glycosylationi | 491 | N-linked (Glc) (glycation) arginineBy similarity | 1 | |
Glycosylationi | 561 | N-linked (Glc) (glycation) arginineBy similarity | 1 | |
Glycosylationi | 566 | N-linked (Glc) (glycation) lysineBy similarity | 1 | |
Modified residuei | 588 | N6-acetyllysine; by CREBBPBy similarity | 1 | |
Modified residuei | 591 | N6-acetyllysine; by CREBBPBy similarity | 1 |
Post-translational modificationi
Keywords - PTMi
Acetylation, Glycation, Glycoprotein, Phosphoprotein, Ubl conjugationProteomic databases
PaxDbi | Q60795 |
PRIDEi | Q60795 |
ProteomicsDBi | 287396 |
PTM databases
iPTMneti | Q60795 |
PhosphoSitePlusi | Q60795 |
Expressioni
Tissue specificityi
Gene expression databases
Bgeei | ENSMUSG00000015839, Expressed in urinary bladder urothelium and 336 other tissues |
Genevisiblei | Q60795, MM |
Interactioni
Subunit structurei
Heterodimer; heterodimerizes with small Maf proteins (PubMed:9240432).
Interacts (via the bZIP domain) with MAFG and MAFK; required for binding to antioxidant response elements (AREs) on DNA (PubMed:9240432, PubMed:31398338).
Interacts with KEAP1; the interaction is direct and promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:9887101, PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:16581765, PubMed:16507366).
Forms a ternary complex with PGAM5 and KEAP1 (By similarity).
Interacts with EEF1D at heat shock promoter elements (HSE) (By similarity).
Interacts via its leucine-zipper domain with the coiled-coil domain of PMF1 (PubMed:11583586).
Interacts with CHD6; involved in activation of the transcription (By similarity).
Interacts with ESRRB; represses NFE2L2 transcriptional activity (PubMed:17920186).
Interacts with MOTS-c, a peptide produced by the mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in the nucleus following metabolic stress (By similarity).
By similarity11 PublicationsBinary interactionsi
Q60795
With | #Exp. | IntAct |
---|---|---|
Arrb1 [Q8BWG8] | 4 | EBI-642563,EBI-641778 |
Keap1 [Q9Z2X8] | 23 | EBI-642563,EBI-647110 |
Pitx2 [P97474] | 2 | EBI-642563,EBI-1175125 |
GO - Molecular functioni
- protein domain specific binding Source: MGI
- RNA polymerase II-specific DNA-binding transcription factor binding Source: MGI
- transcription coregulator binding Source: MGI
- transcription factor binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 201744, 24 interactors |
CORUMi | Q60795 |
DIPi | DIP-49666N |
ELMi | Q60795 |
IntActi | Q60795, 5 interactors |
MINTi | Q60795 |
STRINGi | 10090.ENSMUSP00000099733 |
Chemistry databases
BindingDBi | Q60795 |
Miscellaneous databases
RNActi | Q60795, protein |
Structurei
Secondary structure
3D structure databases
SMRi | Q60795 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | Q60795 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 489 – 552 | bZIPPROSITE-ProRule annotationAdd BLAST | 64 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 327 – 440 | DisorderedSequence analysisAdd BLAST | 114 | |
Regioni | 491 – 510 | Basic motifPROSITE-ProRule annotationAdd BLAST | 20 | |
Regioni | 514 – 521 | Leucine-zipperPROSITE-ProRule annotation | 8 | |
Regioni | 563 – 597 | DisorderedSequence analysisAdd BLAST | 35 | |
Regioni | 583 – 588 | Mediates interaction with CHD6 and is necessary to activate transcriptionBy similarity | 6 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 29 – 31 | DLG motif3 Publications | 3 | |
Motifi | 79 – 82 | ETGE motif3 Publications | 4 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 331 – 351 | Polar residuesSequence analysisAdd BLAST | 21 | |
Compositional biasi | 393 – 423 | Polar residuesSequence analysisAdd BLAST | 31 |
Domaini
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG3863, Eukaryota |
GeneTreei | ENSGT00950000182892 |
HOGENOMi | CLU_498373_0_0_1 |
InParanoidi | Q60795 |
OMAi | PMDLYSL |
OrthoDBi | 1095280at2759 |
PhylomeDBi | Q60795 |
TreeFami | TF326681 |
Family and domain databases
DisProti | DP00968 |
IDEALi | IID50024 |
InterProi | View protein in InterPro IPR004827, bZIP IPR004826, bZIP_Maf IPR029845, Nrf2 IPR008917, TF_DNA-bd_sf |
PANTHERi | PTHR24411:SF3, PTHR24411:SF3, 1 hit |
Pfami | View protein in Pfam PF03131, bZIP_Maf, 1 hit |
SMARTi | View protein in SMART SM00338, BRLZ, 1 hit |
SUPFAMi | SSF47454, SSF47454, 1 hit |
PROSITEi | View protein in PROSITE PS50217, BZIP, 1 hit PS00036, BZIP_BASIC, 1 hit |
i Sequence
Sequence statusi: Complete.
10 20 30 40 50
MMDLELPPPG LQSQQDMDLI DILWRQDIDL GVSREVFDFS QRQKDYELEK
60 70 80 90 100
QKKLEKERQE QLQKEQEKAF FAQFQLDEET GEFLPIQPAQ HIQTDTSGSA
110 120 130 140 150
SYSQVAHIPK QDALYFEDCM QLLAETFPFV DDHESLALDI PSHAESSVFT
160 170 180 190 200
APHQAQSLNS SLEAAMTDLS SIEQDMEQVW QELFSIPELQ CLNTENKQLA
210 220 230 240 250
DTTAVPSPEA TLTEMDSNYH FYSSISSLEK EVGNCGPHFL HGFEDSFSSI
260 270 280 290 300
LSTDDASQLT SLDSNPTLNT DFGDEFYSAF IAEPSDGGSM PSSAAISQSL
310 320 330 340 350
SELLDGTIEG CDLSLCKAFN PKHAEGTMEF NDSDSGISLN TSPSRASPEH
360 370 380 390 400
SVESSIYGDP PPGFSDSEME ELDSAPGSVK QNGPKAQPAH SPGDTVQPLS
410 420 430 440 450
PAQGHSAPMR ESQCENTTKK EVPVSPGHQK APFTKDKHSS RLEAHLTRDE
460 470 480 490 500
LRAKALHIPF PVEKIINLPV DDFNEMMSKE QFNEAQLALI RDIRRRGKNK
510 520 530 540 550
VAAQNCRKRK LENIVELEQD LGHLKDEREK LLREKGENDR NLHLLKRRLS
560 570 580 590
TLYLEVFSML RDEDGKPYSP SEYSLQQTRD GNVFLVPKSK KPDTKKN
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U70475, U70474 Genomic DNA Translation: AAC52983.1 AK142347 mRNA Translation: BAE25040.1 AL772404 Genomic DNA No translation available. BC026943 mRNA Translation: AAH26943.1 U20532 mRNA Translation: AAA68291.1 |
CCDSi | CCDS16150.1 |
PIRi | I49261 |
RefSeqi | NP_035032.1, NM_010902.4 |
Genome annotation databases
Ensembli | ENSMUST00000102672; ENSMUSP00000099733; ENSMUSG00000015839 |
GeneIDi | 18024 |
KEGGi | mmu:18024 |
UCSCi | uc008keq.1, mouse |
Similar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U70475, U70474 Genomic DNA Translation: AAC52983.1 AK142347 mRNA Translation: BAE25040.1 AL772404 Genomic DNA No translation available. BC026943 mRNA Translation: AAH26943.1 U20532 mRNA Translation: AAA68291.1 |
CCDSi | CCDS16150.1 |
PIRi | I49261 |
RefSeqi | NP_035032.1, NM_010902.4 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
1X2R | X-ray | 1.70 | B | 76-84 | [»] | |
2DYH | X-ray | 1.90 | B | 22-36 | [»] | |
3WN7 | X-ray | 1.57 | B/M | 17-51 | [»] | |
SMRi | Q60795 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 201744, 24 interactors |
CORUMi | Q60795 |
DIPi | DIP-49666N |
ELMi | Q60795 |
IntActi | Q60795, 5 interactors |
MINTi | Q60795 |
STRINGi | 10090.ENSMUSP00000099733 |
Chemistry databases
BindingDBi | Q60795 |
ChEMBLi | CHEMBL1075148 |
PTM databases
iPTMneti | Q60795 |
PhosphoSitePlusi | Q60795 |
Proteomic databases
PaxDbi | Q60795 |
PRIDEi | Q60795 |
ProteomicsDBi | 287396 |
Protocols and materials databases
Antibodypediai | 903, 880 antibodies from 46 providers |
DNASUi | 18024 |
Genome annotation databases
Ensembli | ENSMUST00000102672; ENSMUSP00000099733; ENSMUSG00000015839 |
GeneIDi | 18024 |
KEGGi | mmu:18024 |
UCSCi | uc008keq.1, mouse |
Organism-specific databases
CTDi | 4780 |
MGIi | MGI:108420, Nfe2l2 |
VEuPathDBi | HostDB:ENSMUSG00000015839 |
Phylogenomic databases
eggNOGi | KOG3863, Eukaryota |
GeneTreei | ENSGT00950000182892 |
HOGENOMi | CLU_498373_0_0_1 |
InParanoidi | Q60795 |
OMAi | PMDLYSL |
OrthoDBi | 1095280at2759 |
PhylomeDBi | Q60795 |
TreeFami | TF326681 |
Enzyme and pathway databases
Reactomei | R-MMU-8932339, ROS sensing by NFE2L2 |
Miscellaneous databases
BioGRID-ORCSi | 18024, 5 hits in 69 CRISPR screens |
ChiTaRSi | Nfe2l2, mouse |
EvolutionaryTracei | Q60795 |
PROi | PR:Q60795 |
RNActi | Q60795, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSMUSG00000015839, Expressed in urinary bladder urothelium and 336 other tissues |
Genevisiblei | Q60795, MM |
Family and domain databases
DisProti | DP00968 |
IDEALi | IID50024 |
InterProi | View protein in InterPro IPR004827, bZIP IPR004826, bZIP_Maf IPR029845, Nrf2 IPR008917, TF_DNA-bd_sf |
PANTHERi | PTHR24411:SF3, PTHR24411:SF3, 1 hit |
Pfami | View protein in Pfam PF03131, bZIP_Maf, 1 hit |
SMARTi | View protein in SMART SM00338, BRLZ, 1 hit |
SUPFAMi | SSF47454, SSF47454, 1 hit |
PROSITEi | View protein in PROSITE PS50217, BZIP, 1 hit PS00036, BZIP_BASIC, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | NF2L2_MOUSE | |
Accessioni | Q60795Primary (citable) accession number: Q60795 Secondary accession number(s): Q3UQK0 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | July 15, 1999 |
Last sequence update: | January 1, 1998 | |
Last modified: | February 23, 2022 | |
This is version 184 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- MGD cross-references
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families