Q60795 · NF2L2_MOUSE
- ProteinNuclear factor erythroid 2-related factor 2
- GeneNfe2l2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids597 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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:12032331, PubMed:14517554, PubMed:31398338, PubMed:9240432, PubMed:9887101).
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:20173742, PubMed:20421418).
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).
Also plays 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 pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling (PubMed:16585964).
Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (PubMed:27211851).
Binds to the proximity of pro-inflammatory 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).
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:20173742, PubMed:20421418).
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).
Also plays 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 pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling (PubMed:16585964).
Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (PubMed:27211851).
Binds to the proximity of pro-inflammatory 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).
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameNuclear factor erythroid 2-related factor 2
- Short namesNF-E2-related factor 2 ; NFE2-related factor 2
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ60795
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Mice are viable and fertile but have low and uninducible phase 2 detoxifying enzymes, are much more susceptible to carcinogens and the toxicity of oxygen and electrophiles and cannot be protected by inducers (PubMed:11248092, PubMed:12032331, PubMed:9240432).
Mutant mice show an increased mortality during LPS and cecal ligation and puncture-induced septic shock compared to wild-types. They show greater pulmonary inflammation and greater TNF secretion upon LPS administration (PubMed:16585964).
Mice lacking both Nfe2l2/Nrf2 and Keap1 reverse the hyperkeratosis phenotype observed in Keap1 knockout: mice and are healthy and viable in normal conditions (PubMed:14517554).
Mice lacking both Nfe2l1 and Nfe2l2 die early between embryonic days 9 and 10 and exhibit extensive apoptosis due to marked oxidative stress in cells that is indicated by elevated intracellular reactive oxygen species levels and cell death (PubMed:12968018).
Mutant mice show an increased mortality during LPS and cecal ligation and puncture-induced septic shock compared to wild-types. They show greater pulmonary inflammation and greater TNF secretion upon LPS administration (PubMed:16585964).
Mice lacking both Nfe2l2/Nrf2 and Keap1 reverse the hyperkeratosis phenotype observed in Keap1 knockout: mice and are healthy and viable in normal conditions (PubMed:14517554).
Mice lacking both Nfe2l1 and Nfe2l2 die early between embryonic days 9 and 10 and exhibit extensive apoptosis due to marked oxidative stress in cells that is indicated by elevated intracellular reactive oxygen species levels and cell death (PubMed:12968018).
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 18-23 | Does not affect ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm. | ||||
Sequence: DLIDIL → ALIDIA | ||||||
Mutagenesis | 19-23 | Abolished ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm; when associated with A-30. | ||||
Sequence: LIDIL → AIDIA | ||||||
Mutagenesis | 29-31 | Abolished ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm. | ||||
Sequence: DLG → AGE | ||||||
Mutagenesis | 30 | Abolished ubiquitination and degradation by the BCR(KEAP1) complex in the cytoplasm; when associated with 19-A--A-23. | ||||
Sequence: L → A | ||||||
Mutagenesis | 79-82 | Abolished interaction with KEAP1. | ||||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 44 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000076450 | 1-597 | Nuclear factor erythroid 2-related factor 2 | |||
Sequence: MMDLELPPPGLQSQQDMDLIDILWRQDIDLGVSREVFDFSQRQKDYELEKQKKLEKERQEQLQKEQEKAFFAQFQLDEETGEFLPIQPAQHIQTDTSGSASYSQVAHIPKQDALYFEDCMQLLAETFPFVDDHESLALDIPSHAESSVFTAPHQAQSLNSSLEAAMTDLSSIEQDMEQVWQELFSIPELQCLNTENKQLADTTAVPSPEATLTEMDSNYHFYSSISSLEKEVGNCGPHFLHGFEDSFSSILSTDDASQLTSLDSNPTLNTDFGDEFYSAFIAEPSDGGSMPSSAAISQSLSELLDGTIEGCDLSLCKAFNPKHAEGTMEFNDSDSGISLNTSPSRASPEHSVESSIYGDPPPGFSDSEMEELDSAPGSVKQNGPKAQPAHSPGDTVQPLSPAQGHSAPMRESQCENTTKKEVPVSPGHQKAPFTKDKHSSRLEAHLTRDELRAKALHIPFPVEKIINLPVDDFNEMMSKEQFNEAQLALIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLGHLKDEREKLLREKGENDRNLHLLKRRLSTLYLEVFSMLRDEDGKPYSPSEYSLQQTRDGNVFLVPKSKKPDTKKN | ||||||
Modified residue | 40 | Phosphoserine; by PKC | ||||
Sequence: S | ||||||
Modified residue | 207 | Phosphoserine | ||||
Sequence: S | ||||||
Glycosylation | 454 | N-linked (Glc) (glycation) lysine | ||||
Sequence: K | ||||||
Glycosylation | 464 | N-linked (Glc) (glycation) lysine | ||||
Sequence: K | ||||||
Glycosylation | 479 | N-linked (Glc) (glycation) lysine | ||||
Sequence: K | ||||||
Glycosylation | 491 | N-linked (Glc) (glycation) arginine | ||||
Sequence: R | ||||||
Glycosylation | 561 | N-linked (Glc) (glycation) arginine | ||||
Sequence: R | ||||||
Glycosylation | 566 | N-linked (Glc) (glycation) lysine | ||||
Sequence: K | ||||||
Modified residue | 588 | N6-acetyllysine; by CREBBP | ||||
Sequence: K | ||||||
Modified residue | 591 | N6-acetyllysine; by CREBBP | ||||
Sequence: K |
Post-translational modification
Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin ligase complex leading to its degradation (PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:20421418).
In response to oxidative stress, electrophile metabolites, such as sulforaphane, modify KEAP1, leading to inhibit activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and activity (PubMed:15367669).
In response to autophagy, the BCR(KEAP1) complex is inactivated (PubMed:20421418).
In response to oxidative stress, electrophile metabolites, such as sulforaphane, modify KEAP1, leading to inhibit activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and activity (PubMed:15367669).
In response to autophagy, the BCR(KEAP1) complex is inactivated (PubMed:20421418).
Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus.
Acetylation at Lys-588 and Lys-591 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence.
Glycation impairs transcription factor activity by preventing heterodimerization with small Maf proteins (PubMed:31398338).
Deglycation by FN3K restores activity (PubMed:31398338).
Deglycation by FN3K restores activity (PubMed:31398338).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed. Highest expression in liver, skeletal muscle, luminal cells of the stomach and intestine, lining of the bronchi and alveoli, and in renal tubules; followed by heart, spleen, testis and brain.
Gene expression databases
Interaction
Subunit
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:31398338, PubMed:9240432).
Interacts with KEAP1; the interaction is direct and promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:16507366, PubMed:16581765, PubMed:16790436, PubMed:9887101).
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).
Interacts (via the bZIP domain) with MAFG and MAFK; required for binding to antioxidant response elements (AREs) on DNA (PubMed:31398338, PubMed:9240432).
Interacts with KEAP1; the interaction is direct and promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:16507366, PubMed:16581765, PubMed:16790436, PubMed:9887101).
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).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q60795 | Arrb1 Q8BWG8 | 4 | EBI-642563, EBI-641778 | |
BINARY | Q60795 | Keap1 Q9Z2X8 | 25 | EBI-642563, EBI-647110 | |
BINARY | Q60795 | Pitx2 P97474 | 2 | EBI-642563, EBI-1175125 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for motif, region, compositional bias, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Motif | 29-31 | DLG motif | ||||
Sequence: DLG | ||||||
Motif | 79-82 | ETGE motif | ||||
Sequence: ETGE | ||||||
Region | 327-440 | Disordered | ||||
Sequence: TMEFNDSDSGISLNTSPSRASPEHSVESSIYGDPPPGFSDSEMEELDSAPGSVKQNGPKAQPAHSPGDTVQPLSPAQGHSAPMRESQCENTTKKEVPVSPGHQKAPFTKDKHSS | ||||||
Compositional bias | 331-351 | Polar residues | ||||
Sequence: NDSDSGISLNTSPSRASPEHS | ||||||
Compositional bias | 393-423 | Polar residues | ||||
Sequence: GDTVQPLSPAQGHSAPMRESQCENTTKKEVP | ||||||
Domain | 489-552 | bZIP | ||||
Sequence: LIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLGHLKDEREKLLREKGENDRNLHLLKRRLSTL | ||||||
Region | 491-510 | Basic motif | ||||
Sequence: RDIRRRGKNKVAAQNCRKRK | ||||||
Region | 514-521 | Leucine-zipper | ||||
Sequence: IVELEQDL | ||||||
Region | 563-597 | Disordered | ||||
Sequence: EDGKPYSPSEYSLQQTRDGNVFLVPKSKKPDTKKN | ||||||
Region | 583-588 | Mediates interaction with CHD6 and is necessary to activate transcription | ||||
Sequence: VFLVPK |
Domain
The ETGE motif, and to a lower extent the DLG motif, mediate interaction with KEAP1.
Sequence similarities
Belongs to the bZIP family. CNC subfamily.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length597
- Mass (Da)66,901
- Last updated1998-01-01 v2
- Checksum6128707C82CAE239
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 331-351 | Polar residues | ||||
Sequence: NDSDSGISLNTSPSRASPEHS | ||||||
Compositional bias | 393-423 | Polar residues | ||||
Sequence: GDTVQPLSPAQGHSAPMRESQCENTTKKEVP |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
U70475 EMBL· GenBank· DDBJ | AAC52983.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
U70474 EMBL· GenBank· DDBJ | AAC52983.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AK142347 EMBL· GenBank· DDBJ | BAE25040.1 EMBL· GenBank· DDBJ | mRNA | ||
AL772404 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC026943 EMBL· GenBank· DDBJ | AAH26943.1 EMBL· GenBank· DDBJ | mRNA | ||
U20532 EMBL· GenBank· DDBJ | AAA68291.1 EMBL· GenBank· DDBJ | mRNA |