UniProt functional annotation for Q60795



	UniProt functional annotation for Q60795

UniProt code: Q60795.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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: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). {ECO:0000250|UniProtKB:Q16236, ECO:0000269|PubMed:12032331, ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:31398338, ECO:0000269|PubMed:9240432, ECO:0000269|PubMed:9887101}.

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: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). {ECO:0000250|UniProtKB:O54968, ECO:0000250|UniProtKB:Q16236, ECO:0000269|PubMed:11583586, ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:16507366, ECO:0000269|PubMed:16581765, ECO:0000269|PubMed:16790436, ECO:0000269|PubMed:17920186, ECO:0000269|PubMed:31398338, ECO:0000269|PubMed:9240432, ECO:0000269|PubMed:9887101}.

Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:9887101}. Nucleus {ECO:0000255|PROSITE- ProRule:PRU00978, ECO:0000269|PubMed:12032331, ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:9887101}. 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). {ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:15367669}.

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.

Domain: The ETGE motif, and to a lower extent the DLG motif, mediate interaction with KEAP1. {ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:16581765, ECO:0000269|PubMed:16790436}.

Ptm: 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). {ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:16790436, ECO:0000269|PubMed:20421418}.

Ptm: Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus. {ECO:0000250|UniProtKB:O54968}.

Ptm: Acetylation at Lys-588 and Lys-591 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence. {ECO:0000250|UniProtKB:Q16236}.

Ptm: Glycation impairs transcription factor activity by preventing heterodimerization with small Maf proteins (PubMed:31398338). Deglycation by FN3K restores activity (PubMed:31398338). {ECO:0000269|PubMed:31398338}.

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:9240432, PubMed:11248092, PubMed:12032331). 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). {ECO:0000269|PubMed:11248092, ECO:0000269|PubMed:12032331, ECO:0000269|PubMed:12968018, ECO:0000269|PubMed:14517554, ECO:0000269|PubMed:9240432}.

Similarity: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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: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). {ECO:0000250\|UniProtKB:Q16236, ECO:0000269\|PubMed:12032331, ECO:0000269\|PubMed:14517554, ECO:0000269\|PubMed:15282312, ECO:0000269\|PubMed:15367669, ECO:0000269\|PubMed:15581590, ECO:0000269\|PubMed:20173742, ECO:0000269\|PubMed:20421418, ECO:0000269\|PubMed:31398338, ECO:0000269\|PubMed:9240432, ECO:0000269\|PubMed:9887101}.


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: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). {ECO:0000250\|UniProtKB:O54968, ECO:0000250\|UniProtKB:Q16236, ECO:0000269\|PubMed:11583586, ECO:0000269\|PubMed:15282312, ECO:0000269\|PubMed:15367669, ECO:0000269\|PubMed:15581590, ECO:0000269\|PubMed:16507366, ECO:0000269\|PubMed:16581765, ECO:0000269\|PubMed:16790436, ECO:0000269\|PubMed:17920186, ECO:0000269\|PubMed:31398338, ECO:0000269\|PubMed:9240432, ECO:0000269\|PubMed:9887101}.
Subcellular location:		Cytoplasm, cytosol {ECO:0000269\|PubMed:15367669, ECO:0000269\|PubMed:9887101}. Nucleus {ECO:0000255\|PROSITE- ProRule:PRU00978, ECO:0000269\|PubMed:12032331, ECO:0000269\|PubMed:14517554, ECO:0000269\|PubMed:9887101}. 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). {ECO:0000269\|PubMed:14517554, ECO:0000269\|PubMed:15367669}.
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.
Domain:		The ETGE motif, and to a lower extent the DLG motif, mediate interaction with KEAP1. {ECO:0000269\|PubMed:15282312, ECO:0000269\|PubMed:15581590, ECO:0000269\|PubMed:16581765, ECO:0000269\|PubMed:16790436}.
Ptm:		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). {ECO:0000269\|PubMed:15282312, ECO:0000269\|PubMed:15367669, ECO:0000269\|PubMed:15581590, ECO:0000269\|PubMed:16790436, ECO:0000269\|PubMed:20421418}.
Ptm:		Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus. {ECO:0000250\|UniProtKB:O54968}.
Ptm:		Acetylation at Lys-588 and Lys-591 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence. {ECO:0000250\|UniProtKB:Q16236}.
Ptm:		Glycation impairs transcription factor activity by preventing heterodimerization with small Maf proteins (PubMed:31398338). Deglycation by FN3K restores activity (PubMed:31398338). {ECO:0000269\|PubMed:31398338}.
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:9240432, PubMed:11248092, PubMed:12032331). 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). {ECO:0000269\|PubMed:11248092, ECO:0000269\|PubMed:12032331, ECO:0000269\|PubMed:12968018, ECO:0000269\|PubMed:14517554, ECO:0000269\|PubMed:9240432}.
Similarity:		Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.