NFE2L2
entrez
4780
canonical
uniprot
Q16236
canonical
ensembl
ENSG00000116044
resolver
ensp
ENSP00000380252
resolver
ensp
ENSP00000380253
resolver
ensp
ENSP00000400073
resolver
ensp
ENSP00000411575
resolver
ensp
ENSP00000412191
resolver
ensp
ENSP00000514217
resolver
ensp
ENSP00000514280
resolver
enst
ENST00000699223
resolver
enst
ENST00000699300
resolver
genesymbol
NFE2L2
resolver
genesymbol_syn
NRF2
resolver
hgnc
HGNC:7782
resolver
uniprot
A0A8V8TN14
resolver
uniprot
A0A8V8TPA8
resolver
uniprot
B2RBU2
resolver
uniprot
B4E338
resolver
uniprot
E9PGJ7
resolver
uniprot
Q53RW6
resolver
uniprot
Q59HH2
resolver
uniprot
Q96F71
resolver
uniprot_entry
A0A8V8TN14_HUMAN
resolver
uniprot_entry
A0A8V8TPA8_HUMAN
resolver
uniprot_entry
NF2L2_HUMAN
resolver
uniprot_sec
B2RBU2
resolver
uniprot_sec
B4E338
resolver
uniprot_sec
E9PGJ7
resolver
uniprot_sec
Q53RW6
resolver
uniprot_sec
Q59HH2
resolver
uniprot_sec
Q96F71
resolver
activity_regulation
ACTIVITY REGULATION: Activated by cell derived metabolites including itaconate and fumarate. {ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:33009401}.; ACTIVITY REGULATION: (Microbial infection) Transcription factor activity on antioxidant target genes is significantly inhibited by SARS coronavirus-2/SARS-COV-2. {ECO:0000269|PubMed:29018201}.
uniprot
proteins
amino_acid_sequence
MMDLELPPPGLPSQQDMDLIDILWRQDIDLGVSREVFDFSQRRKEYELEKQKKLEKERQEQLQKEQEKAFFAQLQLDEETGEFLPIQPAQHIQSETSGSANYSQVAHIPKSDALYFDDCMQLLAQTFPFVDDNEVSSATFQSLVPDIPGHIESPVFIATNQAQSPETSVAQVAPVDLDGMQQDIEQVWEELLSIPELQCLNIENDKLVETTMVPSPEAKLTEVDNYHFYSSIPSMEKEVGNCSPHFLNAFEDSFSSILSTEDPNQLTVNSLNSDATVNTDFGDEFYSAFIAEPSISNSMPSPATLSHSLSELLNGPIDVSDLSLCKAFNQNHPESTAEFNDSDSGISLNTSPSVASPEHSVESSSYGDTLLGLSDSEVEELDSAPGSVKQNGPKTPVHSSGDMVQPLSPSQGQSTHVHDAQCENTPEKELPVSPGHRKTPFTKDKHSSRLEAHLTRDELRAKALHIPFPVEKIINLPVVDFNEMMSKEQFNEAQLALIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLDHLKDEKEKLLKEKGENDKSLHLLKKQLSTLYLEVFSMLRDEDGKPYSPSEYSLQQTRDGNVFLVPKSKKPDVKKN
uniprot
proteins
disease_involvement
DISEASE: Immunodeficiency, developmental delay, and hypohomocysteinemia (IMDDHH) [MIM:617744]: An early onset multisystem disorder characterized by immunodeficiency, recurrent infections, developmental delay, poor growth, intellectual disability, and hypohomocysteinemia. Some patients manifest congenital cardiac defects. IMDDHH inheritance pattern is autosomal dominant. {ECO:0000269|PubMed:29018201}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
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:11035812, PubMed:19489739, PubMed:29018201, PubMed:31398338). In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex (PubMed:11035812, PubMed:15601839, PubMed:29018201). 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:19489739, PubMed:29590092). 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:20452972). The NFE2L2/NRF2 pathway is also activated during the unfolded protein response (UPR), contributing to redox homeostasis and cell survival following endoplasmic reticulum stress (By similarity). 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 (PubMed:7937919). Also plays an important role in the regulation of the innate immune response and antiviral cytosolic DNA sensing. 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 signaling (By similarity). Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6 (By similarity). 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 (By similarity). 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 (PubMed:30158636). Once activated, limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and to virus-derived ligands through a mechanism that involves inhibition of IRF3 dimerization. Also inhibits both SARS-CoV-2 replication, as well as the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism (PubMed:33009401). {ECO:0000250|UniProtKB:Q60795, ECO:0000269|PubMed:11035812, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:29018201, ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:30158636, ECO:0000269|PubMed:31398338, ECO:0000269|PubMed:33009401, ECO:0000269|PubMed:7937919}.
uniprot
proteins
mass_dalton
67827
uniprot
proteins
mutagenesis
MUTAGEN 79..82; /note="Missing: Abolished interaction with KEAP1."; /evidence="ECO:0000269|PubMed:15601839"; MUTAGEN 80; /note="T->A: Loss of interaction with KEAP1."; /evidence="ECO:0000269|PubMed:16888629"; MUTAGEN 82; /note="E->G: Abolished interaction with KEAP1."; /evidence="ECO:0000269|PubMed:15601839"; MUTAGEN 462; /note="K->A: Loss of function; when associated with A-472; A-487; A-499; A-569 and A-587."; /evidence="ECO:0000269|PubMed:31398338"; MUTAGEN 472; /note="K->A: Loss of function; when associated with A-462; A-487; A-499; A-569 and A-587."; /evidence="ECO:0000269|PubMed:31398338"; MUTAGEN 487; /note="K->A: Loss of function; when associated with A-462; A-472; A-499; A-569 and A-587."; /evidence="ECO:0000269|PubMed:31398338"; MUTAGEN 499; /note="R->A: Loss of function; when associated with A-462; A-472; A-487; A-569 and A-587."; /evidence="ECO:0000269|PubMed:31398338"; MUTAGEN 569; /note="R->A: Loss of function; when associated with A-462; A-472; A-487; A-499 and A-587."; /evidence="ECO:0000269|PubMed:31398338"; MUTAGEN 587; /note="R->A: Loss of function; when associated with A-462; A-472; A-487; A-499 and A-569."; /evidence="ECO:0000269|PubMed:31398338
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin ligase complex leading to its degradation (PubMed:15601839, PubMed:15983046, PubMed:19489739). 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:19489739, PubMed:29590092). In response to autophagy, the BCR(KEAP1) complex is inactivated (By similarity). {ECO:0000250|UniProtKB:Q60795, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:29590092}.; PTM: Phosphorylated by EIF2AK3/PERK following unfolded protein response (UPR), promoting dissociation from its cytoplasmic inhibitor KEAP1, followed by its translocation into the nucleus (By similarity). Phosphorylation of Ser-40 by PKC in response to oxidative stress dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its translocation into the nucleus (By similarity). {ECO:0000250|UniProtKB:O54968, ECO:0000250|UniProtKB:Q60795}.; PTM: Acetylation at Lys-596 and Lys-599 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence. {ECO:0000269|PubMed:21196497}.; 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}.
uniprot
proteins
protein_family
BZIP family
uniprot
proteins
protein_family
CNC subfamily
uniprot
proteins
pubmed
11035812
uniprot
proteins
pubmed
11256947
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15601839
uniprot
proteins
pubmed
15815621
uniprot
proteins
pubmed
15983046
uniprot
proteins
pubmed
16888629
uniprot
proteins
pubmed
17974005
uniprot
proteins
pubmed
18387606
uniprot
proteins
pubmed
19424503
uniprot
proteins
pubmed
19489739
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20452972
uniprot
proteins
pubmed
21196497
uniprot
proteins
pubmed
21597468
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
25995248
uniprot
proteins
pubmed
28842501
uniprot
proteins
pubmed
29018201
uniprot
proteins
pubmed
29590092
uniprot
proteins
pubmed
29983246
uniprot
proteins
pubmed
30158636
uniprot
proteins
pubmed
31398338
uniprot
proteins
pubmed
33009401
uniprot
proteins
pubmed
33087717
uniprot
proteins
pubmed
7937919
uniprot
proteins
sequence_length
605
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:11035812, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:21196497}. Nucleus {ECO:0000255|PROSITE-ProRule:PRU00978, ECO:0000269|PubMed:11035812, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:21196497, ECO:0000269|PubMed:29983246}. Note=Cytosolic under unstressed conditions: ubiquitinated and degraded by the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:15601839, PubMed:21196497). Translocates into the nucleus upon induction by electrophilic agents that inactivate the BCR(KEAP1) E3 ubiquitin ligase complex (PubMed:21196497). {ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:21196497}.
uniprot
proteins