NFE2L2

The ETGE motif, and to a lower extent the DLG motif, mediate interaction with KEAP1.

The protein expressed by the NFE2L2 gene functions as a transcription factor that plays a key role in responding to oxidative stress by binding to antioxidant response elements (ARE) in the promoter regions of various cytoprotective genes, such as phase 2 detoxifying enzymes, to promote their expression and neutralize reactive electrophiles. Under normal conditions, it is ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. However, oxidative stress leads to the inhibition of the BCR(KEAP1) complex, allowing NFE2L2/NRF2 to accumulate in the nucleus, form heterodimers with small Maf proteins, and bind to ARE elements. Additionally, the NFE2L2/NRF2 pathway is activated by selective autophagy, where KEAP1 interacts with SQSTM1/p62, inactivating the BCR(KEAP1) complex and leading to nuclear NFE2L2/NRF2 accumulation and cytoprotective gene expression. It may also be involved in activating genes of the beta-globin cluster by facilitating enhancer activity of hypersensitive site 2 of the beta-globin locus control region. This supplementary information is collated from multiple sources and compiled automatically.

Immunodeficiency, developmental delay, and hypohomocysteinemia

IMDDHH

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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).

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).

Acetylation at Lys-596 and Lys-599 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).

Belongs to the bZIP family. CNC subfamily.

Widely expressed. Highest expression in adult muscle, kidney, lung, liver and in fetal muscle.

• Cytoplasm
• Cytosol
• Nucleus
• 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).

NRF2, NFE2L2, Nuclear factor erythroid 2-related factor 2, NF-E2-related factor 2, NFE2-related factor 2, Nrf-2

• entrezGene:4780
• omim:600492
• swissprot:Q16236

Proteins

Neuroscience

• Epigenetics

67827Da