NFE2L2

GeneName

NFE2L2

Summary

NFE2L2, commonly referred to as Nrf2, is a 68kDa transcription factor that plays a pivotal role in cellular defence against oxidative stress and xenobiotic insults. It is primarily localised in the cytoplasm and nucleus, and is involved in the regulation of various genes associated with the antioxidant response and detoxification pathways. Nrf2 binds to antioxidant response elements (AREs) in the promoter regions of target genes, facilitating their transcription in response to oxidative stress. This protein is also implicated in the regulation of several biological processes, including the cellular response to hypoxia, inflammation, and redox homeostasis, highlighting its importance in maintaining cellular health and function.

Importance

NFE2L2 is relevant to: - The development of therapies targeting oxidative stress-related diseases, such as cancer and neurodegenerative disorders, due to its role in regulating antioxidant responses. - The study of metabolic diseases, as it influences glucose metabolism and cellular responses to nutrient availability. - Research into cardiovascular health, given its involvement in the regulation of vascular smooth muscle cell migration and angiogenesis. - Understanding the mechanisms of inflammation and immune responses, as it modulates the expression of various cytokines and stress response genes.

Top Products

For researchers investigating NFE2L2, we highly recommend the top-selling recombinant antibody, Anti-Nrf2 antibody [EP1808Y] (ab62352). This well-cited antibody has garnered 753 citations, reflecting its strong reputation in the field. It has been validated in knockout models, ensuring reliable performance in various applications, including Western blotting (WB), immunocytochemistry (ICC), and flow cytometry (FC). This versatility makes it an excellent choice for those seeking consistent and effective detection of NFE2L2 in their experiments. The Anti-Nrf2 antibody ELISA Kit (ab62352), supported by 753 citations, is an excellent option for researchers looking to accurately measure NFE2L2 levels in their samples.

Abcam Product Citation Summary

The data indicates that NFE2L2 is extensively studied across various species, particularly in human and rat models, with a strong emphasis on its role in oxidative stress, inflammation, and cancer. The use of Abcam antibodies in Western blotting highlights the importance of NFE2L2 in diverse biological contexts, including COPD, drug resistance, and neuroprotection. The findings suggest a significant interest in understanding the regulatory mechanisms involving NFE2L2 in both health and disease.

Abcam Product Citation Table

Domain

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

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).

Involvement in disease

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.

Post-translational modifications

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).

Sequence Similarities

Belongs to the bZIP family. CNC subfamily.

Tissue Specificity

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

Cellular localization

• 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).

Alternative names

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

Database links

swissprot:Q16236 entrezGene:4780 omim:600492

Other research areas

• Epigenetics