NFE2L2
Description
The NFE2L2 (NFE2 like bZIP transcription factor 2) is a protein-coding gene located on chromosome 2.
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome. NRF2 appears to participate in a complex regulatory network and performs a pleiotropic role in the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology, and immune responses. Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.
== Structure == NRF2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure. NRF2 possesses seven highly conserved domains called NRF2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins (MAFF, MAFG, MAFK).
NFE2L2 is a transcription factor that plays a key role in the cellular response to oxidative stress. It binds to antioxidant response (ARE) elements in the promoter regions of genes encoding cytoprotective proteins, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles. In normal conditions, NFE2L2 is ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. In response to oxidative stress, electrophile metabolites inhibit the activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2, heterodimerization with one of the small Maf proteins, and binding to ARE elements of cytoprotective target genes. The NFE2L2 pathway is also activated in response to selective autophagy, where autophagy promotes interaction between KEAP1 and SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex, nuclear accumulation of NFE2L2, and expression of cytoprotective genes. NFE2L2 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. Furthermore, NFE2L2 plays a crucial role in regulating 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 restraining the dysregulation of pro-inflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling. NFE2L2 suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6. It binds to the proximity of pro-inflammatory genes in macrophages and inhibits RNA Pol II recruitment, independent of the NRF2-binding motif and reactive oxygen species level. NFE2L2 represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1, decreasing responsiveness to STING1 agonists, and increasing susceptibility to infection with DNA viruses. Once activated, NFE2L2 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. It 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.
NFE2L2 is also known as HEBP1, IMDDHH, NRF2, Nrf-2.
