NFE2L2 gene

The NFE2L2 gene (NFE2L2 stands for Nuclear Factor Erythroid 2-Related Factor 2) is a protein-coding gene located on chromosome 2q31.2. Several transcript variants encoding different isoforms have been characterized for this gene.

The NFE2L2 gene encodes a transcription factor(Nuclear Factor Erythroid 2-Related Factor 2) that belongs to a small family of basic leucine zipper (bZIP) proteins. Nuclear Factor Erythroid 2-Related Factor 2 is a transcription factor, a basic leucine zipper (bZIP) protein that preliminary research suggests may regulate the expression of antioxidant proteins that protect against oxidative damage caused by injury and inflammation. 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 (Ahmed Set al. 2017).

The protein also plays an important role in regulating the innate immune response and antiviral cytosolic DNA recognition. It is a critical regulator of innate immune response and survival during sepsis by maintaining redox homeostasis and inhibiting dysregulation of pro-inflammatory pathways such as MyD88-dependent and -independent and TNF-alpha signaling. Suppresses the inflammatory response of macrophages by blocking the transcription of pro-inflammatory cytokines and the induction of IL6. Binds to the proximity of pro-inflammatory genes in macrophages and inhibits the recruitment of RNA Pol II. The inhibition is independent of the NRF2 binding motif and the level of reactive oxygen species. Suppresses antiviral cytosolic DNA sensing by suppressing expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists, while increasing susceptibility to DNA viral infections (Olagnier D et al. 2018). Once activated, it limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and virus-derived ligands through a mechanism involving inhibition of IRF3 dimerization. Also inhibits the replication of SARS-CoV-2 as well as the replication of several other pathogenic viruses, including herpes simplex virus-1 and -2, vaccinia virus and Zika virus, by an interferon (IFN)-independent mechanism (Olagnier D et al. (2020).

Diseases associated with NFE2L2 include immunodeficiency, developmental delay and hypohomocysteinemia as well as squamous cell carcinoma of the lung.

1. Ahmed Set al. (2017). Nrf2 signaling pathway: Pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1863: 585-597.
2. Chan JY et al. (1995) Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization. Human Genetics 95: 265-269.
3. Gureev AP et al. (2020) Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation. Experimental Gerontology 328: 113285.
4. Olagnier D et al. (2018) Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat Commun 9:3506.
5. Olagnier D et al. (2020) SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun 11:4938.
6. Yamamoto T et al. (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Molecular and Cellular Biology 28: 2758-2770.