Nuclear Factor Erythroid 2-Related Factor 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, according to preliminary research, can 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).

NRF2 appears to be involved in a complex regulatory network and to play a pleiotropic role in the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology and immune responses. Several drugs that stimulate the NFE2L2 signaling pathway are currently being investigated for the treatment of diseases caused by oxidative stress.

NRF2 is a basic leucine zipper (bZip) transcription factor with a cap-"n"-collar (CNC) structure[5] NRF2 has seven highly conserved domains, the 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)[13] The Neh2 domain allows NRF2 to bind to its cytosolic repressor Keap1.[14] The Neh3 domain may play a role in the stability of the NRF2 protein and may function as a transactivation domain by interacting with components of the transcriptional apparatus. [15] The Neh4 and Neh5 domains also function as transactivation domains, but bind to another protein called cAMP Response Element Binding Protein (CREB), which has intrinsic histone acetyltransferase activity. 14] The Neh6 domain may contain a degron that is involved in a redox-insensitive process of NRF2 degradation. This occurs even in stressed cells, which normally prolong the half-life of the NRF2 protein compared to unstressed conditions by suppressing other degradation pathways.[16] The "Neh7" domain is involved in the repression of Nrf2 transcriptional activity by the retinoid X receptor α through a physical link between the two proteins.[17]

NFE2L2 and other genes such as NFE2, NFE2L1 and NFE2L3 encode basic leucine zipper (bZIP) transcription factors. They have highly conserved regions that are distinct from other bZIP families such as JUN and FOS, although the remaining regions differ considerably (Chan JY et al. (1995). Under normal or unstressed conditions, NRF2 is maintained in the cytoplasm by a group of proteins that rapidly degrade it. Under oxidative stress, NRF2 is not degraded but migrates to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidant genes and their proteins.

NRF2 is maintained in the cytoplasm by Kelch like-ECH-associated protein 1 (KEAP1) and Cullin 3, which degrade NRF2 by ubiquitination. Cullin 3 ubiquitinates NRF2, while Keap1 is a substrate adaptor protein that facilitates the reaction. Once NRF2 is ubiquitinated, it is transported to the proteasome where it is degraded and its components are recycled.

When NRF2 is not ubiquitinated, it accumulates in the cytoplasm (Yamamoto T et al. (2008) and migrates to the nucleus. In the nucleus, it combines (forms a heterodimer) with one of the small Maf proteins (MAFF, MAFG, MAFK) and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidant genes and initiates their transcription.

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. Yamamoto T et al. (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Molecular and Cellular Biology 28: 2758-2770.