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. [5] 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. [6] In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. [7] NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. [8] NRF2 also inhibits the NLRP3 inflammasome. [9]
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. [10] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress. [6] [11]
NRF2 is a basic leucine zipper ( bZip) transcription factor with a Cap “n” Collar (CNC) structure. [5] 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). [12] The Neh2 domain allows for binding of NRF2 to its cytosolic repressor Keap1. [13] The Neh3 domain may play a role in NRF2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus. [14] The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein ( CREB), which possesses intrinsic histone acetyltransferase activity. [13] The Neh6 domain may contain a degron that is involved in a redox-insensitive process of degradation of NRF2. This occurs even in stressed cells, which normally extend the half-life of NRF2 protein relative to unstressed conditions by suppressing other degradation pathways. [15] The "Neh7" domain is involved in the repression of Nrf2 transcriptional activity by the retinoid X receptor α through a physical association between the two proteins. [16]
NFE2L2 and other genes, such as NFE2, NFE2L1 and NFE2L3, encode basic leucine zipper ( bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other. [17] [18]
Under normal or unstressed conditions, NRF2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, NRF2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.
NRF2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 ( KEAP1) and Cullin 3, which degrade NRF2 by ubiquitination. [19] 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 recycled. Under normal conditions, NRF2 has a half-life of only 20 minutes. [20] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When NRF2 is not ubiquitinated, it builds up in the cytoplasm, [21] [22] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of small Maf proteins ( MAFF, MAFG, MAFK) and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription. [23]
Activation of NRF2 induces the transcription of genes encoding cytoprotective proteins. These include:
NRF2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain. [5]
Dimethyl fumarate, marketed as Tecfidera by Biogen Idec, was approved by the Food and Drug Administration in March 2013 following the conclusion of a Phase III clinical trial which demonstrated that the drug reduced relapse rates and increased time to progression of disability in people with multiple sclerosis. [6] The mechanism of action of dimethyl fumarate is not well understood. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the NRF2 pathway and has been identified as a nicotinic acid receptor agonist in vitro. [37] The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, and liver damage; other adverse effects include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain. [37]
The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is most well understood. [38] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. [39] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity. [39] Oltipraz also generates superoxide radicals, which can be toxic. [40]
Genetic activation of NRF2 may promote the development of de novo cancerous tumors [41] [42] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver. [43] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation. [43] [44]
NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun, [45] CREBBP, [46] EIF2AK3, [47] KEAP1, [48] [47] [49] [50] and UBC. [49] [51]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | NFE2L2, NRF2, HEBP1, nuclear factor, erythroid 2 like 2, IMDDHH, Nrf-2, NFE2 like bZIP transcription factor 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 600492; MGI: 108420; HomoloGene: 2412; GeneCards: NFE2L2; OMA: NFE2L2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] 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. [6] In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. [7] NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. [8] NRF2 also inhibits the NLRP3 inflammasome. [9]
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. [10] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress. [6] [11]
NRF2 is a basic leucine zipper ( bZip) transcription factor with a Cap “n” Collar (CNC) structure. [5] 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). [12] The Neh2 domain allows for binding of NRF2 to its cytosolic repressor Keap1. [13] The Neh3 domain may play a role in NRF2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus. [14] The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein ( CREB), which possesses intrinsic histone acetyltransferase activity. [13] The Neh6 domain may contain a degron that is involved in a redox-insensitive process of degradation of NRF2. This occurs even in stressed cells, which normally extend the half-life of NRF2 protein relative to unstressed conditions by suppressing other degradation pathways. [15] The "Neh7" domain is involved in the repression of Nrf2 transcriptional activity by the retinoid X receptor α through a physical association between the two proteins. [16]
NFE2L2 and other genes, such as NFE2, NFE2L1 and NFE2L3, encode basic leucine zipper ( bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other. [17] [18]
Under normal or unstressed conditions, NRF2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, NRF2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.
NRF2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 ( KEAP1) and Cullin 3, which degrade NRF2 by ubiquitination. [19] 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 recycled. Under normal conditions, NRF2 has a half-life of only 20 minutes. [20] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When NRF2 is not ubiquitinated, it builds up in the cytoplasm, [21] [22] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of small Maf proteins ( MAFF, MAFG, MAFK) and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription. [23]
Activation of NRF2 induces the transcription of genes encoding cytoprotective proteins. These include:
NRF2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain. [5]
Dimethyl fumarate, marketed as Tecfidera by Biogen Idec, was approved by the Food and Drug Administration in March 2013 following the conclusion of a Phase III clinical trial which demonstrated that the drug reduced relapse rates and increased time to progression of disability in people with multiple sclerosis. [6] The mechanism of action of dimethyl fumarate is not well understood. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the NRF2 pathway and has been identified as a nicotinic acid receptor agonist in vitro. [37] The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, and liver damage; other adverse effects include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain. [37]
The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is most well understood. [38] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. [39] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity. [39] Oltipraz also generates superoxide radicals, which can be toxic. [40]
Genetic activation of NRF2 may promote the development of de novo cancerous tumors [41] [42] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver. [43] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation. [43] [44]
NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun, [45] CREBBP, [46] EIF2AK3, [47] KEAP1, [48] [47] [49] [50] and UBC. [49] [51]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.