NFE2L2

Nuclear factor, erythroid 2-like 2
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2FLU​, 2LZ1​, 3ZGC​, 4IFL​
Identifiers
Symbols	NFE2L2 ; NRF2
External IDs	OMIM: 600492 MGI: 108420 HomoloGene: 2412 ChEMBL: 1075094 GeneCards: NFE2L2 Gene
Gene ontology Molecular function • transcription regulatory region sequence-specific DNA binding • RNA polymerase II distal enhancer sequence-specific DNA binding • RNA polymerase II activating transcription factor binding • transcriptional activator activity, RNA polymerase II distal enhancer sequence-specific binding • DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • protein domain specific binding • transcription regulatory region DNA binding Cellular component • chromatin • nucleus • nucleoplasm • cytoplasm • mitochondrion • centrosome • cytosol • plasma membrane • protein-DNA complex Biological process • transcription from RNA polymerase II promoter • proteasomal ubiquitin-independent protein catabolic process • positive regulation of gene expression • protein ubiquitination • positive regulation of blood coagulation • endoplasmic reticulum unfolded protein response • cellular response to oxidative stress • positive regulation of transcription from RNA polymerase II promoter in response to stress • PERK-mediated unfolded protein response • cellular response to glucose starvation • proteasome-mediated ubiquitin-dependent protein catabolic process • cell redox homeostasis • positive regulation of transcription from RNA polymerase II promoter • regulation of embryonic development • positive regulation of glucose import • cellular response to hydrogen peroxide • cellular response to tumor necrosis factor • cellular response to fluid shear stress • cellular response to laminar fluid shear stress • negative regulation of hematopoietic stem cell differentiation • negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway • positive regulation of ER-associated ubiquitin-dependent protein catabolic process • negative regulation of hydrogen peroxide-induced cell death • positive regulation of glutathione biosynthetic process • regulation of removal of superoxide radicals • negative regulation of endothelial cell apoptotic process • positive regulation of reactive oxygen species metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4780	18024
Ensembl	ENSG00000116044	ENSMUSG00000015839
UniProt	Q16236	Q60795
RefSeq (mRNA)	NM_001145412	NM_010902
RefSeq (protein)	NP_001138884	NP_035032
Location (UCSC)	Chr 2: 177.23 – 177.39 Mb	Chr 2: 75.68 – 75.7 Mb
PubMed search

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene.^[1] Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.^[2] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.

Function

NFE2L2 and other genes, such as NFE2 and NFE2L1, 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.^[3][4]

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.^[5] Cullin 3 ubiquitinates its substrate, Nrf2. Keap1 is a substrate adaptor, which helps Cullin 3 ubiquitinate Nrf2. When 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.^[6] 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,^[7][8] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with a small Maf protein and binds to the antioxidant response element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.^[9]

Target genes

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

• NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.^[10]
• Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM) subunits form a heterodimer, which is the rate-limiting step in the synthesis of glutathione (GSH), a very powerful endogenous antioxidant. Both Gclc and Gclm are characteristic Nrf2 target genes, which establish Nrf2 as a regulator of glutathione, one of the most important antioxidants in the body.^[11]
• Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) support the reduction and recovery of peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide and peroxynitrite.^[12][13]
• Heme oxygenase-1 (HMOX1, HO-1) is an enzyme that catalyzes the breakdown of heme into the antioxidant biliverdin, the anti-inflammatory agent carbon monoxide, and iron. HO-1 is a Nrf2 target gene that has been shown to protect from a variety of pathologies, including sepsis, hypertension, atherosclerosis, acute lung injury, kidney injury, and pain.^[14] In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.^[15]
• The glutathione S-transferase (GST) family includes cytosolic, mitochondrial, and microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by GSH conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by Nrf2 activation and represent an important route of detoxification.^[16]
• The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates for glucuronidation include bilirubin and acetaminophen. Nrf2 has been shown to induce UGT1A1 and UGT1A6.^[17]
• Multidrug resistance-associated proteins (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by Nrf2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.^[18][19]

Structure

Nrf2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure.^[1]

Nrf2 possesses six 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.^[20] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.^[21] 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.^[22] 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.^[21] The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.^[23]

Tissue distribution

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.^[1]

Clinical drug target

Tecfidera (dimethyl fumarate or BG-12), marketed by Biogen Idec, was approved by the Food and Drug Administration (FDA) on March 27, 2013 following the conclusion of Phase 3 clinical trials which demonstrated that the drug reduced relapse rates and increased time to progression of disability in patients with multiple sclerosis. The mechanism by which Tecfidera exerts its therapeutic effect is unknown. Tecfidera (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and has been identified as a nicotinic acid receptor agonist in vitro.^[24] Adverse events associated with Tecfidera include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.^[2]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied.^[25] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.^[26] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.^[26] Oltipraz also generates superoxide radical, which can be toxic.^[27]

Bardoxolone methyl, a synthetic oleanane triterpenoid compound, is under clinical investigation for the treatment of pulmonary hypertension.^[28][29][30]

RTA 408 is a synthetic triterpenoid. Preclinical studies have demonstrated that it possesses antioxidative and anti-inflammatory activities,^[31][32] as well as the potential to improve mitochondrial bioenergetics.^[33] A Phase 2 clinical studies is evaluating RTA 408 for the prevention of radiation-induced dermatitis.^[34][35]

Potential adverse effects of NRF2 activation

Activation of NRF2 may promote the development of de novo cancerous tumors^[36][37] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.^[38] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.^[38][39]

Interactions

NFE2L2 has been shown to interact with:

• C-jun,^[40]
• CREBBP,^[41]
• EIF2AK3,^[42]
• KEAP1,^[42][43][44] and
• UBC.^[43][45]

References

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External links

• NFE2L2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.