Nuclear factor (erythroid-derived 2)-like 2
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2FLU
Identifiers
Symbols	NFE2L2; NRF2
External IDs	OMIM: 600492 MGI: 108420 HomoloGene: 2412 ChEMBL: 1075094 GeneCards: NFE2L2 Gene
Gene Ontology Molecular function • DNA binding • sequence-specific DNA binding transcription factor activity • protein domain specific binding • sequence-specific DNA binding • protein dimerization activity Cellular component • chromatin • nucleus • cytoplasm • centrosome • cytosol • plasma membrane Biological process • regulation of transcription, DNA-dependent • transcription from RNA polymerase II promoter • positive regulation of blood coagulation • endoplasmic reticulum unfolded protein response • cellular response to oxidative stress • positive regulation of transcription from RNA polymerase II promoter • regulation of embryonic development • regulation of removal of superoxide radicals • 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_001145412.2	NM_010902.3
RefSeq (protein)	NP_001138884.1	NP_035032.1
Location (UCSC)	Chr 2: 178.09 – 178.26 Mb	Chr 2: 75.51 – 75.54 Mb
PubMed search	[1]	[2]
This box: view talk edit

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] NFE2L2 induces the expression of various genes including those that encode for several antioxidant enzymes, and it may play a physiological role in the regulation of oxidative stress. Investigational drugs that target NFE2L2 are of interest as potential therapeutic interventions for oxidative-stress related pathologies.

Function [link]

NFE2, NFE2L1, and NFE2L2 (this protein) comprise a family of human genes encoding 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.^[2][3]

Under normal or unstressed conditions, Nrf2 is tethered in the cytoplasm by another protein called Kelch like-ECH-associated protein 1 (Keap1).^[4] Keap1 acts as a substrate adaptor protein for Cullin 3-based ubiquitination, which results in the proteasomal degradation of Nrf2, and under normal conditions Nrf2 has a half-life of only 20 minutes.^[5] Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, resulting in a disruption of the Keap1-Cul3 ubiquitination system and a build-up of Nrf2 in the cytoplasm.^[6][7] Unbound Nrf2 is then able to translocate into the nucleus, where it will heterodimerize with a small Maf protein and bind to the Antioxidant Response Element (ARE) in the upstream promoter region of many antioxidative genes, where it will initiate their transcription.^[8]

Target Genes [link]

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.^[9]
• 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.^[10]
• 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.^[11]. In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.^[12]
• 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.^[13]
• 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.^[14]
• 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 pharamacokinetics and toxicity of compounds.^[15][16]

Structure [link]

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.^[17] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.^[18] 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.^[19] The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CBP), which possesses intrinsic histone acetyltransferase activity.^[18] 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.^[20]

Tissue distribution [link]

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

Nrf2 as a drug target [link]

Investigational drugs that target NFE2L2 have been evaluated in animal models as therapeutic interventions for oxidative-stress related pathologies. One such compound, bardoxolone methyl, is undergoing testing in human clinical trials.

The dithiolethiones are a class of organosulfur compounds, of which, oltipraz is the most well-studied. Oltipraz has been shown to inhibit cancer formation in a variety of rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.^[21] However, clinical trials involving oltipraz have demonstrated significant side-effects with no or questionable chemopreventive efficacy.^[21] In one clinical study, side-effects after 8 weeks of treatment included numbness, tingling, and pain in the extremities. In another study, side-effects after 4 weeks included gastrointestinal toxicity. Oltipraz has also been shown to generate superoxide radical, which can be quite toxic.^[22]

A series of synthetic oleane triterpenoid compounds that are Nrf2 activators and referred to as antioxidant inflammation modulators (AIMs), are in clinical development at Reata Pharmaceuticals. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), has completed Phase 2 clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus. Data indicate that bardoxolone methyl improves markers of kidney function, including producing a significant increase in estimated glomerular filtration rate that correlates with changes in blood urea nitrogen, serum phosphorus, uric acid, and magnesium. Improvements were sustained over 6 months of therapy and remained significant compared to placebo.^{[citation needed]}) A Phase 3 outcomes study (BEACON) is scheduled to begin in mid 2011.^{[citation needed]}) Reata also indicates that it has other Nrf2 inducers in the same class that are in preclinical development for the treatment of CNS and respiratory diseases.^{[citation needed]})

Interactions [link]

NFE2L2 has been shown to interact with CREB-binding protein,^[23] KEAP1,^[24][25][26] C-jun,^[27] EIF2AK3^[24] and Ubiquitin C.^[25][28]

References [link]

Further reading [link]

External links [link]

• 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.