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NFE2L2

From Wikipedia, the free encyclopedia
NFE2L2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesNFE2L2,NRF2, HEBP1, nuclear factor, erythroid 2 like 2, IMDDHH, Nrf-2, NFE2 like bZIP transcription factor 2
External IDsOMIM:600492;MGI:108420;HomoloGene:2412;GeneCards:NFE2L2;OMA:NFE2L2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4780

18024

Ensembl

ENSG00000116044

ENSMUSG00000015839

UniProt

Q16236

Q60795

RefSeq (mRNA)

NM_010902
NM_001399226

RefSeq (protein)

NP_035032
NP_001386155

Location (UCSC)Chr 2: 177.23 – 177.39 MbChr 2: 75.51 – 75.53 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nuclear factor erythroid 2-related factor 2(NRF2), also known asnuclear factor erythroid-derived 2-like 2,is atranscription factorthat in humans is encoded by theNFE2L2gene.[5]NRF2 is abasic leucine zipper(bZIP) protein that may regulate the expression ofantioxidantproteins that protect againstoxidative damagetriggered by injury and inflammation, according to preliminary research.[6]In vitro,NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encodingcytoprotective proteins.[7]NRF2 induces the expression ofheme oxygenase 1in vitroleading to an increase inphase II enzymes.[8]NRF2 also inhibits theNLRP3inflammasome.[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]

Structure

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NRF2 is a basic leucine zipper (bZip)transcription factorwith a Cap “n” Collar (CNC) structure.[5]NRF2 possesses seven highly conserved domains called NRF2-ECH homology (Neh) domains. TheNeh1domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize withsmall Mafproteins (MAFF,MAFG,MAFK).[12]TheNeh2domain allows for binding of NRF2 to its cytosolic repressor Keap1.[13] TheNeh3domain may play a role in NRF2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.[14] TheNeh4 and Neh5domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CREB), which possesses intrinsichistone acetyltransferaseactivity.[13] TheNeh6domain 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]

Localization and function

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Activating inputs and functional outputs of the NRF2 pathway

NFE2L2and other genes, such asNFE2,NFE2L1andNFE2L3,encode basicleucine zipper(bZIP)transcription factors.They share highly conserved regions that are distinct from other bZIP families, such asJUNandFOS,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) andCullin 3,which degrade NRF2 byubiquitination.[19]Cullin 3 ubiquitinates NRF2, while Keap1 is a substrate adaptor protein that facilitates the reaction. Once NRF2 is ubiquitinated, it is transported to theproteasome,where it is degraded and its components recycled. Under normal conditions, NRF2 has a half-life of only 20 minutes.[20]Oxidative stressor 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 ofsmall Mafproteins (MAFF,MAFG,MAFK) and binds to the antioxidant response element (ARE) in the upstreampromoter regionof many antioxidative genes, and initiates their transcription.[23]

Target genes

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Activation of NRF2 induces the transcription of genes encodingcytoprotective proteins.These include:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical NRF2 target protein which catalyzes the reduction and detoxification of highly reactivequinonesthat can causeredox cyclingandoxidative stress.[24]
  • Glutamate-cysteine ligasecatalytic subunit (GCLC) and glutamate-cysteine ligase regulatory subunit (GCLM) form a heterodimer, which is the rate-limiting step in the synthesis ofglutathione(GSH), a very powerful endogenousantioxidant.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.[25]
  • Sulfiredoxin1 (SRXN1) andThioredoxin reductase1 (TXNRD1) support the reduction and recovery ofperoxiredoxins,proteins important in the detoxification of highly reactive peroxides, includinghydrogen peroxideandperoxynitrite.[26][27]
  • Heme oxygenase-1 (HMOX1,HO-1) is an enzyme that catalyzes the breakdown ofhemeinto the antioxidantbiliverdin,the anti-inflammatory agentcarbon monoxide,and iron. HO-1 is a NRF2 target gene that has been shown to protect from a variety of pathologies, includingsepsis,hypertension,atherosclerosis,acute lung injury, kidney injury, and pain.[28]In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury afterintracerebral hemorrhage.[29]
  • Theglutathione S-transferase(GST) family includes cytosolic,mitochondrial,andmicrosomalenzymes that catalyze the conjugation of GSH with endogenous andxenobioticelectrophiles.After detoxification byglutathione(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.[30]
  • The UDP-glucuronosyltransferase(UGT) family catalyze the conjugation of aglucuronic acidmoiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates forglucuronidationincludebilirubinandacetaminophen.NRF2 has been shown to induce UGT1A1 and UGT1A6.[31]
  • Multidrug resistance-associated proteins(Mrps) are importantmembrane transportersthat efflux various compounds from various organs and intobileor 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 thepharmacokineticsand toxicity of compounds.[32][33]
  • Kelch-like ECH-associated protein 1is also a primary target of NFE2L2. Several interesting studies have also identified this hidden circuit in NRF2 regulations. In the mouse Keap1 (INrf2) gene, Lee and colleagues[34]found that an AREs located on a negative strand can subtly connect Nrf2 activation to Keap1 transcription. When examining NRF2 occupancies in human lymphocytes, Chorley and colleagues identified an approximately 700 bp locus within the KEAP1 promoter region was consistently top rank enriched, even at the whole-genome scale.[35]These basic findings have depicted a mutually influenced pattern between NRF2 and KEAP1. NRF2-driven KEAP1 expression characterized in human cancer contexts, especially in human squamous cell cancers,[36]implicated a new perspective in understanding NRF2 signaling regulation.

Tissue distribution

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NRF2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[5]

Clinical relevance

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Dimethyl fumarate,marketed as Tecfidera byBiogen Idec,was approved by theFood and Drug Administrationin March 2013 following the conclusion of aPhase III clinical trialwhich demonstrated that the drug reduced relapse rates and increased time to progression of disability in people withmultiple 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 anicotinic acidreceptoragonistin vitro.[37]The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML),lymphopenia,andliver 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 whicholtipraz,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, includingneurotoxicityand gastrointestinal toxicity.[39]Oltipraz also generatessuperoxide radicals,which can be toxic.[40]

Associated pathology

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Genetic activation of NRF2 may promote the development ofde novocancerous 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]

Interactions

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NFE2L2 has been shown tointeractwithMAFF,MAFG,MAFK,C-jun,[45]CREBBP,[46]EIF2AK3,[47]KEAP1,[48][47][49][50]andUBC.[49][51]

See also

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References

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  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000015839–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
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