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NFE2L2

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NFE2L2
Available structures
PDBOrtholog search: PDBe RCSB
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.[6] NRF2 lies at the center of a complex regulatory network and performs pleiotropic vital role in the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology, and immune responses.[7] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.[8]

Structure

NRF2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure.[5] 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 (MAFF, MAFG, MAFK).[9] The Neh2 domain allows for binding of NRF2 to its cytosolic repressor Keap1.[10] 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.[11] 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.[10] 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.[12]

Localization and function

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.[13][14]

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.[15] 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.[16] 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,[17][18] 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.[19]

Target genes

Activation of NRF2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

Tissue distribution

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

Clinical relevance

Dimethyl fumarate, marketed as Tecfidera by Biogen Idec, was approved by the Food and Drug Administration in March 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 people with multiple sclerosis. The mechanism by which it exerts its therapeutic effect is unknown. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the NRF2 pathway and has been identified as a nicotinic acid receptor agonist in vitro.[30] 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.[30]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is the best studied.[31] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[32] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity.[32] Oltipraz also generates superoxide radical, which can be toxic.[33]

Associated pathology

Genetic activation of NRF2 may promote the development of de novo cancerous tumors[34][35] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[36] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.[36][37]

Interactions

NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun,[38] CREBBP,[39] EIF2AK3,[40] KEAP1,[41][40][42][43] and UBC.[42][44]


See also

References

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  2. ^ a b c GRCm38: 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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  7. ^ He F, Ru X, Wen T (January 2020). "NRF2, a Transcription Factor for Stress Response and Beyond". International Journal of Molecular Sciences. 21 (13): 4777. doi:10.3390/ijms21134777. PMID 32640524.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD (January 2019). "Modulating NRF2 in Disease: Timing Is Everything". Annual Review of Pharmacology and Toxicology. 59: 555–575. doi:10.1146/annurev-pharmtox-010818-021856. PMC 6538038. PMID 30256716.
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