NFE2L2

Last updated
NFE2L2
Available structures
PDB Ortholog search: PDBe RCSB
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
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 Mb Chr 2: 75.51 – 75.53 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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 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]

Contents

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]

A mechanism for hormetic dose responses is proposed in which Nrf2 may serve as an hormetic mediator that mediates a vast spectrum of chemopreventive processes. [12]

Structure

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). [13] The Neh2 domain allows for binding of NRF2 to its cytosolic repressor Keap1. [14] 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. [15] 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. [14] 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. [16] 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. [17]

Localization and function

Activating inputs and functional outputs of the NRF2 pathway Inputs and outputs of KEAP1 NRF2 pathway.jpg
Activating inputs and functional outputs of the NRF2 pathway

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. [18] [19]

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. [20] 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. [21] 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, [22] [23] 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. [24]

Target genes

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

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 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. [38] 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. [38]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz, an NRF2 inducer, is most well understood. [39] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. [40] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity. [40] Oltipraz also generates superoxide radicals, which can be toxic. [41]

Associated pathology

Genetic activation of NRF2 may promote the development of de novo cancerous tumors [42] [43] as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver. [44] It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation. [44] [45]

Interactions

NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun, [46] CREBBP, [47] EIF2AK3, [48] KEAP1, [49] [48] [50] [51] and UBC. [50] [52]

See also

Related Research Articles

<span class="mw-page-title-main">Metallothionein</span> Family of proteins

Metallothionein (MT) is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus. MTs have the capacity to bind both physiological and xenobiotic heavy metals through the thiol group of its cysteine residues, which represent nearly 30% of its constituent amino acid residues.

<span class="mw-page-title-main">Thioredoxin</span> Class of reduction–oxidation proteins

Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin is linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. Thioredoxins play a role in cell-to-cell communication.

<span class="mw-page-title-main">Heme oxygenase</span> Class of enzymes

Heme oxygenase, or haem oxygenase, is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.

<span class="mw-page-title-main">Biliverdin reductase</span> Class of enzymes

Biliverdin reductase (BVR) is an enzyme found in all tissues under normal conditions, but especially in reticulo-macrophages of the liver and spleen. BVR facilitates the conversion of biliverdin to bilirubin via the reduction of a double-bond between the second and third pyrrole ring into a single-bond.

<span class="mw-page-title-main">Cystathionine beta synthase</span> Mammalian protein found in humans

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<span class="mw-page-title-main">GABPA</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">KEAP1</span> Protein-coding gene in the species Homo sapiens

Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.

<span class="mw-page-title-main">BACH1</span> Protein-coding gene in the species Homo sapiens

Transcription regulator protein BACH1 is a protein that in humans is encoded by the BACH1 gene.

<span class="mw-page-title-main">CUL3</span> Protein-coding gene in humans

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

<span class="mw-page-title-main">MAFG</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">NFE2L1</span> Protein-coding gene in the species Homo sapiens

Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene. Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).

<span class="mw-page-title-main">MAFK</span> Protein-coding gene in the species Homo sapiens

Transcription factor MafK is a bZip Maf transcription factor protein that in humans is encoded by the MAFK gene.

<span class="mw-page-title-main">MAFF (gene)</span> Protein-coding gene

Transcription factor MafF is a bZip Maf transcription factor protein that in humans is encoded by the MAFF gene.

<span class="mw-page-title-main">KLF9</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">NFE2L3</span> Protein-coding gene in the species Homo sapiens

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References

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