NFE2L2
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]
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
NFE2L2 and other genes, such as
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 (
Target genes
Activation of NRF2 induces the transcription of genes encoding cytoprotective proteins. These include:
- NAD(P)H quinone oxidoreductase 1 (redox cycling and oxidative stress.[25]
- Glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase regulatory subunit (GCLM) 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.[26]
- peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide and peroxynitrite.[27][28]
- Heme oxygenase-1 (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.[29] In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.[30]
- The microsomal enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic electrophiles. After detoxification by glutathione (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.[31]
- The UDP-acetaminophen. NRF2 has been shown to induce UGT1A1 and UGT1A6.[32]
- 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.[33][34]
- Kelch-like ECH-associated protein 1 is 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 [35] 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.[36] 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,[37] implicated a new perspective in understanding NRF2 signaling regulation.
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
The dithiolethiones are a class of organosulfur compounds, of which
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
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000116044 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015839 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 7937919.
- ^ PMID 22992073.
- PMID 32165256.
- S2CID 221863319.
- PMID 27825853.
- PMID 32640524.
- PMID 30256716.
- S2CID 232130837.
- PMID 15087497.
- ^ PMID 15519281.
- PMID 16314513.
- PMID 15143058.
- PMID 28899199.
- S2CID 23774837.
- ^ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2".
- PMID 9887101.
- PMID 15282312.
- PMID 18268004.
- PMID 19560482.
- PMID 9240432.
- PMID 8962164.
- PMID 12007577.
- PMID 19923889.
- PMID 19326073.
- S2CID 36932369.
- PMID 17525142.
- PMID 10816095.
- PMID 17259171.
- S2CID 19513808.
- PMID 19246624.
- PMID 17925401.
- PMID 22581777.
- S2CID 219989242.
- ^ a b "Dimethyl fumarate label" (PDF). FDA. December 2017. Retrieved 19 July 2018. For label updates see FDA index page for NDA 204063
- PMID 19150646.
- ^ PMID 15252150.
- PMID 15680910.
- PMID 21734707.
- ^ "Natural antioxidants could scupper tumour's detox". New Scientist (2820). July 6, 2011. Retrieved 8 October 2014.
- ^ PMID 20947826.
- S2CID 73042634.
- PMID 9872330.
- S2CID 22999855.
- ^ PMID 14517290.
- PMID 26117320.
- ^ PMID 18757741.
- PMID 18417180.
- PMID 18358244.
External links
- NFE2L2+protein,+human at the U.S. 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.