Biology:NFE2L2

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Short description: Human protein and coding gene

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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.[2] In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins.[3] NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes.[4] NRF2 also inhibits the NLRP3 inflammasome.[5]

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.[6] Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.[2][7]

Structure

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.[8][9]

NRF2 is a basic leucine zipper (bZip) transcription factor with a Cap "n" Collar (CNC) structure.[1] NRF2 possesses seven highly conserved domains called NRF2-ECH homology (Neh) domains. From the N-terminus to the C-terminus, they are:

  • Neh2 allows for binding of NRF2 to its cytosolic repressor Keap1,[10] through the conserved sites ETGE and DLG.[11]
  • Neh4 and Neh5 act as transactivation domains by binding to cAMP Response Element Binding Protein (CREB), which possesses intrinsic histone acetyltransferase activity.[10]
  • Neh7 is involved in the repression of Nrf2 transcriptional activity by the retinoid X receptor α through a physical association between the two proteins.[11]
  • Neh6 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] Its two conserved motifs, DSGIS and DSAPGS, are recognized by β-TrCP (BTRC and FBXW11 in mammals).[11]
  • Neh1 is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins (MAFF, MAFG, MAFK).[13]
  • Neh3 may play a role in NRF2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.[14]

The "domains" of Nrf2 are regions of conservation, not protein domains in the structural sense. Neh2, Neh7 and Neh1 are partially unstructured. Neh3 and Nah6 is predicted to be mainly unstructured. Neh4 and Neh5 are disordered, meaning they do not fold into a fixed shape.[15] Neh4 and Neh5 have been predicted as structured, but experimental data show otherwise.[16] The methods employed by InterPro, from curated domain patterns to AlphaFold, cover less than half of human Nrf2.[17]

Tissue distribution

NRF2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[1]

Localization and function

Activating inputs and functional outputs of the NRF2 pathway

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.[18] 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.[19] 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,[20][21] 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.[22]

Target genes

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

  • NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical NRF2 target protein which catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.[23]
  • 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.[24]
  • Sulfiredoxin 1 (SRXN1) and Thioredoxin reductase 1 (TXNRD1) support the reduction and recovery of peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide and peroxynitrite.[25][26]
  • 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.[27] Conversely, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.[28]
  • 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 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.[29]
  • 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.[30]
  • 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 pharmacokinetics and toxicity of compounds.[31][32]
  • 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. An AREs located on a negative strand of the murine Keap1 (INrf2) gene can subtly connect Nrf2 activation to Keap1 transcription.[33] Regarding NRF2 occupancies in human lymphocytes, an approximately 700 bp locus within the KEAP1 promoter region was consistently top rank enriched, even at the whole-genome scale.[34] 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,[35] implicated a new perspective in understanding NRF2 signaling regulation.

Clinical relevance

Disease association

Genetic activation of NRF2 has been implicated in the development of de novo tumors,[36][37] as well as in the progression of atherosclerosis by increasing plasma cholesterol levels and hepatic cholesterol content.[38] It has been suggested that these pro-atherogenic effects may outweigh the protective benefits of NRF2-mediated antioxidant induction.[39]

Therapeutic

Activation of the NRF2 (nuclear factor erythroid 2–related factor 2) pathway has been explored as a therapeutic strategy due to its role in regulating antioxidant and cytoprotective responses. One of the most clinically advanced NRF2 activators is dimethyl fumarate, marketed as Tecfidera by Biogen Idec. It was approved by the Food and Drug Administration in March 2013 following a successful Phase III clinical trial that demonstrated reduced relapse rates and delayed progression of disability in individuals with multiple sclerosis.[2]

Although the precise mechanism of action of dimethyl fumarate is not fully understood, it is known to activate the NRF2 signaling pathway. Both dimethyl fumarate and its active metabolite, monomethyl fumarate, promote NRF2 nuclear translocation and the subsequent transcription of antioxidant response element (ARE)-driven genes. In addition, they have been shown to act as nicotinic acid receptor agonists in vitro.[40]

Despite its clinical efficacy, dimethyl fumarate is associated with several adverse effects, including anaphylaxis, angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, and liver damage. Common side effects include flushing and gastrointestinal symptoms such as diarrhea, nausea, and upper abdominal pain.[40]

Other NRF2 activators have also been investigated. The dithiolethiones are a class of organosulfur compounds known to induce NRF2 activity. Among them, oltipraz is the most extensively studied.[41] Oltipraz has been shown to suppress tumor formation in multiple rodent tissues, including the bladder, colon, liver, lung, and pancreas, by upregulating NRF2-dependent detoxification pathways.[42] However, clinical trials of oltipraz have failed to demonstrate clear therapeutic benefit and have reported significant toxicities, including neurotoxicity and gastrointestinal disturbances. Additionally, oltipraz has been found to generate superoxide radicals, which may offset its NRF2-mediated protective effects.[42][43]

MIND4-17 is a selective NRF2 activator which is used for research into this pathway.[44]

Interactions

NFE2L2 has been shown to interact with MAFF, MAFG, MAFK, C-jun,[45] CREBBP,[46] EIF2AK3,[47] KEAP1,[48][47][49][50] and UBC.[49][51]

See also

References

  1. ↑ 1.0 1.1 1.2 "Isolation of NF-E2-related factor 2 (NRF2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region". Proceedings of the National Academy of Sciences of the United States of America 91 (21): 9926–9930. October 1994. doi:10.1073/pnas.91.21.9926. PMID 7937919. Bibcode: 1994PNAS...91.9926M. 
  2. ↑ 2.0 2.1 2.2 "Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis". The New England Journal of Medicine 367 (12): 1098–1107. September 2012. doi:10.1056/NEJMoa1114287. PMID 22992073. 
  3. ↑ "Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation". Experimental Neurology 328. 2020. doi:10.1016/j.expneurol.2020.113285. PMID 32165256. 
  4. ↑ "Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer". European Journal of Pharmacology 887. 2020. doi:10.1016/j.ejphar.2020.173588. PMID 32961170. 
  5. ↑ "Nrf2 signaling pathway: Pivotal roles in inflammation". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1863 (2): 585–597. 2017. doi:10.1016/j.bbadis.2016.11.005. PMID 27825853. 
  6. ↑ "NRF2, a Transcription Factor for Stress Response and Beyond.". International Journal of Molecular Sciences 21 (13): 4777. January 2020. doi:10.3390/ijms21134777. PMID 32640524.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  7. ↑ "Modulating NRF2 in Disease: Timing Is Everything". Annual Review of Pharmacology and Toxicology 59: 555–575. January 2019. doi:10.1146/annurev-pharmtox-010818-021856. PMID 30256716. 
  8. ↑ "Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization". Human Genetics 95 (3): 265–269. March 1995. doi:10.1007/BF00225191. PMID 7868116. 
  9. ↑ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=4780. 
  10. ↑ 10.0 10.1 "Nrf2-Keap1 defines a physiologically important stress response mechanism". Trends in Molecular Medicine 10 (11): 549–557. November 2004. doi:10.1016/j.molmed.2004.09.003. PMID 15519281. 
  11. ↑ 11.0 11.1 11.2 "Transcriptional Regulation by Nrf2". Antioxidants & Redox Signaling 29 (17): 1727–1745. December 2018. doi:10.1089/ars.2017.7342. PMID 28899199. 
  12. ↑ "Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron". The Journal of Biological Chemistry 279 (30): 31556–31567. July 2004. doi:10.1074/jbc.M403061200. PMID 15143058. 
  13. ↑ "Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway". Proceedings of the National Academy of Sciences of the United States of America 101 (17): 6379–6384. April 2004. doi:10.1073/pnas.0305902101. PMID 15087497. Bibcode: 2004PNAS..101.6379M. 
  14. ↑ "The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation". Molecular and Cellular Biology 25 (24): 10895–10906. December 2005. doi:10.1128/MCB.25.24.10895-10906.2005. PMID 16314513. 
  15. ↑ "Overlooked and valuable facts to know in the NRF2/KEAP1 field". Free Radical Biology & Medicine 192: 37–49. November 2022. doi:10.1016/j.freeradbiomed.2022.08.044. PMID 36100148. 
  16. ↑ "Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response". Protein Science 33 (9). September 2024. doi:10.1002/pro.5137. PMID 39150085. 
  17. ↑ "InterPro: Q16236 Nuclear factor erythroid 2-related factor 2". https://www.ebi.ac.uk/interpro/protein/UniProt/Q16236/. 
  18. ↑ "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes & Development 13 (1): 76–86. January 1999. doi:10.1101/gad.13.1.76. PMID 9887101. 
  19. ↑ "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2". Molecular and Cellular Biology 24 (16): 7130–7139. August 2004. doi:10.1128/MCB.24.16.7130-7139.2004. PMID 15282312. 
  20. ↑ "Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity". Molecular and Cellular Biology 28 (8): 2758–2770. April 2008. doi:10.1128/MCB.01704-07. PMID 18268004. 
  21. ↑ "Cysteine-based regulation of the CUL3 adaptor protein Keap1". Toxicology and Applied Pharmacology 244 (1): 21–26. April 2010. doi:10.1016/j.taap.2009.06.016. PMID 19560482. Bibcode: 2010ToxAP.244...21S. 
  22. ↑ "An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements". Biochemical and Biophysical Research Communications 236 (2): 313–322. July 1997. doi:10.1006/bbrc.1997.6943. PMID 9240432. Bibcode: 1997BBRC..236..313I. 
  23. ↑ "Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene". Proceedings of the National Academy of Sciences of the United States of America 93 (25): 14960–14965. December 1996. doi:10.1073/pnas.93.25.14960. PMID 8962164. Bibcode: 1996PNAS...9314960V. 
  24. ↑ "Glutamate-cysteine ligase modifier subunit: mouse Gclm gene structure and regulation by agents that cause oxidative stress". Biochemical Pharmacology 63 (9): 1739–1754. May 2002. doi:10.1016/S0006-2952(02)00897-3. PMID 12007577. 
  25. ↑ "Peroxiredoxin 1 and its role in cell signaling". Cell Cycle (Georgetown, Tex.) 8 (24): 4072–4078. December 2009. doi:10.4161/cc.8.24.10242. PMID 19923889. PMC 7161701. https://www.landesbioscience.com/journals/cc/11NeumannCC8-24.pdf. 
  26. ↑ "Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin". Molecules and Cells 27 (3): 279–282. March 2009. doi:10.1007/s10059-009-0050-y. PMID 19326073. 
  27. ↑ "Heme oxygenase and renal disease". Current Hypertension Reports 11 (1): 56–62. February 2009. doi:10.1007/s11906-009-0011-z. PMID 19146802. 
  28. ↑ "Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage". Brain: A Journal of Neurology 130 (Pt 6): 1643–1652. June 2007. doi:10.1093/brain/awm095. PMID 17525142. 
  29. ↑ "The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin". Biochemical Society Transactions 28 (2): 33–41. February 2000. doi:10.1042/bst0280033. PMID 10816095. 
  30. ↑ "Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice". The Journal of Biological Chemistry 282 (12): 8749–8758. March 2007. doi:10.1074/jbc.M610790200. PMID 17259171. 
  31. ↑ "Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway". Hepatology (Baltimore, Md.) 46 (5): 1597–1610. November 2007. doi:10.1002/hep.21831. PMID 17668877. 
  32. ↑ "Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice". Toxicological Sciences 109 (1): 31–40. May 2009. doi:10.1093/toxsci/kfp047. PMID 19246624. 
  33. ↑ "An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance". The Journal of Biological Chemistry 282 (50): 36412–36420. December 2007. doi:10.1074/jbc.M706517200. PMID 17925401. 
  34. ↑ "Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha". Nucleic Acids Research 40 (15): 7416–7429. August 2012. doi:10.1093/nar/gks409. PMID 22581777. 
  35. ↑ "NRF2-Driven KEAP1 Transcription in Human Lung Cancer". Molecular Cancer Research 18 (10): 1465–1476. October 2020. doi:10.1158/1541-7786.MCR-20-0108. PMID 32571982. 
  36. ↑ "Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis". Nature 475 (7354): 106–109. July 2011. doi:10.1038/nature10189. PMID 21734707. 
  37. ↑ "Natural antioxidants could scupper tumour's detox". New Scientist (2820). July 6, 2011. https://www.newscientist.com/article/mg21128204.500-natural-antioxidants-could-scupper-tumours-detox.html#.VDW3Tfl4pcR. Retrieved 8 October 2014. 
  38. ↑ "NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection". Arteriosclerosis, Thrombosis, and Vascular Biology 31 (1): 58–66. January 2011. doi:10.1161/ATVBAHA.110.210906. PMID 20947826. 
  39. ↑ "Nrf2 and the promotion of atherosclerosis: lessons to be learned". Clin. Lipidol 7 (2): 123–126. 2012. doi:10.2217/clp.12.5. 
  40. ↑ 40.0 40.1 "Dimethyl fumarate label". FDA. December 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204063s020lbl.pdf.  For label updates see FDA index page for NDA 204063
  41. ↑ "Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice". Toxicology Letters 185 (3): 180–186. March 2009. doi:10.1016/j.toxlet.2008.12.014. PMID 19150646. Bibcode: 2009ToxL..185..180P. 
  42. ↑ 42.0 42.1 "A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway". Molecular Cancer Therapeutics 3 (7): 885–893. July 2004. doi:10.1158/1535-7163.885.3.7. PMID 15252150. 
  43. ↑ "Cancer chemopreventive oltipraz generates superoxide anion radical". Archives of Biochemistry and Biophysics 435 (1): 83–88. March 2005. doi:10.1016/j.abb.2004.11.028. PMID 15680910. 
  44. ↑ Quinti L, Casale M, Moniot S, Pais TF, Van Kanegan MJ, Kaltenbach LS, Pallos J, Lim RG, Naidu SD, Runne H, Meisel L, Rauf NA, Leyfer D, Maxwell MM, Saiah E, Landers JE, Luthi-Carter R, Abagyan R, Dinkova-Kostova AT, Steegborn C, Marsh JL, Lo DC, Thompson LM, Kazantsev AG. SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models. Cell Chem Biol. 2016 Jul 21;23(7):849-861. doi:10.1016/j.chembiol.2016.05.015 PMID 27427231
  45. ↑ "Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes". Oncogene 17 (24): 3145–3156. December 1998. doi:10.1038/sj.onc.1202237. PMID 9872330. 
  46. ↑ "Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription". Genes to Cells 6 (10): 857–868. October 2001. doi:10.1046/j.1365-2443.2001.00469.x. PMID 11683914. 
  47. ↑ 47.0 47.1 "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology 23 (20): 7198–7209. October 2003. doi:10.1128/MCB.23.20.7198-7209.2003. PMID 14517290. 
  48. ↑ "Epigenetic regulation of Keap1-Nrf2 signaling". Free Radical Biology & Medicine 88 (Pt B): 337–349. November 2015. doi:10.1016/j.freeradbiomed.2015.06.013. PMID 26117320. 
  49. ↑ 49.0 49.1 "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proceedings of the National Academy of Sciences of the United States of America 105 (36): 13568–13573. September 2008. doi:10.1073/pnas.0806268105. PMID 18757741. Bibcode: 2008PNAS..10513568S. 
  50. ↑ "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicology and Applied Pharmacology 230 (3): 383–389. August 2008. doi:10.1016/j.taap.2008.03.003. PMID 18417180. Bibcode: 2008ToxAP.230..383W. 
  51. ↑ "Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs". Free Radical Biology & Medicine 44 (11): 1897–1911. June 2008. doi:10.1016/j.freeradbiomed.2008.02.006. PMID 18358244. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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