NFE2L2

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Nuclear factor (erythroid-derived 2)-like 2
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsNFE2L2; NRF2
External IDsOMIM: 600492 MGI: 108420 HomoloGene: 2412 ChEMBL: 1075094 GeneCards: NFE2L2 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez478018024
EnsemblENSG00000116044ENSMUSG00000015839
UniProtQ16236Q60795
RefSeq (mRNA)NM_001145412NM_010902
RefSeq (protein)NP_001138884NP_035032
Location (UCSC)Chr 2:
178.09 – 178.26 Mb		Chr 2:
75.68 – 75.7 Mb
PubMed search
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Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor that in humans is encoded by the NFE2L2 gene.[1] The Nrf2 antioxidant response pathway is "the primary cellular defense against the cytotoxic effects of oxidative stress."[2] Among other effects, NFE2L2 increases the expression of several antioxidant enzymes. Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress, and dimethyl fumarate significantly reduced the progression of disability in multiple sclerosis.[3]

Function

NFE2L2 and other genes, such as NFE2 and NFE2L1, 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.[4][5]

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.[6] Cullin 3 ubiquitinates its substrate, Nrf2. Keap1 is a substrate adaptor, which helps Cullin 3 ubiquitinate Nrf2. When 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.[7] 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,[8][9] and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with a small Maf protein and binds to the Antioxidant Response Element (ARE) in the upstream promoter region of many antioxidative genes, and initiates their transcription.[10]

Target Genes

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1) is a prototypical Nrf2 target gene that catalyzes the reduction and detoxification of highly reactive quinones that can cause redox cycling and oxidative stress.[11]
  • Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM) subunits 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.[12]
  • 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.[13] In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.[14]
  • 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 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.[15]
  • 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.[16]
  • 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.[17][18]

Structure

Nrf2 is a basic leucine zipper (bZip) transcription factor with a Cap “n” Collar (CNC) structure.[1]

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.[19] The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1.[20] 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.[21] 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.[20] The Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.[22]

Tissue distribution

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.[1]

As a drug target

No Nrf2 inhibitors have been approved for the treatment of human diseases, although some compounds have been investigated in experimental models and preliminary clinical trials. In a phase 3 clinical trial, dimethyl fumarate (BG-12), which upregulates Nrf2, was reported to significantly reduce relapse and disability progression rates in patients with relapsing-remitting multiple sclerosis.[2] In a mouse model of experimental autoimmune encephalomyelitis, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid trifluoroethyl amide (CDDO-TFEA) suppressed by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease.[23]

The dithiolethiones are a class of organosulfur compounds, of which oltipraz is the best studied.[24] Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue.[25] However, clinical trials of oltipraz have not demonstrated efficacy and have shown significantside effects, including neurotoxicity and gastrointestinal toxicity.[25] Oltipraz also generates superoxide radical, which can be toxic.[26]

The diabetes drug lipoic acid is a potent activator of Nrf2 and thus increases Gluthation levels, which may explain its protective effect against diabetic comorbidities.[27]

Interactions

NFE2L2 has been shown to interact with:

References

  1. ↑ 1.0 1.1 1.2 Moi P, Chan K, Asunis I, Cao A, Kan YW (October 1994). "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". Proc. Natl. Acad. Sci. U.S.A. 91 (21): 9926–30. doi:10.1073/pnas.91.21.9926. PMC 44930. PMID 7937919. 
  2. ↑ 2.0 2.1 Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (September 2012). "Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis". N. Engl. J. Med. 367 (12): 1098–107. doi:10.1056/NEJMoa1114287. PMID 22992073. 
  3. ↑ Placebo-controlled phase 3 study of oral BG-12 for relapsing Multiple Sclerosis, N Engl J Med 367:1098
  4. ↑ Chan JY, Cheung MC, Moi P, Chan K, Kan YW (March 1995). "Chromosomal localization of the human NF-E2 family of bZIP transcription factors by fluorescence in situ hybridization". Hum. Genet. 95 (3): 265–9. doi:10.1007/BF00225191. PMID 7868116. 
  5. ↑ "Entrez Gene: NFE2L2 nuclear factor (erythroid-derived 2)-like 2". 
  6. ↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (January 1999). "Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain". Genes Dev. 13 (1): 76–86. doi:10.1101/gad.13.1.76. PMC 316370. PMID 9887101. 
  7. ↑ Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (August 2004). "Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2". Mol. Cell. Biol. 24 (16): 7130–9. doi:10.1128/MCB.24.16.7130-7139.2004. PMC 479737. PMID 15282312. 
  8. ↑ Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M (April 2008). "Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity". Mol. Cell. Biol. 28 (8): 2758–70. doi:10.1128/MCB.01704-07. PMC 2293100. PMID 18268004. 
  9. ↑ Sekhar KR, Rachakonda G, Freeman ML (June 2009). "Cysteine-based Regulation of the CUL3 Adaptor Protein Keap1". Toxicol. Appl. Pharmacol. 244 (1): 21–6. doi:10.1016/j.taap.2009.06.016. PMC 2837771. PMID 19560482. 
  10. ↑ Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (July 1997). "An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements". Biochem. Biophys. Res. Commun. 236 (2): 313–22. doi:10.1006/bbrc.1997.6943. PMID 9240432. 
  11. ↑ Venugopal R, Jaiswal AK (December 1996). "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". Proc. Natl. Acad. Sci. U.S.A. 93 (25): 14960–5. doi:10.1073/pnas.93.25.14960. PMC 26245. PMID 8962164. 
  12. ↑ Solis WA, Dalton TP, Dieter MZ, Freshwater S, Harrer JM, He L, Shertzer HG, Nebert DW (May 2002). "Glutamate-cysteine ligase modifier subunit: mouse Gclm gene structure and regulation by agents that cause oxidative stress". Biochem. Pharmacol. 63 (9): 1739–54. doi:10.1016/S0006-2952(02)00897-3. PMID 12007577. 
  13. ↑ Jarmi T, Agarwal A (February 2009). "Heme oxygenase and renal disease". Curr. Hypertens. Rep. 11 (1): 56–62. doi:10.1007/s11906-009-0011-z. PMID 19146802. 
  14. ↑ Wang J, Doré S (2007). "Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage.". Brain 130 (6): 1643–52. doi:10.1093/brain/awm095. PMC 2291147. PMID 17525142. 
  15. ↑ Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M (February 2000). "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". Biochem. Soc. Trans. 28 (2): 33–41. PMID 10816095. 
  16. ↑ Yueh MF, Tukey RH (March 2007). "Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice". J. Biol. Chem. 282 (12): 8749–58. doi:10.1074/jbc.M610790200. PMID 17259171. 
  17. ↑ Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, Dalton TP, Yamamoto M, Klaassen CD (November 2007). "Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway". Hepatology 46 (5): 1597–610. doi:10.1002/hep.21831. PMID 17668877. 
  18. ↑ Reisman SA, Csanaky IL, Aleksunes LM, Klaassen CD (May 2009). "Altered Disposition of Acetaminophen in Nrf2-null and Keap1-knockdown Mice". Toxicol. Sci. 109 (1): 31–40. doi:10.1093/toxsci/kfp047. PMC 2675638. PMID 19246624. 
  19. ↑ Motohashi H, Katsuoka F, Engel JD, Yamamoto M. (April 2004). "Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1–Nrf2 regulatory pathway". Proc Natl Acad Sci U S A. 101 (17): 6379–84. doi:10.1073/pnas.0305902101. PMC 404053. PMID 15087497. 
  20. ↑ 20.0 20.1 Motohashi H, Yamamoto M (November 2004). "Nrf2-Keap1 defines a physiologically important stress response mechanism". Trends Mol Med 10 (11): 549–57. doi:10.1016/j.molmed.2004.09.003. PMID 15519281. 
  21. ↑ Nioi P, Nguyen T, Sherratt PJ, Pickett CB (December 2005). "The Carboxy-Terminal Neh3 Domain of Nrf2 Is Required for Transcriptional Activation". Mol. Cell. Biol. 25 (24): 10895–906. doi:10.1128/MCB.25.24.10895-10906.2005. PMC 1316965. PMID 16314513. 
  22. ↑ McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (July 2004). "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". J. Biol. Chem. 279 (30): 31556–67. doi:10.1074/jbc.M403061200. PMID 15143058. 
  23. ↑ Pareek TK, Belkadi A, Kesavapany S, Zaremba A, Loh SL, Bai L, Cohen ML, Meyer C, Liby KT, Miller RH, Sporn MB, Letterio JJ (2011). "Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis". Sci Rep 1: 201. doi:10.1038/srep00201. PMC 3242013. PMID 22355716. 
  24. ↑ Prince M, Li Y, Childers A, Itoh K, Yamamoto M, Kleiner HE (March 2009). "Comparison of citrus coumarins on carcinogen-detoxifying enzymes in Nrf2 knockout mice". Toxicol. Lett. 185 (3): 180–6. doi:10.1016/j.toxlet.2008.12.014. PMC 2676710. PMID 19150646. 
  25. ↑ 25.0 25.1 Zhang Y, Gordon GB (July 2004). "A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway". Mol. Cancer Ther. 3 (7): 885–93. PMID 15252150. 
  26. ↑ Velayutham M, Villamena FA, Fishbein JC, Zweier JL (March 2005). "Cancer chemopreventive oltipraz generates superoxide anion radical". Arch. Biochem. Biophys. 435 (1): 83–8. doi:10.1016/j.abb.2004.11.028. PMID 15680910. 
  27. ↑ Mah E, Noh SK, Ballard KD, Park HJ, Volek JS, Bruno RS (March 2004). "Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid.". Proc. Natl. Acad. Sci. USA 101 (10): 3381–6. doi:10.1073/pnas.0400282101. PMID 14985508. 
  28. ↑ Venugopal R, Jaiswal AK (1998). "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): 3145–56. doi:10.1038/sj.onc.1202237. PMID 9872330. 
  29. ↑ Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (2001). "Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription". Genes Cells 6 (10): 857–68. doi:10.1046/j.1365-2443.2001.00469.x. PMID 11683914. 
  30. ↑ 30.0 30.1 Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290. 
  31. ↑ 31.0 31.1 Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (2008). "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy". Proc. Natl. Acad. Sci. U.S.A. 105 (36): 13568–73. doi:10.1073/pnas.0806268105. PMC 2533230. PMID 18757741. 
  32. ↑ Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (2008). "Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction". Toxicol. Appl. Pharmacol. 230 (3): 383–9. doi:10.1016/j.taap.2008.03.003. PMC 2610481. PMID 18417180. 
  33. ↑ Patel R, Maru G (2008). "Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs". Free Radic. Biol. Med. 44 (11): 1897–911. doi:10.1016/j.freeradbiomed.2008.02.006. PMID 18358244. 

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