Biology:NFE2L1

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Short description: Protein-coding gene in the species Homo sapiens


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

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.[1][2][3] Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).

NFE2L1 is a cap ‘n’ collar, basic-leucine zipper (bZIP) transcription factor. Several isoforms of NFE2L1 have been described for both human and mouse genes. NFE2L1 was first cloned in yeast using a genetic screening method. NFE2L1 is ubiquitously expressed, and high levels of transcript are detected in the heart, kidney, skeletal muscle, fat, and brain.[1] Four separate regions — an asparagine/serine/threonine, acidic domains near the N-terminus, and a serine-rich domain located near the CNC motif — are required for full transactivation function of NFE2L1.[4][5][6] NFE2L1 is a key regulator of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, cholesterol handling[7] and maintaining proteostasis.

Interactions

NFE2L1 binds DNA as heterodimers with one of small Maf proteins (MAFF, MAFG, MAFK).[8][9][6] NFE2L1 has been shown to interact with C-jun.[10]

Cellular homeostasis

NFE2L1 regulates a wide variety of cellular responses, several of which are related to important aspects of protection from stress stimuli. NFE2L1 is involved in providing cellular protection against oxidative stress through the induction of antioxidant genes. The glutathione synthesis pathway is catalyzed by glutamate-cysteine ligase, which contains the catalytic GCLC and regulatory GCLM, and glutathione synthetase (GSS).[11] Nfe2l1 was found to regulate Gclm and Gss expression in mouse fibroblasts.[12] Gclm was found to be a direct target of Nfe2l1, and Nfe2l1 also regulates Gclc expression through an indirect mechanism.[13][14] Nfe2l1 knockout mice also exhibit down-regulation of Gpx1 and Hmox1, and Nfe2l1 (this gene)-deficient hepatocytes from liver-specific Nfe2l1 knockout mice showed decreased expression of various Gst genes.[15][16] Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of Nfe2l1.[17]

Nfe2l1 is also involved in maintaining proteostasis. Brains of mice with conditional knockout of Nfe2l1 in neuronal cells showed decreased proteasome activity and accumulation of ubiquitin-conjugated proteins, and down regulation of genes encoding the 20S core and 19S regulatory sub-complexes of the 26S proteasome.[18] A similar effect on proteasome gene expression and function was observed in livers of mice with Nfe2l1 conditional knockout in hepatocytes.[19] Induction of proteasome genes was also lost in brains and livers of Nfe2l1 conditional knockout mice. Re-establishment of Nfe2l1 function in Nfe2l1 null cells rescued proteasome expression and function, indicating Nfe2l1 was necessary for induction of proteasome genes (bounce-back response) in response to proteasome inhibition.[20] This compensatory up-regulation of proteasome genes in response to proteasome inhibition has also been demonstrated to be Nfe2l1-dependent in various other cell types.[21][22] NFE2L1 was shown to directly bind and activate expression of the PsmB6 gene, which encodes a catalytic subunit of the 20S core.[18][20] Nfe2l1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway.[23][22]

Nfe2l1 also plays a role in metabolic processes. Loss of hepatic Nfe2l1 has been shown to result in lipid accumulation, hepatocellular damage, cysteine accumulation, and altered fatty acid composition.[16][24] Glucose homeostasis and insulin secretion have also been found to be under the control of Nfe2l1.[25] Insulin-regulated glycolytic genes—Gck, Aldob, Pgk1, and Pklr, hepatic glucose transporter gene — SLC2A2, and gluconeogenic genes — Fbp1 and Pck1 were repressed in livers of Nfe2l1 transgenic mice.[26] Nfe2l1 may also play a role in maintaining chromosomal stability and genomic integrity by inducing expression of genes encoding components of the spindle assembly and kinetochore.[27] Nfe2l1 has also been shown to sense and respond to excess cholesterol in the ER.[7]

Regulation

NFE2L1 is an ER membrane protein. Its N-terminal domain (NTD) anchors the protein to the membrane. Specifically, amino acid residues 7 to 24 are known to be a hydrophobic domain that serves as a transmembrane region.[28] The concerted mechanism of HRD1, a member of E3-ubiquitin ligase family, and p97/VCP1 was found to play an important role in the degradation of NFE2L1 through the ER Associated Degradation (ERAD) pathway and the release of NFE2L1 from the ER membrane.[21][29][30] NFE2L1 is also regulated by other ubiquitin ligases and kinases. FBXW7, a member of the SCF ubiquitin ligase family, targets NFE2L1 for proteolytic degradation by the proteasome.[31] FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3.[32] Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression.[33] NFE2L1 also interacts with another member of the SCF ligase ubiquitin family known as β-TrCP. β-TrCP also binds to the DSGLC motif, a highly conserved region of CNC-bZIP proteins, in order to poly-ubiquitinate NFE2L1 prior to its proteolytic degradation.[29] Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation.[34] NFE2L1 expression and activation is also controlled by cellular stresses. Oxidative stress induced by arsenic and t-butyl hydroquinone leads to accumulation of NFE2L1 protein inside the nucleus as well as higher activation on antioxidant genes.[5][35] Treatment with an ER stress inducer tunicamycin was shown to induce accumulation of NFE2L1 inside the nucleus; however, it was not associated with increased activity, suggesting further investigation is needed to elucidate the role of ER stress on NFE2L1.[36][5] Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1.[37] Growth factors affect expression of NFE2L1 through a mTORC and SREBP-1 mediated pathway. Growth factors induce higher activity of mTORC, which then promotes activity of its downstream protein SREBP-1, a transcription factor for NFE2L1.[38][39]

Animal studies

Loss and gain of function studies in mice showed that dysregulation of Nfe2l1 leads to pathological states that could have relevance in human diseases. Nfe2l1 is crucial for embryonic development and survival of hepatocytes during development.[2][15] Loss of Nfe2l1 in mouse hepatocytes leads to steatosis, inflammation, and tumorigenesis.[16] Nfe2l1 is also necessary for neuronal homeostasis.[18] Loss of Nfe2l1 function is also associated with insulin resistance. Mice with conditional deletion of Nfe2l1 in pancreatic β-cells exhibited severe fasting hyperinsulinemia and glucose intolerance, suggesting that Nfe2l1 may play a role in the development of type-2 diabetes[25] Future studies may provide therapeutic efforts involving Nfe2l1 for cancer, neurodegeneration, and metabolic diseases.

Notes

References

  1. ↑ 1.0 1.1 "Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast". Proceedings of the National Academy of Sciences of the United States of America 90 (23): 11371–5. Dec 1993. doi:10.1073/pnas.90.23.11371. PMID 8248256. Bibcode: 1993PNAS...9011371C. 
  2. ↑ 2.0 2.1 "Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice". The EMBO Journal 17 (6): 1779–87. Mar 1998. doi:10.1093/emboj/17.6.1779. PMID 9501099. 
  3. ↑ "Entrez Gene: NFE2L1 nuclear factor (erythroid-derived 2)-like 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4779. 
  4. ↑ "Two domains of the human bZIP transcription factor TCF11 are necessary for transactivation". The Journal of Biological Chemistry 276 (21): 17641–52. May 2001. doi:10.1074/jbc.M007951200. PMID 11278371. http://www.tara.tcd.ie/bitstream/2262/34766/1/Husberg%20et%20al%202001.pdf. 
  5. ↑ 5.0 5.1 5.2 "The Nrf1 CNC/bZIP protein is a nuclear envelope-bound transcription factor that is activated by t-butyl hydroquinone but not by endoplasmic reticulum stressors". The Biochemical Journal 418 (2): 293–310. Mar 2009. doi:10.1042/BJ20081575. PMID 18990090. https://hal.science/hal-00479080/file/PEER_stage2_10.1042%252FBJ20081575.pdf. 
  6. ↑ 6.0 6.1 "The p65 isoform of Nrf1 is a dominant negative inhibitor of ARE-mediated transcription". The Journal of Biological Chemistry 282 (34): 24670–8. Aug 2007. doi:10.1074/jbc.M700159200. PMID 17609210. 
  7. ↑ 7.0 7.1 "NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis". Cell 171 (5): 1094–1109.e15. November 2017. doi:10.1016/j.cell.2017.10.003. PMID 29149604. 
  8. ↑ "hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2". The Journal of Biological Chemistry 272 (26): 16490–7. Jun 1997. doi:10.1074/jbc.272.26.16490. PMID 9195958. 
  9. ↑ "Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription". Nucleic Acids Research 26 (2): 512–20. Jan 1998. doi:10.1093/nar/26.2.512. PMID 9421508. 
  10. ↑ "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. Dec 1998. doi:10.1038/sj.onc.1202237. PMID 9872330. 
  11. ↑ "Regulation of glutathione synthesis". Molecular Aspects of Medicine 30 (1–2): 42–59. 2009. doi:10.1016/j.mam.2008.05.005. PMID 18601945. 
  12. ↑ "The CNC basic leucine zipper factor, Nrf1, is essential for cell survival in response to oxidative stress-inducing agents. Role for Nrf1 in gamma-gcs(l) and gss expression in mouse fibroblasts". The Journal of Biological Chemistry 274 (52): 37491–8. Dec 1999. doi:10.1074/jbc.274.52.37491. PMID 10601325. 
  13. ↑ "TCF11/Nrf1 overexpression increases the intracellular glutathione level and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1517 (2): 212–9. Jan 2001. doi:10.1016/s0167-4781(00)00276-1. PMID 11342101. 
  14. ↑ "Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1". Molecular and Cellular Biology 25 (14): 5933–46. Jul 2005. doi:10.1128/MCB.25.14.5933-5946.2005. PMID 15988009. 
  15. ↑ 15.0 15.1 "Nrf1 is critical for redox balance and survival of liver cells during development". Molecular and Cellular Biology 23 (13): 4673–86. Jul 2003. doi:10.1128/mcb.23.13.4673-4686.2003. PMID 12808106. 
  16. ↑ 16.0 16.1 16.2 "Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia". Proceedings of the National Academy of Sciences of the United States of America 102 (11): 4120–5. Mar 2005. doi:10.1073/pnas.0500660102. PMID 15738389. Bibcode: 2005PNAS..102.4120X. 
  17. ↑ "Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes". The Journal of Biological Chemistry 283 (48): 33554–62. Nov 2008. doi:10.1074/jbc.M804597200. PMID 18826952. 
  18. ↑ 18.0 18.1 18.2 "Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration". Proceedings of the National Academy of Sciences of the United States of America 108 (20): 8408–13. May 2011. doi:10.1073/pnas.1019209108. PMID 21536885. Bibcode: 2011PNAS..108.8408L. 
  19. ↑ "Nuclear factor-erythroid 2-related factor 1 regulates expression of proteasome genes in hepatocytes and protects against endoplasmic reticulum stress and steatosis in mice". The FEBS Journal 280 (15): 3609–20. Aug 2013. doi:10.1111/febs.12350. PMID 23702335. 
  20. ↑ 20.0 20.1 "Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells". Molecular Cell 38 (1): 17–28. Apr 2010. doi:10.1016/j.molcel.2010.02.029. PMID 20385086. 
  21. ↑ 21.0 21.1 "Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop". Molecular Cell 40 (1): 147–58. Oct 2010. doi:10.1016/j.molcel.2010.09.012. PMID 20932482. 
  22. ↑ 22.0 22.1 "Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97". Current Biology 24 (14): 1573–83. Jul 2014. doi:10.1016/j.cub.2014.06.004. PMID 24998528. 
  23. ↑ "Induction of Herpud1 expression by ER stress is regulated by Nrf1". FEBS Letters 589 (5): 615–20. Feb 2015. doi:10.1016/j.febslet.2015.01.026. PMID 25637874. 
  24. ↑ "Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes". Molecular and Cellular Biology 34 (20): 3800–16. Oct 2014. doi:10.1128/MCB.00110-14. PMID 25092871. 
  25. ↑ 25.0 25.1 "CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion". Antioxidants & Redox Signaling 22 (10): 819–31. Apr 2015. doi:10.1089/ars.2014.6017. PMID 25556857. 
  26. ↑ "Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice". Genes to Cells 19 (8): 650–65. Aug 2014. doi:10.1111/gtc.12165. PMID 25041126. 
  27. ↑ "Deficiency in the nuclear-related factor erythroid 2 transcription factor (Nrf1) leads to genetic instability". The FEBS Journal 279 (22): 4121–30. Nov 2012. doi:10.1111/febs.12005. PMID 22971132. 
  28. ↑ "Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function". The Journal of Biological Chemistry 281 (28): 19676–87. Jul 2006. doi:10.1074/jbc.M602802200. PMID 16687406.  https://pubpeer.com/publications/34FAE52A483C74E4D42770D878A999}
  29. ↑ 29.0 29.1 "Dual regulation of the transcriptional activity of Nrf1 by β-TrCP- and Hrd1-dependent degradation mechanisms". Molecular and Cellular Biology 31 (22): 4500–12. Nov 2011. doi:10.1128/MCB.05663-11. PMID 21911472. 
  30. ↑ "p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition". eLife 3: e01856. 2014. doi:10.7554/eLife.01856. PMID 24448410. 
  31. ↑ "The Fbw7 tumor suppressor regulates nuclear factor E2-related factor 1 transcription factor turnover through proteasome-mediated proteolysis". The Journal of Biological Chemistry 286 (45): 39282–9. Nov 2011. doi:10.1074/jbc.M111.253807. PMID 21953459. 
  32. ↑ "Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1". Experimental Cell Research 319 (13): 1922–31. Aug 2013. doi:10.1016/j.yexcr.2013.04.013. PMID 23623971. 
  33. ↑ "The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression". Molecular and Cellular Biology 33 (17): 3461–72. Sep 2013. doi:10.1128/MCB.01271-12. PMID 23816881. 
  34. ↑ "The CCAAT enhancer-binding protein (C/EBP)beta and Nrf1 interact to regulate dentin sialophosphoprotein (DSPP) gene expression during odontoblast differentiation". The Journal of Biological Chemistry 279 (44): 45423–32. Oct 2004. doi:10.1074/jbc.M405031200. PMID 15308669. 
  35. ↑ "Long isoforms of NRF1 contribute to arsenic-induced antioxidant response in human keratinocytes". Environmental Health Perspectives 119 (1): 56–62. Jan 2011. doi:10.1289/ehp.1002304. PMID 20805060. 
  36. ↑ "Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum". The Biochemical Journal 399 (3): 373–85. Nov 2006. doi:10.1042/BJ20060725. PMID 16872277. 
  37. ↑ "The Nrf1 CNC-bZIP protein is regulated by the proteasome and activated by hypoxia". PLOS ONE 6 (12): e29167. 2011. doi:10.1371/journal.pone.0029167. PMID 22216197. Bibcode: 2011PLoSO...629167C. 
  38. ↑ "mTORC1 signaling activates NRF1 to increase cellular proteasome levels". Cell Cycle 14 (13): 2011–7. 2015. doi:10.1080/15384101.2015.1044188. PMID 26017155. 
  39. ↑ "Coordinated regulation of protein synthesis and degradation by mTORC1". Nature 513 (7518): 440–3. Sep 2014. doi:10.1038/nature13492. PMID 25043031. Bibcode: 2014Natur.513..440Z. 

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