NFE2L1

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.[5][6][7] Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).

NFE2L1
Identifiers
Aliases	NFE2L1, LCR-F1, NRF1, TCF11, nuclear factor, erythroid 2 like 1
External IDs	OMIM: 163260 MGI: 99421 HomoloGene: 20685 GeneCards: NFE2L1
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q21.32 Start 48,048,329 bp[1] End 48,061,545 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 D|11 60.12 cM Start 96,817,414 bp[2] End 96,829,968 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001104 transcription coregulator activity • transcription regulatory region sequence-specific DNA binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • GO:0001948 protein binding • protein domain specific binding • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • cholesterol binding • protein heterodimerization activity • lipid binding • GO:0032403 macromolecular complex binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • chromatin binding • promoter-specific chromatin binding Cellular component • integral component of membrane • endoplasmic reticulum membrane • membrane • endoplasmic reticulum • cell nucleus • cytoplasm • cytosol • integral component of endoplasmic reticulum membrane • macromolecular complex Biological process • regulation of transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • anatomical structure morphogenesis • transcription, DNA-templated • positive regulation of transcription, DNA-templated • heme biosynthetic process • erythrocyte differentiation • inflammatory response • positive regulation of transcription from RNA polymerase II promoter • negative regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • cellular response to oxidative stress • positive regulation of transcription from RNA polymerase II promoter in response to stress • cell redox homeostasis • lipid homeostasis • cellular response to cholesterol • negative regulation of transcription from RNA polymerase II promoter in response to stress • regulation of odontoblast differentiation • lipid metabolism • steroid metabolic process • cholesterol metabolic process • cholesterol homeostasis • protein polyubiquitination • fructose 6-phosphate metabolic process • glutathione metabolic process • regulation of mitotic nuclear division • regulation of gene expression • regulation of glucose metabolic process • regulation of lipid metabolic process • regulation of fatty acid metabolic process • cellular homeostasis • spinal cord motor neuron differentiation • glial cell fate commitment • response to endoplasmic reticulum stress • cysteine transport • regulation of inflammatory response • glucose 6-phosphate metabolic process • regulation of proteasomal protein catabolic process • cellular response to cold • regulation of nucleus organization • regulation of response to endoplasmic reticulum stress Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4779	18023
Ensembl	ENSG00000082641	ENSMUSG00000038615
UniProt	Q14494	Q61985
RefSeq (mRNA)	NM_003204 NM_001330261 NM_001330262	NM_001130450 NM_001130451 NM_001130452 NM_001130453 NM_001130454 NM_008686 NM_001361682
RefSeq (protein)	NP_001317190 NP_001317191 NP_003195	NP_001123922 NP_001123923 NP_001123924 NP_001123925 NP_001123926 NP_032712 NP_001348611
Location (UCSC)	Chr 17: 48.05 – 48.06 Mb	Chr 11: 96.82 – 96.83 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5] 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.[8][9][10] NFE2L1 is a key regulator of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, cholesterol handling[11] and maintaining proteostasis.

Interactions

NFE2L1 binds DNA as heterodimers with one of small Maf proteins (MAFF, MAFG, MAFK).[12][13][10] NFE2L1 has been shown to interact with C-jun.[14]

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).[15] Nfe2l1 was found to regulate Gclm and Gss expression in mouse fibroblasts.[16] Gclm was found to be a direct target of Nfe2l1, and Nfe2l1 also regulates Gclc expression through an indirect mechanism.[17][18] 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.[19][20] Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of Nfe2l1.[21]

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.[22] A similar effect on proteasome gene expression and function was observed in livers of mice with Nfe2l1 conditional knockout in hepatocytes.[23] 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.[24] 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.[25][26] NFE2L1 was shown to directly bind and activate expression of the PsmB6 gene, which encodes a catalytic subunit of the 20S core.[22][24] Nfe2l1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway.[27][26]

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.[20][28] Glucose homeostasis and insulin secretion have also been found to be under the control of Nfe2l1.[29] 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.[30] 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.[31] Nfe2l1 has also been shown to sense and respond to excess cholesterol in the ER.[11]

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.[32] 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.[25][33][34] 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.[35] FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3.[36] Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression.[37] 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.[33] Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation.[38] 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.[9][39] 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.[40][9] Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1.[41] 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.[42][43]

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.[6][19] Loss of Nfe2l1 in mouse hepatocytes leads to steatosis, inflammation, and tumorigenesis.[20] Nfe2l1 is also necessary for neuronal homeostasis.[22] 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[29] Future studies may provide therapeutic efforts involving Nfe2l1 for cancer, neurodegeneration, and metabolic diseases.

Notes

References

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Further reading

• Zhang Y, Xiang Y (April 2016). "Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity". The Biochemical Journal. 473 (8): 961–1000. doi:10.1042/BJ20151182. PMID 27060105.
• Yuan J, Zhang S, Zhang Y (September 2018). "Nrf1 is paved as a new strategic avenue to prevent and treat cancer, neurodegenerative and other diseases". Toxicology and Applied Pharmacology. 360: 273–283. doi:10.1016/j.taap.2018.09.037. PMID 30267745.
• Luna L, Skammelsrud N, Johnsen O, Abel KJ, Weber BL, Prydz H, Kolstø AB (May 1995). "Structural organization and mapping of the human TCF11 gene". Genomics. 27 (2): 237–44. doi:10.1006/geno.1995.1037. PMID 7557987.
• Luna L, Johnsen O, Skartlien AH, Pedeutour F, Turc-Carel C, Prydz H, Kolstø AB (Aug 1994). "Molecular cloning of a putative novel human bZIP transcription factor on chromosome 17q22". Genomics. 22 (3): 553–62. doi:10.1006/geno.1994.1428. PMID 8001966.
• Caterina JJ, Donze D, Sun CW, Ciavatta DJ, Townes TM (Jun 1994). "Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression". Nucleic Acids Research. 22 (12): 2383–91. doi:10.1093/nar/22.12.2383. PMC 523699. PMID 8036168.
• Johnsen O, Skammelsrud N, Luna L, Nishizawa M, Prydz H, Kolstø AB (Nov 1996). "Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1". Nucleic Acids Research. 24 (21): 4289–97. doi:10.1093/nar/24.21.4289. PMC 146217. PMID 8932385.
• Toki T, Itoh J, Kitazawa J, Arai K, Hatakeyama K, Akasaka J, Igarashi K, Nomura N, Yokoyama M, Yamamoto M, Ito E (Apr 1997). "Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif". Oncogene. 14 (16): 1901–10. doi:10.1038/sj.onc.1201024. PMID 9150357.
• Novotny V, Prieschl EE, Csonga R, Fabjani G, Baumruker T (Dec 1998). "Nrf1 in a complex with fosB, c-jun, junD and ATF2 forms the AP1 component at the TNF alpha promoter in stimulated mast cells". Nucleic Acids Research. 26 (23): 5480–5. doi:10.1093/nar/26.23.5480. PMC 147998. PMID 9826775.
• Murphy P, Kolstø A (Oct 2000). "Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development". Mechanisms of Development. 97 (1–2): 141–8. doi:10.1016/S0925-4773(00)00413-5. PMID 11025215. S2CID 17474070.
• Jiang LQ, Wen SJ, Wang HY, Chen LY (Jul 2002). "Screening the proteins that interact with calpain in a human heart cDNA library using a yeast two-hybrid system". Hypertension Research. 25 (4): 647–52. doi:10.1291/hypres.25.647. PMID 12358155.
• Husberg C, Murphy P, Bjørgo E, Kalland KH, Kolstø AB (May 2003). "Cellular localisation and nuclear export of the human bZIP transcription factor TCF11". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1640 (2–3): 143–51. doi:10.1016/S0167-4889(03)00041-7. PMID 12729924.
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External links

• NFE2L1+protein,+human at the US 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.