Affinage

NFE2L1

Endoplasmic reticulum membrane sensor NFE2L1 · UniProt Q14494

Length
772 aa
Mass
84.7 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NFE2L1 (NRF-1/TCF11/LCR-F1) is a CNC-bZIP transcription factor that serves dual master-regulatory roles in mitochondrial biogenesis and proteostasis (PMID:2166701, PMID:20932482). It was first defined as a sequence-specific activator of nuclear-encoded respiratory genes, binding recognition elements through specific guanine contacts and trans-activating cytochrome c, cytochrome oxidase subunit VIc, ATP synthase γ-subunit, and other respiratory and housekeeping genes via a single ~68-kDa factor (PMID:2547796, PMID:2166701, PMID:1348057); its DNA-binding domain lies in the amino-terminal half (PMID:8253388). NRF-1 directly drives the mitochondrial transcription machinery, with NRF-1 sites in the Tfam, TFB1M, and TFB2M promoters required for coactivation by PGC-1 family members (PGC-1α, PGC-1β, PRC) that bind NRF-1 directly, integrating it into the program of mitochondrial biogenesis (PMID:15684387, PMID:16908542, PMID:20561910); serum-stimulated phosphorylation enhances its transactivation and respiratory output (PMID:10777619). The protein heterodimerizes with small Maf proteins (MafG/MafK), which increase its affinity for NF-E2/ARE sites yet can repress its transactivation, enabling combinatorial control of antioxidant and target genes such as the glutathione-synthesis gene GCS-h (PMID:8932385, PMID:9421508, PMID:11342101). As a proteostatic regulator, NFE2L1 is synthesized into the ER membrane and constitutively targeted to ERAD, then retrotranslocated by p97, deglycosylated, and proteolytically processed by DDI-1/2 to generate active nuclear isoforms; upon proteasome inhibition it accumulates in the nucleus and binds AREs in proteasome subunit gene promoters to mount the proteasome bounce-back response (PMID:20932482, PMID:30287392, PMID:39384955). This non-canonical activation is restrained by SCFFBS2–ARIH1, which ubiquitinates NFE2L1 through oxyester bonds on N-GlcNAc residues to block DDI2-mediated processing (PMID:39116872). Beyond proteasome subunits, NFE2L1 couples this response to aggrephagy by inducing p62/SQSTM1 and GABARAPL1 (PMID:37658135) and protects against ferroptosis by sustaining GPX4 expression and proteasomal activity (PMID:35271393, PMID:34999280). Isoform-specific control is intrinsic to the locus: long isoforms (TCF11) act as transcriptional activators, while the short LCR-F1 isoform lacks transactivation domains and behaves as a dominant-negative inhibitor (PMID:11278371). Genetic studies establish essential physiological roles, with Nfe2l1 loss causing gastrulation failure and defective definitive erythropoiesis in mice and tissue-specific phenotypes in adipose, bone, and muscle (PMID:9087432, PMID:9501099, PMID:34763297, PMID:29935181).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1990 High

    Established NRF-1 as a single trans-acting factor coordinating multiple nuclear-encoded respiratory genes, defining its core role in mitochondrial gene expression.

    Evidence DNA competition binding, chromatographic copurification, methylation interference footprinting, and in vivo transfection across cytochrome c, COX VIc, reductase, and MRP RNA genes

    PMID:2166701 PMID:2547796

    Open questions at the time
    • Did not identify coactivators or upstream signals
    • Protein identity not yet cloned
  2. 1993 High

    Cloning and domain mapping defined NRF-1 as a new class of DNA-binding protein and localized its DNA-binding activity to the N-terminal half, enabling molecular dissection.

    Evidence cDNA cloning from HeLa tryptic peptides, deletion mapping, recombinant protein, supershift

    PMID:8253388

    Open questions at the time
    • Transactivation domain architecture not yet mapped
    • Regulation of activity unknown
  3. 1998 High

    Showed NFE2L1 partners with small Maf proteins at NF-E2/ARE sites and that dimer composition tunes both DNA affinity and transactivation, revealing combinatorial regulation.

    Evidence In vitro heterodimerization, EMSA/supershift, SELEX, and reporter assays with MafG

    PMID:8932385 PMID:9421508

    Open questions at the time
    • Cellular context determining activation versus repression unclear
    • ARE target gene repertoire not defined
  4. 1998 High

    Knockout mice established NFE2L1 as developmentally essential, required non-cell-autonomously for gastrulation and definitive erythropoiesis.

    Evidence Gene targeting, blastocyst chimeras, and developmental/hematological phenotyping in mice

    PMID:9087432 PMID:9501099

    Open questions at the time
    • The signaling molecules mediating the non-cell-autonomous effect not identified
    • Direct target genes underlying the phenotype unknown
  5. 2001 Medium

    Defined isoform-based regulation: full-length TCF11 carries two transactivation domains while the short LCR-F1 isoform is a dominant-negative inhibitor.

    Evidence Domain deletion/swap mutants and reporter assays across cell lines; antioxidant GCS-h promoter activation via ARE

    PMID:11278371 PMID:11342101

    Open questions at the time
    • Physiological balance of isoforms in tissues not measured
    • Mechanism of dominant-negative action not resolved
  6. 2006 High

    Linked NRF-1 to the PGC-1/PRC coactivator program and the mitochondrial transcription machinery, positioning it as an integrator of biogenesis signals.

    Evidence NRF-1 site mutagenesis in Tfam/TFB1M/TFB2M promoters, ectopic PGC-1α expression, reciprocal Co-IP, ChIP, and respiratory growth assays for PRC; serum-induced phosphorylation

    PMID:10777619 PMID:15684387 PMID:16908542 PMID:20561910

    Open questions at the time
    • Kinases phosphorylating NRF-1 not identified
    • Structural basis of coactivator binding unknown
  7. 2009 High

    Identified physical partners beyond transcription, including dynein light chain and a PARP-1·DNA-PK·Ku·topoisomerase IIβ complex that NRF-1 can recruit and that PARylates its DNA-binding domain.

    Evidence Yeast two-hybrid, crosslinking of purified proteins, Co-IP, domain mapping, PARylation assay, and ChIP

    PMID:11069771 PMID:19181665

    Open questions at the time
    • Functional consequence of dynein interaction for NRF-1 trafficking unclear
    • Genome-wide impact of PARP-1 recruitment not defined
  8. 2010 High

    Revealed NFE2L1 as the transcription factor driving the proteasome bounce-back response, controlled by ER residence and ERAD requiring HRD1 and p97.

    Evidence Cell-based factor identification, subcellular fractionation, dominant-negative ERAD components, and promoter-binding assays after proteasome inhibition

    PMID:20932482

    Open questions at the time
    • Protease generating the active form not yet identified
    • Retrotranslocation-to-nucleus steps not fully ordered
  9. 2018 High

    Resolved the sequential post-translational processing pathway converting ER-bound glycoprotein NFE2L1 into active nuclear isoforms via p97 retrotranslocation, deglycosylation, and DDI-1/2 cleavage.

    Evidence Mutagenesis, glycosylation/deglycosylation assays, p97/ERAD and proteasome inhibitors, isoform western blots

    PMID:30287392

    Open questions at the time
    • Quantitative feedback dynamics not modeled
    • Glycosidase identities incompletely defined
  10. 2023 High

    Extended NFE2L1's proteostatic output to selective autophagy and demonstrated therapeutic gain-of-function, coupling the bounce-back response to aggrephagy and neuroprotection.

    Evidence RNA-seq, knockdown, immunofluorescence of p62/ULK1/TBK1 puncta and Ser403 phosphorylation; AAV overexpression in mouse retina with proteasome and survival readouts

    PMID:37450596 PMID:37658135

    Open questions at the time
    • Direct versus indirect induction of autophagy genes not fully separated
    • Durability of neuroprotective effect not established
  11. 2022 High

    Established NFE2L1 as a ferroptosis-resistance factor acting through GPX4 maintenance and proteasomal capacity, distinct from NFE2L2.

    Evidence Gene knockout cell and mouse models (Gpx4-KO, Nfe2l1-deficient), ferroptosis induction, GPX4 and proteasome activity assays, patient-derived cells

    PMID:34999280 PMID:35271393

    Open questions at the time
    • Whether GPX4 is a direct transcriptional target not resolved
    • Tissue specificity of ferroptosis protection incompletely mapped
  12. 2024 High

    Defined the non-canonical ubiquitin switch and proteolytic activation controlling NFE2L1: SCFFBS2–ARIH1 ubiquitinates N-GlcNAc residues to block activation, while DDI2 cleavage activates the factor during ferroptosis-induced proteasome stress.

    Evidence In vitro reconstitution on glycopeptides, E3/UBE2L3 identification, mass spectrometry, DDI2 knockout, proteomic ubiquitylation mapping, nelfinavir inhibition

    PMID:32344880 PMID:39116872 PMID:39384955

    Open questions at the time
    • Spatial coordination of ENGASE/ARIH1/DDI2 steps not defined
    • Physiological triggers tuning this switch incompletely characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NFE2L1 integrates its mitochondrial-biogenesis and proteostasis programs within a single cell, and how isoform balance and metabolic sensing (e.g., AMPK inhibition) are coordinated in vivo, remains open.
  • No unified model linking respiratory-gene activation and proteasome bounce-back
  • Direct AMPK-inhibition mechanism rests on single-lab Co-IP
  • In vivo determinants of isoform choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 2 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
AMPKDDI2MAFGMAFKPARP-1PGC-1ΑPGC-1ΒPRC

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 NRF-1 (NFE2L1) was identified as a sequence-specific transcriptional activator binding to a recognition element in the rat somatic cytochrome c promoter; mutational analysis showed the NRF-1 site is required for maximal cytochrome c promoter activity, and the factor makes specific guanine nucleotide contacts within its recognition sequence. Promoter mutational analysis, DNA-binding/competition assays, in vivo transfection reporter assays The Journal of biological chemistry High 2547796
1990 NRF-1 functions as a trans-activator of multiple nuclear-encoded respiratory genes (cytochrome c, cytochrome oxidase subunit VIc, ubiquinone-binding protein of reductase complex, MRP RNA gene); NRF-1-binding activities for each site copurify chromatographically, have the same thermal lability, and make similar guanine nucleotide contacts, indicating a single factor recognizes all sites; in vitro recognition correlates with in vivo transcriptional activation. DNA competition binding assays, chromatographic copurification, methylation interference footprinting, in vivo transfection assays Genes & development High 2166701
1992 NRF-1 directly binds and activates functional recognition sites in the ATP synthase γ-subunit gene (complex V), eukaryotic initiation factor 2α gene, and tyrosine aminotransferase gene; the binding activities for all sites copurify ~33,000-fold and reside in a single 68-kDa protein. Competition binding assays, methylation interference footprinting, UV-induced DNA cross-linking, chromatographic copurification, transfection reporter assays The Journal of biological chemistry High 1348057
1993 The NRF-1 DNA-binding domain was mapped to the amino-terminal half of the protein by deletion analysis; cloning revealed NRF-1 defines a new class of DNA-binding proteins sharing sequence identity with sea urchin P3A2 and Drosophila EWG; recombinant NRF-1 reproduced the DNA-binding specificity and transcriptional activation of authentic HeLa NRF-1. cDNA cloning from HeLa cells using tryptic peptide sequences, deletion mapping, recombinant protein production, transcription activation assays, antiserum supershift Genes & development High 8253388
1996 TCF11/NFE2L1 forms heterodimers with small Maf proteins (MafG, MafK); heterodimerization with small Maf proteins alters DNA-binding characteristics of TCF11, producing stronger binding to NF-E2 sites than TCF11 alone; TCF11 isoforms bound to NF-E2 sites were detected in K562 erythroid cell nuclear extracts by antibody supershift. In vitro heterodimerization assays, EMSA/supershift assays, antibody detection in nuclear extracts Nucleic acids research High 8932385
1997 LCR-F1/NFE2L1 is essential for gastrulation in mice; homozygous null embryos fail to form a primitive streak and lack detectable mesoderm, demonstrating a non-cell-autonomous role; LCR-F1 null ES cells contribute normally to mesodermally derived tissues including erythroid cells in chimeras, indicating the function is mediated through signaling molecules rather than cell-intrinsic globin gene regulation. Gene targeting/knockout in mouse ES cells, blastocyst injection chimeras, developmental phenotype analysis Genes & development High 9087432
1998 TCF11/NFE2L1 and MafG form a heterodimer that preferentially recognizes the NF-E2/antioxidant response element (ARE) sequence 5'-TGCTgaGTCAT-3'; MafG alone acts as a transcriptional repressor, while TCF11 alone activates transcription; when co-expressed, MafG inhibits TCF11 transactivation in a dose-dependent manner despite the higher DNA affinity of the heterodimer. Binding-site selection assay (SELEX), transient transfection reporter assays, in vitro dimerization assays Nucleic acids research High 9421508
1998 Homozygous disruption of Nrf1/NFE2L1 in mice causes anemia due to a non-cell-autonomous defect in definitive erythropoiesis and embryonic lethality in utero. Targeted gene disruption in mice (knockout), histological and hematological analysis The EMBO journal High 9501099
1998 NRF-1 binding sites in both human TFB1M and TFB2M (mitochondrial transcription specificity factor) promoters are required for maximal trans-activation by PGC-1α and PRC coactivators; ectopic expression of PGC-1α induces TFB1M, TFB2M, and Tfam coordinately along with NRF-1 target respiratory subunits. Promoter mutational analysis, transient transfection reporter assays, ectopic expression of PGC-1α Molecular and cellular biology High 15684387
2000 NRF-1 is phosphorylated sequentially after serum stimulation, and this phosphorylation increases its trans-activation activity on the cytochrome c promoter, leading to enhanced mitochondrial respiration; both NRF-1 and CREB binding sites contribute equally to serum-induced cytochrome c expression. Promoter mutant transfections, phosphorylation analysis, mitochondrial respiration measurement The Journal of biological chemistry Medium 10777619
2000 Dynein light chain physically interacts with NRF-1, requiring the first 26 amino acids of NRF-1; interaction was confirmed by yeast two-hybrid screening, chemical crosslinking of purified native proteins, and co-immunoprecipitation from mammalian cells; both NRF-1 and dynein light chain display similar nuclear staining patterns. The same interaction is conserved with Drosophila EWG, which also binds and trans-activates through NRF-1 binding sites. Yeast two-hybrid screening, chemical crosslinking of purified proteins, co-immunoprecipitation, immunolocalization/confocal microscopy, transcription assays Journal of cell science High 11069771
2000 NRF-1 (alpha-Pal/Nrf-1) binds the FMR1 promoter in brain and testis extracts; methylation of the NRF-1 site abolishes NRF-1 binding to the FMR1 promoter, suggesting that DNA methylation silences FMR1 in part by blocking NRF-1 access. EMSA with nuclear extracts, transcription factor binding-site analysis, methylation interference The Journal of biological chemistry Medium 11058604
2001 TCF11/NFE2L1 transactivates the GCS heavy subunit (GCS-h) promoter through antioxidant response elements (AREs), with EMSA showing TCF11 binds one specific ARE as a heterodimer with small Maf proteins; TCF11 overexpression increases intracellular glutathione levels in COS-1 cells. Overexpression in COS-1 cells, co-transfection reporter assays, EMSA, glutathione measurement Biochimica et biophysica acta Medium 11342101
2001 Full-length TCF11 requires two separate transactivation domains (an N-terminal acidic domain and a serine-rich stretch adjacent to the CNC-bZIP domains) for transcriptional activity; the shorter LCR-F1 isoform lacks transactivation ability but can act as a dominant-negative inhibitor of the full-length form, providing an isoform-based regulatory mechanism. Domain deletion/swapping mutants, transient transfection reporter assays in multiple cell lines The Journal of biological chemistry Medium 11278371
2003 c-Myc directly activates cytochrome c gene expression through NRF-1 target sites; NRF-1 overexpression sensitizes cells to apoptosis on serum depletion; dominant-negative NRF-1 prevents c-Myc-induced apoptosis without affecting c-Myc-dependent proliferation, placing NRF-1 downstream of c-Myc specifically in the apoptotic branch. Northern analysis, transactivation assays, in vitro and in vivo promoter binding assays, dominant-negative NRF-1 expression, apoptosis assays Genes & development High 12533512
2003 TCF11/NFE2L1 is exported from the nucleus via a nuclear export signal (NES) in its N-terminus through the CRM1/exportin pathway; the full-length form is both cytoplasmic and nuclear, while the shorter internally initiated isoform is restricted to the nucleus; mutating three leucine residues in the NES largely blocks export. Alternative-splicing isoforms lacking the NES are constitutively nuclear. Cellular fractionation, immunofluorescence localization, leptomycin B treatment, NES mutagenesis Biochimica et biophysica acta High 12729924
2004 NRF-1 (alpha-Pal/NRF-1) occupies the FMR1 promoter in vivo (chromatin immunoprecipitation); NRF-1 and Sp1 synergistically activate FMR1 transcription; NRF-1 transactivation is sensitive to dense CpG methylation of the promoter; siRNA knockdown of endogenous NRF-1 reduces FMR1 reporter activity in HeLa cells. Chromatin immunoprecipitation (ChIP), transient transfection reporter assays, siRNA knockdown, methylation sensitivity assay Human molecular genetics High 15175277
2006 PRC (PGC-1-related coactivator) physically binds NRF-1 in vitro and forms a complex with NRF-1 in cell extracts; CREB also binds PRC at overlapping sites; a CREB/NRF-1 interaction domain on PRC is required for transactivation of the cytochrome c promoter; PRC occupies the cytochrome c promoter in vivo and its occupancy is elevated upon serum induction. In vitro binding assays, co-immunoprecipitation from cell extracts, chromatin immunoprecipitation, dominant-negative lentivirus expression, respiratory growth assay Molecular and cellular biology High 16908542
2007 TCF11/MafG heterodimer binds an element in the iNOS promoter (identified by ChIP and mutation analyses) and represses iNOS induction; TGF-β1 induces TCF11/MafG binding to this site via a protein kinase C-dependent mechanism; siRNA knockdown of TCF11 blocks TGF-β-mediated suppression of iNOS. Chromatin immunoprecipitation, promoter mutation analysis, siRNA knockdown, PKC inhibitor studies, in vivo rat endotoxemia model The Journal of biological chemistry High 17928287
2009 NRF-1 directly interacts with PARP-1 and co-purifies a PARP-1·DNA-PK·Ku80·Ku70·topoisomerase IIβ-containing complex; the DNA-binding/dimerization domain of NRF-1 and the N-terminal zinc finger/auto-modification domain of PARP-1 mediate the interaction; DNA-bound NRF-1 can recruit this complex to promoters; PARP-1 can PARylate the DNA-binding domain of NRF-1 and negatively regulate the NRF-1·PARP-1 interaction. In vitro binding assays, co-purification, domain mapping, PARylation assay, ChIP, transient transfection The Journal of biological chemistry High 19181665
2010 TCF11 (long isoform of NFE2L1) is identified as the key transcription factor driving 26S proteasome gene expression in response to proteasome inhibition (bounce-back response). Under basal conditions, TCF11 resides in the ER membrane and is targeted to ER-associated degradation (ERAD) requiring E3 ubiquitin ligase HRD1 and AAA-ATPase p97; proteasome inhibition promotes nuclear translocation of TCF11, where it binds antioxidant response elements (AREs) in proteasome gene promoters. Transcription factor identification by cell-based assays, subcellular fractionation, dominant-negative ERAD component expression, promoter-binding assays Molecular cell High 20932482
2013 Sox9 directly regulates Nfe2l1 expression in gliogenic radial glia; Nfe2l1 promotes glial fate under direct Sox9 regulatory control in developing spinal cord. Gene expression profiling, chromatin immunoprecipitation, functional assays in developing CNS Glia Medium 23840004
2014 PARK2/Parkin-mediated mitophagy is required for NFE2L1 nuclear translocation and subsequent proteasome activation during denervation-induced muscle atrophy; in both autophagy-deficient and Park2-knockout muscles, NFE2L1 nuclear translocation was absent and proteasome activation failed, while polyubiquitinated proteins accumulated. Autophagy-deficient and Park2-knockout mouse models, denervation atrophy model, subcellular fractionation, proteasome activity assays Autophagy Medium 24451648
2018 NFE2L1 undergoes multi-step post-translational processing: the nascent polypeptide is transiently translocated into the ER lumen and becomes an inactive glycoprotein (glycosylation by OST); it is then retrotranslocated by p97; deglycosylated by glycosidases to yield a deglycoprotein; and proteolytically processed by cytosolic DDI-1/2 and proteasomes to generate N-terminally truncated active isoforms. Coupled positive and negative feedback circuits exist between NFE2L1 and its regulators (p97, Hrd1, DDI-1, proteasomes). Cell-based mutagenesis, glycosylation/deglycosylation assays, pharmacological inhibitors of p97/ERAD, proteasome inhibitors, western blot isoform analysis Toxicology and applied pharmacology High 30287392
2020 NFE2L1 and NFE2L3 complementarily maintain basal proteasome activity in cancer cells; double knockdown of NFE2L1 and NFE2L3 impairs basal proteasome activity and reduces expression of seven proteasome-related genes; NFE2L3 represses NFE2L1 translation via induction of CPEB3, which binds the NFE2L1 3' UTR and decreases polysome formation on NFE2L1 mRNA. Double siRNA knockdown, proteasome activity assays, mRNA polysome analysis, CPEB3 binding assays, gene expression analysis Molecular and cellular biology High 32366381
2022 NFE2L1 promotes ferroptosis resistance independent of NFE2L2 by maintaining expression of glutathione peroxidase 4 (GPX4), a key inhibitor of lethal lipid peroxidation; NFE2L2 promotes ferroptosis resistance through a distinct mechanism that appears independent of GPX4 protein expression. NFE2L1/NFE2L2 gene knockout cellular models, ferroptosis induction assays, GPX4 expression analysis Proceedings of the National Academy of Sciences of the United States of America High 35271393
2022 NFE2L1 loss reduces cellular viability after ferroptosis induction; NFE2L1 protects from ferroptosis by sustaining proteasomal activity; Gpx4-deficient mice show reduced proteasomal activity associated with ferroptosis; Nfe2l1-deficient mice show brown adipose tissue involution, hyperubiquitination of ferroptosis regulators including the GPX4 pathway, and other ferroptosis hallmarks. NFE2L1 loss-of-function in cellular systems and mouse models (Gpx4-KO, Nfe2l1-deficient), proteasome activity assays, patient-derived cell line with GPX4 mutation Molecular metabolism High 34999280
2022 Glycosylation of NFE2L1 enables it to sense the energy state; loss of NFE2L1 in hepatocytes leads to lethality upon glucose deprivation and affects glucose uptake; NFE2L1 directly interacts with and inhibits AMPK (demonstrated by co-expression and co-immunoprecipitation), placing NFE2L1 as a negative regulator of AMPK signaling. NFE2L1 silencing in HepG2 cells, glucose deprivation assays, co-immunoprecipitation, transcriptome and metabolome analysis, Seahorse assay Cell death & disease Medium 35614059
2023 NRF1/NFE2L1 transcriptionally induces p62/SQSTM1 and GABARAPL1 (an ATG8 family gene) after proteasome inhibition, activating aggrephagy; NRF1 is required for formation of p62-positive puncta, their colocalization with ULK1 and TBK1, and Ser403 phosphorylation of p62; NRF1 thus couples the proteasome bounce-back response to selective autophagy. Genome-wide transcriptome analysis (RNA-seq), NRF1 knockdown, immunofluorescence, co-immunoprecipitation, phosphorylation assays Scientific reports High 37658135
2024 SCFFBS2 (an N-glycan-recognizing E3 ligase) cooperates with the RBR-type E3 ligase ARIH1 to ubiquitinate NFE2L1 through oxyester bonds at N-GlcNAc residues (generated by ENGASE from N-glycans); this non-canonical ubiquitination assembles atypical ubiquitin chains (requiring UBE2L3) and inhibits DDI2-mediated proteolytic activation of NFE2L1. The polyubiquitination was biochemically reconstituted on glycopeptides. In vitro reconstitution of polyubiquitination on glycopeptides, identification of SCFFBS2-ARIH1 E3 complex, ENGASE activity assay, mass spectrometry of ubiquitination sites, cell-based NFE2L1 activation assays Molecular cell High 39116872
2024 DDI2 protease-mediated proteolytic cleavage of NFE2L1 is a critical step for ferroptosis-induced feedback activation of proteasome function; cells lacking DDI2 cannot activate NFE2L1 in response to RSL3 and show global hyperubiquitylation; ferroptosis induction leads to proteasome inhibition that activates NFE2L1 through DDI2 cleavage. DDI2 genetic disruption, proteomic ubiquitylation site mapping, RSL3-induced ferroptosis, proteasome activity assays, nelfinavir (DDI2 inhibitor) treatment Cell death and differentiation High 39384955
2020 Nelfinavir inhibits the TCF11/Nrf1-driven proteasome recovery pathway by dual mechanism: decreasing total TCF11/Nrf1 protein level and inhibiting its DDI2-mediated proteolytic processing, thereby reducing nuclear TCF11/Nrf1 and proteasome gene re-synthesis. TCF11/Nrf1 protein level and nuclear fraction analysis, proteasome gene expression assays, DDI2 inhibition in multiple myeloma cells Cancers Medium 32344880
2021 NFE2L1 regulates osteoclast differentiation in an isoform-specific manner: long isoforms of NFE2L1 accelerate Nfatc1/α induction and antioxidant gene expression, while the short isoform NFE2L1-453 suppresses these effects; myeloid-specific Nfe2l1 knockout mice show increased osteoclast activity, decreased bone mass, and worsened osteoporosis. NFE2L1 deficiency leads to enhanced ROS accumulation in early osteoclastogenesis. Myeloid-specific conditional KO (LysM-Cre), ovariectomy and aging models, bone marrow cell and RAW 264.7 cell differentiation assays, isoform-specific knockdown Redox biology High 34763297
2018 Adipocyte-specific Nfe2l1 knockout mice exhibit reduced subcutaneous adipose tissue mass, insulin resistance, adipocyte hypertrophy, and severe adipose inflammation; mechanistic studies revealed Nfe2l1 deficiency disturbs expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation and pyroptosis. Adipocyte-specific conditional KO (Nfe2l1(f)-KO), metabolic phenotyping, gene expression analysis of lipolytic genes Biochemical and biophysical research communications Medium 29935181
2010 PGC-1β promotes mitochondrial biogenesis and function in myotubes through direct interaction with NRF-1 and ERRα; deletion or mutation of NRF-1 and/or ERRα binding sites in target gene promoters attenuates PGC-1β-mediated activation; siRNA inhibition of NRF-1 or ERRα abolishes the mitochondrial biogenesis function of PGC-1β. Overexpression, siRNA knockdown, promoter deletion/mutation reporter assays, co-immunoprecipitation Mitochondrion Medium 20561910
2017 HTLV-1 bZIP factor (HBZ) physically interacts with NRF-1 and inhibits NRF-1's DNA-binding ability, thereby suppressing NRF-1-dependent TDP1 gene transcription; this mechanism underlies reduced TDP1 in adult T-cell leukemia cells, making them susceptible to abacavir. Co-immunoprecipitation of HBZ and NRF-1, dominant-negative NRF-1, luciferase reporter assays, shNRF-1 knockdown Scientific reports Medium 28993637
2023 NFE2L1 overexpression stimulates proteasome biogenesis and activity in retinal neurons and delays photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins, demonstrating that a transcription-driven increase in the proteasome pool can enhance proteolytic capacity and confer neuroprotection. Nfe2l1 adeno-associated virus overexpression in mouse retina, proteasome activity assays, ubiquitin-proteasomal reporter clearance assay, photoreceptor neuron survival analysis Science advances High 37450596

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Molecular and cellular biology 557 15684387
2001 Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. American journal of physiology. Endocrinology and metabolism 449 11701451
1990 NRF-1: a trans-activator of nuclear-encoded respiratory genes in animal cells. Genes & development 379 2166701
2010 Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Molecular cell 313 20932482
1993 NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes & development 300 8253388
1998 Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. The EMBO journal 243 9501099
1989 Interaction of nuclear factors with multiple sites in the somatic cytochrome c promoter. Characterization of upstream NRF-1, ATF, and intron Sp1 recognition sequences. The Journal of biological chemistry 213 2547796
2000 Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome c. The Journal of biological chemistry 153 10777619
2010 PGC-1 beta-regulated mitochondrial biogenesis and function in myotubes is mediated by NRF-1 and ERR alpha. Mitochondrion 128 20561910
2011 PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Molecular neurodegeneration 120 21595933
1992 Nuclear respiratory factor 1 activation sites in genes encoding the gamma-subunit of ATP synthase, eukaryotic initiation factor 2 alpha, and tyrosine aminotransferase. Specific interaction of purified NRF-1 with multiple target genes. The Journal of biological chemistry 110 1348057
1998 Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription. Nucleic acids research 105 9421508
2003 c-MYC apoptotic function is mediated by NRF-1 target genes. Genes & development 99 12533512
1997 The bZIP transcription factor LCR-F1 is essential for mesoderm formation in mouse development. Genes & development 99 9087432
2016 Nuclear Factor Erythroid-2 Like 1 (NFE2L1): Structure, function and regulation. Gene 97 26947393
2006 PGC-1-related coactivator: immediate early expression and characterization of a CREB/NRF-1 binding domain associated with cytochrome c promoter occupancy and respiratory growth. Molecular and cellular biology 94 16908542
2022 Ferroptosis regulation by the NGLY1/NFE2L1 pathway. Proceedings of the National Academy of Sciences of the United States of America 85 35271393
1996 Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1. Nucleic acids research 82 8932385
2000 Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. Implications for Fragile X mental retardation syndrome. The Journal of biological chemistry 77 11058604
2011 Overexpression of TFAM, NRF-1 and myr-AKT protects the MPP(+)-induced mitochondrial dysfunctions in neuronal cells. Biochimica et biophysica acta 71 21856379
2001 TCF11/Nrf1 overexpression increases the intracellular glutathione level and can transactivate the gamma-glutamylcysteine synthetase (GCS) heavy subunit promoter. Biochimica et biophysica acta 62 11342101
2013 Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 58 23840004
2007 Negative regulation of inducible nitric-oxide synthase expression mediated through transforming growth factor-beta-dependent modulation of transcription factor TCF11. The Journal of biological chemistry 53 17928287
2009 Poly(ADP-ribose) Polymerase 1 Interacts with Nuclear Respiratory Factor 1 (NRF-1) and Plays a Role in NRF-1 Transcriptional Regulation. The Journal of biological chemistry 50 19181665
2023 Unravelling the role of NFE2L1 in stress responses and related diseases. Redox biology 49 37473701
2022 NFE2L1-mediated proteasome function protects from ferroptosis. Molecular metabolism 47 34999280
1998 Promoter analysis of the human succinate dehydrogenase iron-protein gene--both nuclear respiratory factors NRF-1 and NRF-2 are required. European journal of biochemistry 46 9492280
2000 Dynein light chain interacts with NRF-1 and EWG, structurally and functionally related transcription factors from humans and drosophila. Journal of cell science 45 11069771
2000 Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development. Mechanisms of development 43 11025215
2020 NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression. Molecular and cellular biology 42 32366381
2014 PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation. Autophagy 40 24451648
2004 Alpha-Pal/NRF-1 regulates the promoter of the human integrin-associated protein/CD47 gene. The Journal of biological chemistry 40 14747477
2018 Adipocyte-specific deficiency of Nfe2l1 disrupts plasticity of white adipose tissues and metabolic homeostasis in mice. Biochemical and biophysical research communications 37 29935181
2008 NRF-1 is the major transcription factor regulating the expression of the human TOMM34 gene. Biochemistry and cell biology = Biochimie et biologie cellulaire 37 18364745
2019 ANGPTL2 regulates autophagy through the MEK/ERK/Nrf-1 pathway and affects the progression of renal fibrosis in diabetic nephropathy. American journal of translational research 35 31632523
2015 Expression of Mitochondria-Associated Genes (PPARGC1A, NRF-1, BCL-2 and BAX) in Follicular Development and Atresia of Goat Ovaries. Reproduction in domestic animals = Zuchthygiene 35 25779891
1998 Activation of the cytochrome c gene by electrical stimulation in neonatal rat cardiac myocytes. Role of NRF-1 and c-Jun. The Journal of biological chemistry 35 9575220
2016 TCF11/Nrf1-Mediated Induction of Proteasome Expression Prevents Cytotoxicity by Rotenone. Antioxidants & redox signaling 34 27345029
1995 Structural organization and mapping of the human TCF11 gene. Genomics 34 7557987
2015 Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER stress-induced apoptosis. PloS one 33 25806530
2001 Two domains of the human bZIP transcription factor TCF11 are necessary for transactivation. The Journal of biological chemistry 32 11278371
2018 Mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct isoforms within the coupled positive and negative feedback circuits. Toxicology and applied pharmacology 31 30287392
2020 Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma. Cancers 30 32344880
2007 Icariin promotes expression of PGC-1alpha, PPARalpha, and NRF-1 during cardiomyocyte differentiation of murine embryonic stem cells in vitro. Acta pharmacologica Sinica 30 17883938
2004 Occupancy and synergistic activation of the FMR1 promoter by Nrf-1 and Sp1 in vivo. Human molecular genetics 30 15175277
2020 Dehydroepiandrosterone protects against hepatic glycolipid metabolic disorder and insulin resistance induced by high fat via activation of AMPK-PGC-1α-NRF-1 and IRS1-AKT-GLUT2 signaling pathways. International journal of obesity (2005) 29 31911660
2005 A novel function of transcription factor alpha-Pal/NRF-1: increasing neurite outgrowth. Biochemical and biophysical research communications 29 15992771
1999 Expression of mitochondrial genes and of the transcription factors involved in the biogenesis of mitochondria Tfam, NRF-1 and NRF-2, in rat liver, testis and brain. Biochimie 29 10575350
2024 Sugar-mediated non-canonical ubiquitination impairs Nrf1/NFE2L1 activation. Molecular cell 28 39116872
2023 EIF4A3-Induced Exosomal circLRRC8A Alleviates Granulosa Cells Senescence Via the miR-125a-3p/NFE2L1 axis. Stem cell reviews and reports 28 37243831
2023 The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis. Scientific reports 28 37658135
2022 Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming. Cell death & disease 28 35614059
1995 Cloning and mapping of murine Nfe2l1. Genomics 28 7759107
2018 Nuclear Respiratory Factor 1 (NRF-1) Controls the Activity Dependent Transcription of the GABA-A Receptor Beta 1 Subunit Gene in Neurons. Frontiers in molecular neuroscience 26 30186109
2018 AMPK Activation of PGC-1α/NRF-1-Dependent SELENOT Gene Transcription Promotes PACAP-Induced Neuroendocrine Cell Differentiation Through Tolerance to Oxidative Stress. Molecular neurobiology 26 30267375
2020 Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis. Cancers 25 32942643
2017 Exercise increases hyper-acetylation of histones on the Cis-element of NRF-1 binding to the Mef2a promoter: Implications on type 2 diabetes. Biochemical and biophysical research communications 25 28263745
2017 Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells to arsenite-induced cytotoxicity. Toxicology and applied pharmacology 25 28549828
2009 Involvement of PGC-1, NRF-1, and NRF-2 in metabolic response by rat liver to hormonal and environmental signals. Molecular and cellular endocrinology 25 19433258
2007 NRF-1, and AP-1 regulate the promoter of the human calpain small subunit 1 (CAPNS1) gene. Gene 25 18234454
2020 NRF-1 and HIF-1α contribute to modulation of human VDAC1 gene promoter during starvation and hypoxia in HeLa cells. Biochimica et biophysica acta. Bioenergetics 24 32810507
2005 The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter. The Biochemical journal 24 15479157
2002 Upregulation and activation of the Nrf-1 transcription factor in the lesioned hippocampus. The European journal of neuroscience 24 12059978
2016 Nuclear respiratory factor-1 (NRF-1) regulated hypoxia-inducible factor-1α (HIF-1α) under hypoxia in HEK293T. IUBMB life 23 27491637
1997 Role of NRF-1 in bidirectional transcription of the human GPAT-AIRC purine biosynthesis locus. Nucleic acids research 23 9108165
2021 Vitamin D and rosuvastatin obliterate peripheral neuropathy in a type-2 diabetes model through modulating Notch1, Wnt-10α, TGF-β and NRF-1 crosstalk. Life sciences 22 34102194
2021 CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners. Redox biology 22 34763297
2021 The roles of NFE2L1 in adipocytes: Structural and mechanistic insight from cell and mouse models. Redox biology 21 34058615
2020 Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 32543769
2018 Tetramethylpyrazine in a Murine Alkali-Burn Model Blocks NFκB/NRF-1/CXCR4-Signaling-Induced Corneal Neovascularization. Investigative ophthalmology & visual science 21 29801148
2017 Nfe2l1-silenced insulinoma cells acquire aggressiveness and chemoresistance. Endocrine-related cancer 21 29203613
2003 Cellular localisation and nuclear export of the human bZIP transcription factor TCF11. Biochimica et biophysica acta 21 12729924
2020 SLCO4A1-AS1 promotes cell growth and induces resistance in lung adenocarcinoma by modulating miR-4701-5p/NFE2L1 axis to activate WNT pathway. Cancer medicine 20 32762035
2013 Estradiol and tamoxifen regulate NRF-1 and mitochondrial function in mouse mammary gland and uterus. Journal of molecular endocrinology 20 23892277
2023 NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases. Redox biology 19 38150994
2022 Pharmacological activation of PPARβ/δ preserves mitochondrial respiratory function in ischemia/reperfusion via stimulation of fatty acid oxidation-linked respiration and PGC-1α/NRF-1 signaling. Frontiers in endocrinology 19 36046786
2010 The kinesin superfamily protein KIF17 is regulated by the same transcription factor (NRF-1) as its cargo NR2B in neurons. Biochimica et biophysica acta 19 21172391
2024 Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis. Cell death and differentiation 18 39384955
2012 Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission. Biochimica et biophysica acta 18 23085505
2023 Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness. Science advances 17 37450596
2021 TCF11 Has a Potent Tumor-Repressing Effect Than Its Prototypic Nrf1α by Definition of Both Similar Yet Different Regulatory Profiles, With a Striking Disparity From Nrf2. Frontiers in oncology 17 34268128
2013 Novel genes FAM134C, C3orf10 and ENOX1 are regulated by NRF-1 and differentially regulate neurite outgrowth in neuroblastoma cells and hippocampal neurons. Gene 17 23939472
2011 TCF11 at the crossroads of oxidative stress and the ubiquitin proteasome system. Cell cycle (Georgetown, Tex.) 17 21412055
2023 Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases. Biology 16 37759569
2022 Effects of NRF-1 and PGC-1α cooperation on HIF-1α and rat cardiomyocyte apoptosis under hypoxia. Gene 16 35569770
2022 Silibinin ameliorates cisplatin-induced acute kidney injury via activating Nfe2l1-mediated antioxidative response to suppress the ROS/MAPK signaling pathway. Journal of molecular histology 16 35727472
2021 LncRNA DLGAP1-AS1 accelerates glioblastoma cell proliferation through targeting miR-515-5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway. Brain and behavior 16 34536977
2018 Benfotiamine, a Lipid-Soluble Analog of Vitamin B1, Improves the Mitochondrial Biogenesis and Function in Blunt Snout Bream (Megalobrama amblycephala) Fed High-Carbohydrate Diets by Promoting the AMPK/PGC-1β/NRF-1 Axis. Frontiers in physiology 16 30233383
2021 Metformin leads to accumulation of reactive oxygen species by inhibiting the NFE2L1 expression in human hepatocellular carcinoma cells. Toxicology and applied pharmacology 15 33838154
2017 HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia. Scientific reports 15 28993637
2022 Long-isoform NFE2L1 silencing inhibits acquisition of malignant phenotypes induced by arsenite in human bronchial epithelial cells. Ecotoxicology and environmental safety 14 35124418
2021 Feedback regulation of antioxidant transcription factor NFE2L1 and immunostimulatory factor 41BBL mediates the crosstalk between oxidative stress and tumor immunity. Molecular immunology 14 34902807
2016 Elucidation of the therapeutic role of mitochondrial biogenesis transducers NRF-1 in the regulation of renal fibrosis. Experimental cell research 14 27634749
2011 Decreased expression of BRCA1 in SK-BR-3 cells is the result of aberrant activation of the GABP Beta promoter by an NRF-1-containing complex. Molecular cancer 14 21609478
2004 The NRF-1/alpha-PAL transcription factor regulates human E2F6 promoter activity. The Biochemical journal 13 15257658
2024 Neonatal high-dose riboflavin treatment channels energy expenditure towards sensorimotor and somatic development and reduces rodent growth and weight gain by modulating NRF-1 in the hypothalamus. Physiology & behavior 12 39255868
2023 NFE2L1 restrains ferroptosis by transcriptionally regulating HJURP and participates in the progress of oral squamous cell carcinoma. Journal of bioenergetics and biomembranes 12 37848756
2020 Protracted rosiglitazone treatment exacerbates inflammation in white adipose tissues of adipocyte-specific Nfe2l1 knockout mice. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 12 33137425
2021 NRF-1 directly regulates TFE3 and promotes the proliferation of renal cancer cells. Oncology letters 11 34345304
2024 Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer. Antioxidants (Basel, Switzerland) 10 39061827

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