Affinage

EDF1

Endothelial differentiation-related factor 1 · UniProt O60869

Length
148 aa
Mass
16.4 kDa
Annotated
2026-06-09
15 papers in source corpus 13 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EDF1 is a conserved basic intracellular protein that couples ribosome quality control to transcriptional and signaling responses, acting as a sensor of translational distress that also moonlights between the cytosol and nucleus (PMID:32744497, PMID:16055206). During translational distress EDF1 is recruited to collided ribosomes, binding the 40S subunit at the mRNA entry channel near the collision interface, where it recruits the translational repressors GIGYF2 and EIF4E2 to establish a negative-feedback loop that prevents new ribosomes from translating defective mRNAs (PMID:32744497); it concurrently directs an immediate-early transcriptional response to ribosome collisions, linking quality control to global gene regulation (PMID:32744497). In the cytosol EDF1 binds and sequesters calmodulin, thereby limiting calmodulin availability for eNOS activation and NO production; VEGF promotes dissociation of calmodulin from EDF1, and EDF1 silencing elevates basal NO while abolishing VEGF-induced eNOS Ser1177 phosphorylation, placing EDF1 upstream of a PP2A/eNOS axis (PMID:20605058, PMID:20185128). In the nucleus EDF1 functions as a transcriptional coactivator, co-immunoprecipitating with PPARγ and being required for ligand-dependent PPARγ activity and adipocyte differentiation independent of PPARγ protein levels (PMID:19554257), with VEGF driving its nuclear translocation to support PPARγ-dependent FABP4 expression (PMID:29933613). Loss of EDF1 in endothelial cells inhibits proliferation, drives a cobblestone-to-fibroblast/spindle morphological transition, and accelerates capillary-like network formation (PMID:9813014, PMID:20185128). EDF1 abundance is controlled by proteasomal degradation in non-proliferating cells, with nuclear redistribution in senescence (PMID:16055206).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 Medium

    Established EDF1 as a basic intracellular protein homologous to insect MBF1 with a functional requirement in endothelial cell proliferation and morphology, before any molecular mechanism was known.

    Evidence cDNA cloning and antisense-mediated knockdown with phenotypic readout in endothelial cells

    PMID:9813014

    Open questions at the time
    • No molecular activity or binding partner defined
    • Phenotype based on antisense without rescue
  2. 2005 Medium

    Resolved EDF1's dual subcellular roles—cytosolic calmodulin binding versus nuclear coactivation—and showed its downregulation in quiescent/senescent cells is proteasome-dependent, framing EDF1 as a localization-regulated factor.

    Evidence Subcellular fractionation and MG132 proteasome inhibition with western blot

    PMID:16055206

    Open questions at the time
    • Signals governing cytosol/nucleus partitioning not defined
    • Calmodulin-binding interface not mapped
  3. 2006 Medium

    Defined how EDF1 expression itself is controlled, identifying Sp1/Sp3 and NF-Y as drivers of its minimal promoter.

    Evidence EMSA supershift, ChIP, and luciferase reporter deletion constructs

    PMID:16567061

    Open questions at the time
    • Does not address inducible or stress-responsive regulation of EDF1
  4. 2009 Medium

    Demonstrated EDF1 acts as a bona fide transcriptional coactivator by binding PPARγ and being required for ligand-dependent PPARγ activity independent of PPARγ levels, explaining its role in adipogenesis.

    Evidence Co-IP, shRNA knockdown, luciferase reporter, lipid staining, and target gene expression in 3T3-L1 cells

    PMID:19554257

    Open questions at the time
    • Coactivation mechanism (bridging vs. chromatin effect) not resolved
    • Generality across nuclear receptors untested here
  5. 2010 Medium

    Established the cytosolic calmodulin-sequestration mechanism by which EDF1 restrains eNOS/NO signaling, positioning it upstream of a PP2A/eNOS phosphorylation axis and VEGF-regulated calmodulin release.

    Evidence shRNA silencing, reciprocal Co-IP of calmodulin/eNOS, phosphorylation assays, okadaic acid and calmidazolium rescue, and NO measurement in endothelial cells

    PMID:20185128 PMID:20605058

    Open questions at the time
    • Direct EDF1–calmodulin binding interface not structurally defined
    • Link between calmodulin sequestration and PP2A activity is correlative
  6. 2013 Low

    Extended the calmodulin-sequestration model to the calmodulin/calcineurin/NFAT pathway during early adipogenesis.

    Evidence Co-immunoprecipitation and gene expression analysis during differentiation

    PMID:23376715

    Open questions at the time
    • Single Co-IP without reconstitution or mutagenesis
    • Causality between NFAT inactivation and adipogenesis not directly tested
  7. 2018 Medium

    Connected the cytosolic and nuclear functions by showing VEGF triggers EDF1 nuclear translocation to enable PPARγ-dependent gene expression in endothelial cells.

    Evidence Immunofluorescence/fractionation for translocation, reporter assay, shRNA, and qPCR for FABP4

    PMID:29933613

    Open questions at the time
    • Molecular trigger/transport machinery for translocation unidentified
  8. 2020 High

    Identified EDF1's core conserved activity as a ribosome-collision sensor, structurally mapping it to the 40S mRNA entry channel and showing it recruits GIGYF2/EIF4E2 repressors and drives an immediate-early transcriptional response—uniting quality control with gene regulation.

    Evidence Sucrose gradient proteomics, cryo-EM of EDF1 and yeast Mbf1, and loss-of-function functional genetics

    PMID:32744497

    Open questions at the time
    • Identity and mechanism of the immediate-early transcriptional program not fully reconstituted
    • How collision sensing relates to the cytosol/nucleus coactivator roles unresolved
  9. 2025 Low

    Implicated EDF1's nuclear coactivator function in disease, as part of an NF-κB/RelA/EDF1 complex that protects ST8SIA1 from promoter methylation to drive ganglioside GD3 accumulation and CD8+ T cell dysfunction in neuroblastoma.

    Evidence RNA-seq, lipidomics, Co-IP for complex, promoter methylation assays, and immune functional assays

    PMID:39905449

    Open questions at the time
    • Direct EDF1–RelA binding interface not mapped
    • Mechanism by which the complex prevents methylation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EDF1's single conserved ribosome-collision-sensing activity mechanistically connects to its distinct cytosolic calmodulin sequestration and nuclear transcriptional coactivation roles remains unresolved.
  • No structural or biochemical model links the ribosome-bound state to the calmodulin-binding or coactivator states
  • Determinants of subcellular partitioning unknown
  • Whether transcriptional outputs are downstream of collision sensing untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005840 ribosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CALCINEURINCALM1EIF4E2ENOS/NOS3GIGYF2PPARGRELA
Complex memberships
40S ribosomal subunit (collided ribosome)NF-κB/RelA/EDF1 complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 EDF1 is recruited to collided ribosomes during translational distress and binds the 40S ribosomal subunit at the mRNA entry channel near the collision interface, as revealed by cryo-EM of EDF1 and its yeast homolog Mbf1. Sucrose gradient fractionation with quantitative proteomics; cryo-electron microscopy structural analysis eLife High 32744497
2020 EDF1 recruits translational repressors GIGYF2 and EIF4E2 to collided ribosomes, initiating a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Proteomics of collided ribosome fractions; functional genetic experiments (loss-of-function); co-immunoprecipitation implied by recruitment assays eLife High 32744497
2020 EDF1 regulates an immediate-early transcriptional response to ribosomal collisions, linking ribosome-mediated quality control with global transcriptional regulation. Loss-of-function genetic experiments with transcriptional readout following ribosome collision induction eLife Medium 32744497
1998 EDF1 (EDF-1) encodes a basic intracellular 148-amino-acid protein homologous to Bombyx mori MBF1 (multiprotein-bridging factor 1); inhibition of EDF-1 translation by antisense constructs inhibits endothelial cell growth and induces morphological transition from cobblestone to fibroblast-like phenotype. cDNA cloning, RNA fingerprinting, antisense-mediated knockdown with phenotypic readout The Journal of biological chemistry Medium 9813014
2005 EDF1 acts in the cytosol as a calmodulin-binding protein and in the nucleus as a transcriptional coactivator; its degradation via the proteasome is responsible for downregulation in non-proliferating (quiescent and senescent) endothelial cells, with a shift to predominantly nuclear localization in senescent cells. Subcellular fractionation, proteasome inhibitor treatment (MG132), western blot Biochimica et biophysica acta Medium 16055206
2010 VEGF promotes dissociation of calmodulin from EDF1, correlating with increased calmodulin binding to eNOS and NO release; silencing EDF1 increases free calmodulin available to activate eNOS, elevating basal NO production but abolishing VEGF-induced eNOS Ser1177 phosphorylation; PP2A inhibition by okadaic acid restores eNOS Ser1177 phosphorylation in EDF1-silenced cells, placing EDF1 upstream of the PP2A/eNOS axis. shRNA-mediated stable silencing, co-immunoprecipitation of calmodulin/eNOS, phosphorylation assays (western blot), pharmacological inhibition (okadaic acid), NO measurement European journal of cell biology Medium 20605058
2010 Silencing EDF1 in endothelial cells increases calmodulin–eNOS interaction and NO production without altering total eNOS levels or phosphorylation state, indicating EDF1 sequesters calmodulin to limit eNOS activation; EDF1 knockdown also promotes spindle morphology, inhibits proliferation, and accelerates capillary-like network formation on fibrin gels. shRNA knockdown, co-immunoprecipitation of calmodulin and eNOS, calmodulin inhibitor (calmidazolium) rescue, NO assay, fibrin gel organization assay Atherosclerosis Medium 20185128
2009 EDF1 co-immunoprecipitates with PPARγ and is required for PPARγ transcriptional activation during adipogenesis; silencing EDF1 by shRNA blocks 3T3-L1 differentiation into adipocytes and reduces ligand-dependent PPARγ reporter activity even when PPARγ is overexpressed, demonstrating a coactivator role independent of PPARγ protein levels. Co-immunoprecipitation, shRNA knockdown, luciferase reporter assay, lipid staining, target gene (aP2) expression Cellular and molecular life sciences : CMLS Medium 19554257
2018 VEGF stimulates nuclear translocation of EDF1 in endothelial cells; in the nucleus EDF1 acts as a transcriptional coactivator of PPARγ, and EDF1 silencing prevents VEGF-induced PPARγ activity and FABP4 expression. Immunofluorescence/subcellular fractionation for translocation, gene reporter assay, shRNA silencing, qPCR for FABP4 expression International journal of molecular sciences Medium 29933613
2013 EDF1 associates with calmodulin and calcineurin (demonstrated by co-immunoprecipitation) during early adipogenesis, sequestering calmodulin and thereby inactivating the calmodulin/calcineurin/NFAT signaling pathway to permit adipogenesis. Co-immunoprecipitation, gene expression analysis during differentiation Biochemical and biophysical research communications Low 23376715
2006 The EDF-1 minimal promoter is regulated by Sp1/Sp3 and NF-Y transcription factors binding to GC boxes and a CAAT box respectively; deletion of these sites abolishes promoter activity. EMSA supershift, chromatin immunoprecipitation (ChIP), luciferase reporter deletion constructs Gene Medium 16567061
2008 HIV-Tat transcriptionally inhibits EDF-1 mRNA via its promoter (demonstrated by luciferase reporter assay), but this does not alter EDF-1 protein levels; in response to HIV-Tat, EDF-1 is retained predominantly in the cytosol, where it sequesters calmodulin and thereby prevents eNOS activation and NO induction. Luciferase reporter assay, western blot with proteasome inhibitor (MG132), subcellular fractionation International journal of immunopathology and pharmacology Low 18547486
2025 EDF1 is recruited as a coactivator to form an NF-κB/RelA/EDF1 complex that prevents promoter methylation of ST8SIA1, elevating its transcription and thereby increasing ganglioside GD3 accumulation in neuroblastoma cells, which drives CD8+ T cell dysfunction. Bioinformatics, bulk RNA-seq, lipidomics, and biological validation assays (co-immunoprecipitation for complex, methylation assays for promoter, functional immune assays) Journal of experimental & clinical cancer research : CR Low 39905449
2024 In situ cryo-EM of human cells revealed EDF1 bound to ribosomes in the cellular context at functional states not observed with purified ribosomes in vitro, consistent with its role as a ribosome-associated factor. In situ cryo-EM (cryo-FIB milling combined with single-particle cryo-EM) at 2.19 Å consensus resolution bioRxivpreprint Medium bio_10.1101_2024.07.02.601723
2023 HBS1L depletion causes reduction of EDF1 protein levels in retinal tissue, indicating EDF1 protein stability or abundance is functionally linked to the HBS1L ribosomal rescue pathway. Mass spectrometry proteomics of Hbs1l hypomorph mouse retina; comparison with patient data bioRxivpreprint Low 37905068

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 EDF1 coordinates cellular responses to ribosome collisions. eLife 148 32744497
1998 EDF-1, a novel gene product down-regulated in human endothelial cell differentiation. The Journal of biological chemistry 48 9813014
2010 EDF-1 contributes to the regulation of nitric oxide release in VEGF-treated human endothelial cells. European journal of cell biology 19 20605058
2005 Differential expression of EDF-1 and endothelial nitric oxide synthase by proliferating, quiescent and senescent microvascular endothelial cells. Biochimica et biophysica acta 19 16055206
2009 Transcriptional coactivator EDF-1 is required for PPARgamma-stimulated adipogenesis. Cellular and molecular life sciences : CMLS 17 19554257
2018 The Contribution of EDF1 to PPARγ Transcriptional Activation in VEGF-Treated Human Endothelial Cells. International journal of molecular sciences 12 29933613
2006 Characterization of the human EDF-1 minimal promoter: involvement of NFY and Sp1 in the regulation of basal transcription. Gene 11 16567061
2013 EDF-1 downregulates the CaM/Cn/NFAT signaling pathway during adipogenesis. Biochemical and biophysical research communications 5 23376715
2010 The effects of silencing EDF-1 in human endothelial cells. Atherosclerosis 5 20185128
2001 Cloning and characterization of murine EDF-1. Gene 5 11587857
2020 LncPrep + 96kb 2.2 kb Inhibits Estradiol Secretion From Granulosa Cells by Inducing EDF1 Translocation. Frontiers in cell and developmental biology 4 32695776
2025 EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma. Journal of experimental & clinical cancer research : CR 3 39905449
2023 Genetic deficiency of ribosomal rescue factor HBS1L causes retinal dystrophy associated with Pelota and EDF1 depletion. bioRxiv : the preprint server for biology 1 37905068
2008 Impact of extracellular HIV-TAT on the regulation of EDF-1 levels in human endothelial cells. International journal of immunopathology and pharmacology 1 18547486
2010 Molecular cloning, characterization, and expression of the endothelial differentiation-related factor-1 (EDF-1) in Gekko japonicus. Molekuliarnaia biologiia 0 20198862

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