{"gene":"EDF1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2020,"finding":"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.","method":"Sucrose gradient fractionation with quantitative proteomics; cryo-electron microscopy structural analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with defined binding site, combined with quantitative proteomics and functional follow-up in a single rigorous study","pmids":["32744497"],"is_preprint":false},{"year":2020,"finding":"EDF1 recruits translational repressors GIGYF2 and EIF4E2 to collided ribosomes, initiating a negative-feedback loop that prevents new ribosomes from translating defective mRNAs.","method":"Proteomics of collided ribosome fractions; functional genetic experiments (loss-of-function); co-immunoprecipitation implied by recruitment assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, fractionation, functional genetic assays) in a single rigorous study establishing pathway position","pmids":["32744497"],"is_preprint":false},{"year":2020,"finding":"EDF1 regulates an immediate-early transcriptional response to ribosomal collisions, linking ribosome-mediated quality control with global transcriptional regulation.","method":"Loss-of-function genetic experiments with transcriptional readout following ribosome collision induction","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, defined cellular phenotype with functional genetic evidence, but transcriptional mechanism not fully reconstituted in vitro","pmids":["32744497"],"is_preprint":false},{"year":1998,"finding":"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.","method":"cDNA cloning, RNA fingerprinting, antisense-mediated knockdown with phenotypic readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antisense knockdown with specific phenotypic readouts, single lab, no in vitro reconstitution","pmids":["9813014"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Subcellular fractionation, proteasome inhibitor treatment (MG132), western blot","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by fractionation and pharmacological inhibitor experiment, single lab, two orthogonal methods","pmids":["16055206"],"is_preprint":false},{"year":2010,"finding":"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.","method":"shRNA-mediated stable silencing, co-immunoprecipitation of calmodulin/eNOS, phosphorylation assays (western blot), pharmacological inhibition (okadaic acid), NO measurement","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phosphorylation assay, pharmacological rescue), single lab","pmids":["20605058"],"is_preprint":false},{"year":2010,"finding":"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.","method":"shRNA knockdown, co-immunoprecipitation of calmodulin and eNOS, calmodulin inhibitor (calmidazolium) rescue, NO assay, fibrin gel organization assay","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pharmacological rescue with defined cellular phenotypes, single lab","pmids":["20185128"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, shRNA knockdown, luciferase reporter assay, lipid staining, target gene (aP2) expression","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional reporter assay and rescue experiment, single lab","pmids":["19554257"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Immunofluorescence/subcellular fractionation for translocation, gene reporter assay, shRNA silencing, qPCR for FABP4 expression","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple readouts, single lab","pmids":["29933613"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, gene expression analysis during differentiation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-immunoprecipitation, single lab, no in vitro reconstitution or mutagenesis","pmids":["23376715"],"is_preprint":false},{"year":2006,"finding":"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.","method":"EMSA supershift, chromatin immunoprecipitation (ChIP), luciferase reporter deletion constructs","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA supershift and ChIP with deletion mutagenesis, single lab, two orthogonal methods","pmids":["16567061"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Luciferase reporter assay, western blot with proteasome inhibitor (MG132), subcellular fractionation","journal":"International journal of immunopathology and pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — reporter assay and fractionation, single lab, limited orthogonal validation","pmids":["18547486"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Bioinformatics, bulk RNA-seq, lipidomics, and biological validation assays (co-immunoprecipitation for complex, methylation assays for promoter, functional immune assays)","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic complex identified by Co-IP and promoter methylation assay in a single study; abstract does not detail all orthogonal validations","pmids":["39905449"],"is_preprint":false},{"year":2024,"finding":"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.","method":"In situ cryo-EM (cryo-FIB milling combined with single-particle cryo-EM) at 2.19 Å consensus resolution","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution in situ structure, but EDF1-specific functional validation is not reported in this abstract; single preprint study","pmids":["bio_10.1101_2024.07.02.601723"],"is_preprint":true},{"year":2023,"finding":"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.","method":"Mass spectrometry proteomics of Hbs1l hypomorph mouse retina; comparison with patient data","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomics observation in a model organism, no direct mechanistic experiment on EDF1 itself; preprint with single method","pmids":["37905068"],"is_preprint":true}],"current_model":"EDF1 is a conserved intracellular protein that functions as a sensor of ribosome collisions—binding the 40S subunit at the mRNA entry channel near the collision interface and recruiting translational repressors GIGYF2 and EIF4E2 to suppress translation of defective mRNAs—while also shuttling between the cytosol, where it sequesters calmodulin to modulate eNOS activity and the calcineurin/NFAT pathway, and the nucleus, where it acts as a transcriptional coactivator for PPARγ, NF-κB/RelA, and other factors; additionally, EDF1 coordinates an immediate-early transcriptional response to translational stress, linking ribosome quality control to global gene regulation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9813014"],"confidence":"Medium","gaps":["No molecular activity or binding partner defined","Phenotype based on antisense without rescue"]},{"year":2005,"claim":"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","pmids":["16055206"],"confidence":"Medium","gaps":["Signals governing cytosol/nucleus partitioning not defined","Calmodulin-binding interface not mapped"]},{"year":2006,"claim":"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","pmids":["16567061"],"confidence":"Medium","gaps":["Does not address inducible or stress-responsive regulation of EDF1"]},{"year":2009,"claim":"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","pmids":["19554257"],"confidence":"Medium","gaps":["Coactivation mechanism (bridging vs. chromatin effect) not resolved","Generality across nuclear receptors untested here"]},{"year":2010,"claim":"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","pmids":["20605058","20185128"],"confidence":"Medium","gaps":["Direct EDF1–calmodulin binding interface not structurally defined","Link between calmodulin sequestration and PP2A activity is correlative"]},{"year":2013,"claim":"Extended the calmodulin-sequestration model to the calmodulin/calcineurin/NFAT pathway during early adipogenesis.","evidence":"Co-immunoprecipitation and gene expression analysis during differentiation","pmids":["23376715"],"confidence":"Low","gaps":["Single Co-IP without reconstitution or mutagenesis","Causality between NFAT inactivation and adipogenesis not directly tested"]},{"year":2018,"claim":"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","pmids":["29933613"],"confidence":"Medium","gaps":["Molecular trigger/transport machinery for translocation unidentified"]},{"year":2020,"claim":"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","pmids":["32744497"],"confidence":"High","gaps":["Identity and mechanism of the immediate-early transcriptional program not fully reconstituted","How collision sensing relates to the cytosol/nucleus coactivator roles unresolved"]},{"year":2025,"claim":"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","pmids":["39905449"],"confidence":"Low","gaps":["Direct EDF1–RelA binding interface not mapped","Mechanism by which the complex prevents methylation undefined"]},{"year":null,"claim":"How EDF1's single conserved ribosome-collision-sensing activity mechanistically connects to its distinct cytosolic calmodulin sequestration and nuclear transcriptional coactivation roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,7,8,12]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,7,8]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,13]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]}],"complexes":["40S ribosomal subunit (collided ribosome)","NF-κB/RelA/EDF1 complex"],"partners":["GIGYF2","EIF4E2","CALM1","ENOS/NOS3","PPARG","RELA","CALCINEURIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60869","full_name":"Endothelial differentiation-related factor 1","aliases":["Multiprotein-bridging factor 1","MBF1"],"length_aa":148,"mass_kda":16.4,"function":"Transcriptional coactivator stimulating NR5A1 and ligand-dependent NR1H3/LXRA and PPARG transcriptional activities. Enhances the DNA-binding activity of ATF1, ATF2, CREB1 and NR5A1. Regulates nitric oxid synthase activity probably by sequestering calmodulin in the cytoplasm. May function in endothelial cells differentiation, hormone-induced cardiomyocytes hypertrophy and lipid metabolism","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O60869/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EDF1","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":1208,"dependency_fraction":0.04718543046357616},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000107223","cell_line_id":"CID001744","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"G3BP2","stoichiometry":0.2},{"gene":"LRP6","stoichiometry":0.2},{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP19","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001744","total_profiled":1310},"omim":[{"mim_id":"605107","title":"ENDOTHELIAL DIFFERENTIATION-RELATED FACTOR 1; EDF1","url":"https://www.omim.org/entry/605107"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EDF1"},"hgnc":{"alias_symbol":["EDF-1","CFAP280"],"prev_symbol":[]},"alphafold":{"accession":"O60869","domains":[{"cath_id":"1.10.260.40","chopping":"74-135","consensus_level":"high","plddt":92.8747,"start":74,"end":135}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60869","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60869-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60869-F1-predicted_aligned_error_v6.png","plddt_mean":83.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EDF1","jax_strain_url":"https://www.jax.org/strain/search?query=EDF1"},"sequence":{"accession":"O60869","fasta_url":"https://rest.uniprot.org/uniprotkb/O60869.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60869/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60869"}},"corpus_meta":[{"pmid":"32744497","id":"PMC_32744497","title":"EDF1 coordinates cellular responses to ribosome collisions.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32744497","citation_count":148,"is_preprint":false},{"pmid":"9813014","id":"PMC_9813014","title":"EDF-1, a novel gene product down-regulated in human endothelial cell differentiation.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9813014","citation_count":48,"is_preprint":false},{"pmid":"20605058","id":"PMC_20605058","title":"EDF-1 contributes to the regulation of nitric oxide release in VEGF-treated human endothelial cells.","date":"2010","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20605058","citation_count":19,"is_preprint":false},{"pmid":"16055206","id":"PMC_16055206","title":"Differential expression of EDF-1 and endothelial nitric oxide synthase by proliferating, quiescent and senescent microvascular endothelial cells.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16055206","citation_count":19,"is_preprint":false},{"pmid":"19554257","id":"PMC_19554257","title":"Transcriptional coactivator EDF-1 is required for PPARgamma-stimulated adipogenesis.","date":"2009","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/19554257","citation_count":17,"is_preprint":false},{"pmid":"29933613","id":"PMC_29933613","title":"The Contribution of EDF1 to PPARγ Transcriptional Activation in VEGF-Treated Human Endothelial Cells.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29933613","citation_count":12,"is_preprint":false},{"pmid":"16567061","id":"PMC_16567061","title":"Characterization of the human EDF-1 minimal promoter: involvement of NFY and Sp1 in the regulation of basal transcription.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16567061","citation_count":11,"is_preprint":false},{"pmid":"23376715","id":"PMC_23376715","title":"EDF-1 downregulates the CaM/Cn/NFAT signaling pathway during adipogenesis.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23376715","citation_count":5,"is_preprint":false},{"pmid":"11587857","id":"PMC_11587857","title":"Cloning and characterization of murine EDF-1.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11587857","citation_count":5,"is_preprint":false},{"pmid":"20185128","id":"PMC_20185128","title":"The effects of silencing EDF-1 in human endothelial cells.","date":"2010","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/20185128","citation_count":5,"is_preprint":false},{"pmid":"32695776","id":"PMC_32695776","title":"LncPrep + 96kb 2.2 kb Inhibits Estradiol Secretion From Granulosa Cells by Inducing EDF1 Translocation.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32695776","citation_count":4,"is_preprint":false},{"pmid":"39905449","id":"PMC_39905449","title":"EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/39905449","citation_count":3,"is_preprint":false},{"pmid":"37905068","id":"PMC_37905068","title":"Genetic deficiency of ribosomal rescue factor HBS1L causes retinal dystrophy associated with Pelota and EDF1 depletion.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37905068","citation_count":1,"is_preprint":false},{"pmid":"18547486","id":"PMC_18547486","title":"Impact of extracellular HIV-TAT on the regulation of EDF-1 levels in human endothelial cells.","date":"2008","source":"International journal of immunopathology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18547486","citation_count":1,"is_preprint":false},{"pmid":"20198862","id":"PMC_20198862","title":"Molecular cloning, characterization, and expression of the endothelial differentiation-related factor-1 (EDF-1) in Gekko japonicus.","date":"2010","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/20198862","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.02.601723","title":"Visualizing the translation landscape in human cells at high 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microscopy structural analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with defined binding site, combined with quantitative proteomics and functional follow-up in a single rigorous study\",\n      \"pmids\": [\"32744497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EDF1 recruits translational repressors GIGYF2 and EIF4E2 to collided ribosomes, initiating a negative-feedback loop that prevents new ribosomes from translating defective mRNAs.\",\n      \"method\": \"Proteomics of collided ribosome fractions; functional genetic experiments (loss-of-function); co-immunoprecipitation implied by recruitment assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, fractionation, functional genetic assays) in a single rigorous study establishing pathway position\",\n      \"pmids\": [\"32744497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EDF1 regulates an immediate-early transcriptional response to ribosomal collisions, linking ribosome-mediated quality control with global transcriptional regulation.\",\n      \"method\": \"Loss-of-function genetic experiments with transcriptional readout following ribosome collision induction\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, defined cellular phenotype with functional genetic evidence, but transcriptional mechanism not fully reconstituted in vitro\",\n      \"pmids\": [\"32744497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning, RNA fingerprinting, antisense-mediated knockdown with phenotypic readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antisense knockdown with specific phenotypic readouts, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"9813014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, proteasome inhibitor treatment (MG132), western blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by fractionation and pharmacological inhibitor experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"16055206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA-mediated stable silencing, co-immunoprecipitation of calmodulin/eNOS, phosphorylation assays (western blot), pharmacological inhibition (okadaic acid), NO measurement\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phosphorylation assay, pharmacological rescue), single lab\",\n      \"pmids\": [\"20605058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation of calmodulin and eNOS, calmodulin inhibitor (calmidazolium) rescue, NO assay, fibrin gel organization assay\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pharmacological rescue with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"20185128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, luciferase reporter assay, lipid staining, target gene (aP2) expression\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional reporter assay and rescue experiment, single lab\",\n      \"pmids\": [\"19554257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation for translocation, gene reporter assay, shRNA silencing, qPCR for FABP4 expression\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple readouts, single lab\",\n      \"pmids\": [\"29933613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, gene expression analysis during differentiation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-immunoprecipitation, single lab, no in vitro reconstitution or mutagenesis\",\n      \"pmids\": [\"23376715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"EMSA supershift, chromatin immunoprecipitation (ChIP), luciferase reporter deletion constructs\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA supershift and ChIP with deletion mutagenesis, single lab, two orthogonal methods\",\n      \"pmids\": [\"16567061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay, western blot with proteasome inhibitor (MG132), subcellular fractionation\",\n      \"journal\": \"International journal of immunopathology and pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reporter assay and fractionation, single lab, limited orthogonal validation\",\n      \"pmids\": [\"18547486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Bioinformatics, bulk RNA-seq, lipidomics, and biological validation assays (co-immunoprecipitation for complex, methylation assays for promoter, functional immune assays)\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic complex identified by Co-IP and promoter methylation assay in a single study; abstract does not detail all orthogonal validations\",\n      \"pmids\": [\"39905449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"In situ cryo-EM (cryo-FIB milling combined with single-particle cryo-EM) at 2.19 Å consensus resolution\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution in situ structure, but EDF1-specific functional validation is not reported in this abstract; single preprint study\",\n      \"pmids\": [\"bio_10.1101_2024.07.02.601723\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry proteomics of Hbs1l hypomorph mouse retina; comparison with patient data\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomics observation in a model organism, no direct mechanistic experiment on EDF1 itself; preprint with single method\",\n      \"pmids\": [\"37905068\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EDF1 is a conserved intracellular protein that functions as a sensor of ribosome collisions—binding the 40S subunit at the mRNA entry channel near the collision interface and recruiting translational repressors GIGYF2 and EIF4E2 to suppress translation of defective mRNAs—while also shuttling between the cytosol, where it sequesters calmodulin to modulate eNOS activity and the calcineurin/NFAT pathway, and the nucleus, where it acts as a transcriptional coactivator for PPARγ, NF-κB/RelA, and other factors; additionally, EDF1 coordinates an immediate-early transcriptional response to translational stress, linking ribosome quality control to global gene regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4]. 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 [#0, #1]; it concurrently directs an immediate-early transcriptional response to ribosome collisions, linking quality control to global gene regulation [#2]. 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 [#5, #6]. In the nucleus EDF1 functions as a transcriptional coactivator, co-immunoprecipitating with PPAR\\u03b3 and being required for ligand-dependent PPAR\\u03b3 activity and adipocyte differentiation independent of PPAR\\u03b3 protein levels [#7], with VEGF driving its nuclear translocation to support PPAR\\u03b3-dependent FABP4 expression [#8]. Loss of EDF1 in endothelial cells inhibits proliferation, drives a cobblestone-to-fibroblast/spindle morphological transition, and accelerates capillary-like network formation [#3, #6]. EDF1 abundance is controlled by proteasomal degradation in non-proliferating cells, with nuclear redistribution in senescence [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning and antisense-mediated knockdown with phenotypic readout in endothelial cells\",\n      \"pmids\": [\"9813014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular activity or binding partner defined\", \"Phenotype based on antisense without rescue\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved EDF1's dual subcellular roles\\u2014cytosolic calmodulin binding versus nuclear coactivation\\u2014and showed its downregulation in quiescent/senescent cells is proteasome-dependent, framing EDF1 as a localization-regulated factor.\",\n      \"evidence\": \"Subcellular fractionation and MG132 proteasome inhibition with western blot\",\n      \"pmids\": [\"16055206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals governing cytosol/nucleus partitioning not defined\", \"Calmodulin-binding interface not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined how EDF1 expression itself is controlled, identifying Sp1/Sp3 and NF-Y as drivers of its minimal promoter.\",\n      \"evidence\": \"EMSA supershift, ChIP, and luciferase reporter deletion constructs\",\n      \"pmids\": [\"16567061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address inducible or stress-responsive regulation of EDF1\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated EDF1 acts as a bona fide transcriptional coactivator by binding PPAR\\u03b3 and being required for ligand-dependent PPAR\\u03b3 activity independent of PPAR\\u03b3 levels, explaining its role in adipogenesis.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, luciferase reporter, lipid staining, and target gene expression in 3T3-L1 cells\",\n      \"pmids\": [\"19554257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coactivation mechanism (bridging vs. chromatin effect) not resolved\", \"Generality across nuclear receptors untested here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"shRNA silencing, reciprocal Co-IP of calmodulin/eNOS, phosphorylation assays, okadaic acid and calmidazolium rescue, and NO measurement in endothelial cells\",\n      \"pmids\": [\"20605058\", \"20185128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct EDF1\\u2013calmodulin binding interface not structurally defined\", \"Link between calmodulin sequestration and PP2A activity is correlative\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the calmodulin-sequestration model to the calmodulin/calcineurin/NFAT pathway during early adipogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation and gene expression analysis during differentiation\",\n      \"pmids\": [\"23376715\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reconstitution or mutagenesis\", \"Causality between NFAT inactivation and adipogenesis not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected the cytosolic and nuclear functions by showing VEGF triggers EDF1 nuclear translocation to enable PPAR\\u03b3-dependent gene expression in endothelial cells.\",\n      \"evidence\": \"Immunofluorescence/fractionation for translocation, reporter assay, shRNA, and qPCR for FABP4\",\n      \"pmids\": [\"29933613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger/transport machinery for translocation unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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\\u2014uniting quality control with gene regulation.\",\n      \"evidence\": \"Sucrose gradient proteomics, cryo-EM of EDF1 and yeast Mbf1, and loss-of-function functional genetics\",\n      \"pmids\": [\"32744497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and mechanism of the immediate-early transcriptional program not fully reconstituted\", \"How collision sensing relates to the cytosol/nucleus coactivator roles unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated EDF1's nuclear coactivator function in disease, as part of an NF-\\u03baB/RelA/EDF1 complex that protects ST8SIA1 from promoter methylation to drive ganglioside GD3 accumulation and CD8+ T cell dysfunction in neuroblastoma.\",\n      \"evidence\": \"RNA-seq, lipidomics, Co-IP for complex, promoter methylation assays, and immune functional assays\",\n      \"pmids\": [\"39905449\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct EDF1\\u2013RelA binding interface not mapped\", \"Mechanism by which the complex prevents methylation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EDF1's single conserved ribosome-collision-sensing activity mechanistically connects to its distinct cytosolic calmodulin sequestration and nuclear transcriptional coactivation roles remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 7, 8, 12]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"40S ribosomal subunit (collided ribosome)\", \"NF-\\u03baB/RelA/EDF1 complex\"],\n    \"partners\": [\"GIGYF2\", \"EIF4E2\", \"CALM1\", \"eNOS/NOS3\", \"PPARG\", \"RELA\", \"calcineurin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}