Affinage

ETF1

Eukaryotic peptide chain release factor subunit 1 · UniProt P62495

Length
437 aa
Mass
49.0 kDa
Annotated
2026-06-11
47 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETF1 encodes eukaryotic release factor 1 (eRF1), a class-1 translation termination factor that recognizes all three stop codons and catalyzes peptide release at the ribosome, a role first inferred from its strong sequence homology to the yeast omnipotent suppressor SUP45 (PMID:1537561, PMID:11996793). Reconstituted mammalian translation assays establish that eRF1 binds ribosomal subunits and pre-termination complexes, interacts with eRF3a, and stimulates its GTPase activity to drive termination; a shorter isoform 2 retains ribosome and eRF3a binding but exhibits reduced codon recognition and peptide release, UGA unipotency, and weak eRF3a GTPase stimulation, and accordingly suppresses uORF readthrough and dampens translation of long coding sequences (PMID:39063238). The fidelity of eRF1-mediated termination is tuned by its localization: under arsenite-induced oxidative stress eRF1 is sequestered into stress granules concurrent with elevated stop-codon readthrough and reinitiation (PMID:36672194), and in C9orf72-repeat-expansion ALS/FTD neurons its nucleocytoplasmic redistribution can be exploited—co-overexpression with UPF1 shifts the cell toward NMD-dependent mRNA degradation and rescues toxicity in vivo (PMID:32059759). Beyond termination per se, ETF1 contributes to gene-expression buffering, with its knockdown altering mRNA stability inversely to transcription rate (PMID:31116665). ETF1 is also a small-molecule target: stereoprobes that bind purified eRF1 modulate programmed ribosomal frameshifting and suppress SARS-CoV-2 and other viral replication (PMID:40909472), and a KDM3B-ETF1 fusion protein binds and represses the LMO2 locus to activate WNT/β-catenin signaling and promote breast cancer invasion (PMID:33828234).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1992 Medium

    Established the candidate identity of the human gene by showing it encodes a protein homologous to a known translation termination factor, framing it as the mammalian release factor.

    Evidence cDNA cloning and sequence homology comparison to yeast SUP45

    PMID:1537561 PMID:1546371

    Open questions at the time
    • Function inferred from homology only, no biochemical termination assay
    • Genomic signals mapped to multiple chromosomes, functional locus not yet resolved
  2. 2000 High

    Resolved which locus carries the functional gene versus pseudogenes, placing ETF1 at 5q31 within a region deleted in myelodysplasia/AML and motivating disease relevance.

    Evidence FISH and microsatellite marker mapping; identification of processed pseudogenes

    PMID:10773672

    Open questions at the time
    • Chromosomal location does not establish a causal role in the associated malignancies
    • No mutation or expression analysis tying ETF1 to MDS/AML phenotype
  3. 2003 Medium

    Characterized ETF1 as a housekeeping-type gene with constitutive yet tissue-regulated transcription, consistent with a ubiquitously required termination factor.

    Evidence Promoter mapping (Inr, Sp1/Sp3, no TATA box), footprinting, transient expression and RT-PCR

    PMID:11996793 PMID:14563555

    Open questions at the time
    • Catalytic release-factor activity asserted from homology, not directly assayed here
    • Regulatory elements defined in reporters, not validated at endogenous locus
  4. 2011 Medium

    Showed ETF1 pre-mRNA is itself a substrate of splicing regulation, revealing a layer of post-transcriptional control over the factor.

    Evidence TDP-43 UG-repeat splicing assays with ETF1 minigene reporters

    PMID:22100394

    Open questions at the time
    • Effect on endogenous ETF1 isoform ratios in cells not quantified
    • Functional consequence for termination activity not assessed
  5. 2019 Medium

    Connected ETF1 to gene-expression homeostasis beyond termination by demonstrating its role in buffering mRNA abundance through coupled decay and transcription.

    Evidence siRNA knockdown in HepG2 with mRNA stability and transcription-rate readouts

    PMID:31116665

    Open questions at the time
    • Mechanistic link between termination activity and transcriptional feedback unresolved
    • Buffering shown for specific transcripts, generality untested
  6. 2020 High

    Linked eRF1 localization to neurodegeneration, showing C9-HRE-driven redistribution and that boosting eRF1/UPF1 redirects the cell toward NMD and mitigates toxicity.

    Evidence Fractionation-MS, iPSC neuron/postmortem imaging, eRF1/UPF1 overexpression rescue in Drosophila and zebrafish

    PMID:32059759

    Open questions at the time
    • Whether endogenous eRF1 levels are limiting in disease not established
    • Direct contribution of termination activity versus NMD coupling to rescue not dissected
  7. 2023 Medium

    Demonstrated stress-dependent regulation of termination fidelity by showing eRF1 sequestration in stress granules coincides with increased readthrough.

    Evidence Immunofluorescence of eRF1 to stress granules plus readthrough and reinitiation reporters under arsenite stress

    PMID:36672194

    Open questions at the time
    • Causal link between sequestration and readthrough is correlative
    • Quantitative contribution of eRF1 depletion versus other factors unresolved
  8. 2024 High

    Provided direct biochemical definition of eRF1 termination activity and showed isoform 2 is a functionally attenuated, UGA-restricted variant that reshapes readthrough and elongation.

    Evidence Reconstituted mammalian in vitro translation: ribosome/pre-termination binding, codon recognition, peptide release, eRF3a GTPase stimulation, readthrough reporters

    PMID:39063238

    Open questions at the time
    • Physiological abundance and regulation of isoform 2 in tissues not established
    • Structural basis of UGA unipotency not resolved
  9. 2021 Medium

    Revealed a non-canonical oncogenic activity of an ETF1 fusion, repurposing the protein as a chromatin-targeting repressor of LMO2 that drives WNT/β-catenin-dependent invasion.

    Evidence ChIP, Western blot, Transwell invasion and xenograft assays with KDM3B-ETF1 overexpression/knockdown

    PMID:33828234

    Open questions at the time
    • Applies to the fusion protein, not wild-type ETF1
    • Contribution of the ETF1 moiety versus KDM3B moiety to LMO2 targeting not dissected
  10. 2025 Medium

    Established eRF1 as a druggable target for antiviral intervention via small molecules that modulate programmed ribosomal frameshifting without degrading the protein.

    Evidence Phenotypic stereoprobe screen, chemical proteomics, recombinant ETF1 binding, frameshifting and viral replication assays (preprint)

    PMID:40909472

    Open questions at the time
    • Preprint, single lab, not peer-reviewed
    • Binding site on eRF1 and mechanism of frameshifting modulation not defined
    • Selectivity over canonical termination activity not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How eRF1 catalytic engagement, subcellular sequestration, and isoform choice are coordinated to set readthrough and termination fidelity across physiological and disease states remains unresolved.
  • No structural model of human eRF1 in the termination complex in the corpus
  • Regulation of isoform 1 versus isoform 2 expression in vivo unknown
  • Mechanism connecting stress-granule sequestration to specific readthrough events undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0140098 catalytic activity, acting on RNA 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ETF1 (ERF3A/GSPT1)UPF1
Complex memberships
pre-termination complex / ribosome

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Human TB3-1 (ETF1) encodes a 47.8-kDa protein sharing 73% amino acid similarity with yeast omnipotent suppressor 45 (SUP45), suggesting a conserved role in translation termination/stop codon recognition in mammalian cells. cDNA cloning from T84 adenocarcinoma library, open reading frame analysis, sequence homology comparison Gene Medium 1537561
1992 TB3-1 (ETF1) genomic sequences map to human chromosomes 5, 6, 7, and X; the gene is well conserved in higher vertebrates including mammals and chicken. Human-mouse somatic cell panel analysis, Southern blot of mammalian and chicken genomic DNA Somatic cell and molecular genetics Medium 1546371
2000 The functional ETF1 gene resides on chromosome 5q31 at locus D5S500 (within the smallest commonly deleted segment in myelodysplastic syndromes/AML); three processed pseudogenes exist on chromosomes 6, 7, and X. Fluorescence in situ hybridization (FISH), microsatellite marker identification in intron 7 Cytogenetics and cell genetics High 10773672
2002 ETF1/eRF1 is a class-1 release factor that catalyses termination of protein synthesis at all three stop codons; the ETF1 promoter lacks a TATA box but contains an initiator element (Inr) and Sp1/Sp3 binding sites consistent with housekeeping gene regulation, with tissue-specific expression detected by RT-PCR. Primer extension, RNase protection mapping, DNase I hypersensitive site analysis, transient expression assays, in vivo/in vitro footprinting, real-time quantitative RT-PCR Cancer genetics and cytogenetics Medium 11996793
2003 The ETF1 gene promoter contains a basal promoter (−210/+117) with an Inr element and Sp1/Sp3 binding sites (no TATA box), plus an upstream region with both positive and negative regulatory elements, consistent with constitutive but tissue-regulated expression. Primer extension, RNase protection, DNase I hypersensitivity, transient expression assays, in vivo and in vitro footprinting, quantitative RT-PCR in mouse tissues Gene Medium 14563555
2011 TDP-43 binding to UG-repeated sequences near the 5' splice site of ETF1 pre-mRNA can act as either an activator or a suppressor of 5' splice-site recognition, depending on splice-site strength and additional splicing regulatory sequences. Splicing assays with artificial and natural substrates; UG-repeat mutagenesis; minigene reporters for BRCA1, ETF1, and RXRG Journal of molecular biology Medium 22100394
2019 Knockdown of ETF1 in human HepG2 cells alters the stability of specific mRNAs, and this change in mRNA half-life is inversely associated with altered transcription rates, such that mRNA abundance is buffered—demonstrating that ETF1 participates in a gene-expression buffering mechanism linking mRNA decay to transcription. siRNA knockdown of ETF1, mRNA stability measurements, transcription rate assays RNA biology Medium 31116665
2020 eRF1 (ETF1 protein) accumulates within nuclear envelope invaginations in C9orf72-HRE patient iPSC neurons and postmortem tissue; its cytoplasmic redistribution is driven by nucleocytoplasmic transport disruption caused by C9-HRE. Overexpression of eRF1 together with UPF1 shifts translation toward NMD-dependent mRNA degradation and ameliorates C9-HRE toxicity in vivo. Subcellular fractionation coupled with tandem mass spectrometry; iPSC neuron and postmortem tissue immunostaining; eRF1/UPF1 overexpression in Drosophila and zebrafish C9-HRE models Neuron High 32059759
2023 Upon arsenite-induced oxidative stress, eRF1 (ETF1) relocalizes to stress granules (SGs) coinciding with a dramatic increase in stop-codon readthrough rate and elevated translation reinitiation levels, suggesting eRF1 sequestration in SGs contributes to reduced translation termination fidelity under stress. Immunofluorescence localization of eRF1 and other translation factors to SGs; stop-codon readthrough reporter assays; translation reinitiation assays on uORF-containing and bicistronic mRNAs Cells Medium 36672194
2024 ETF1 isoform 2 (33 amino acids shorter than canonical eRF1 isoform 1) retains the ability to interact with ribosomal subunits and pre-termination complexes and to interact with eRF3a, but shows decreased codon recognition and peptide release activities, exhibits UGA unipotency, and stimulates eRF3a GTPase activity significantly less than isoform 1; it suppresses stop-codon readthrough of uORFs and decreases translation efficiency of long coding sequences. Reconstituted mammalian in vitro translation system; ribosome-binding and pre-termination complex interaction assays; GTPase activity assay; stop-codon readthrough reporters; cell-free translation system International journal of molecular sciences High 39063238
2025 Small-molecule photo-stereoprobes identified by phenotypic screening bind directly to ETF1 (eRF1) — confirmed by chemical proteomics and recombinant purified ETF1 — and modulate programmed ribosomal frameshifting essential for SARS-CoV-2 replication without causing ETF1 degradation, thereby suppressing replication of multiple viruses with non-canonical frameshifting mechanisms. Phenotypic screening of photoreactive small-molecule library; chemical proteomics (photoaffinity labeling); binding confirmation with recombinant purified ETF1; frameshifting reporter assays; viral replication assays bioRxivpreprint Medium 40909472
2021 The KDM3B-ETF1 fusion gene (arising from chromosomal rearrangement) targets the LMO2 locus via chromatin immunoprecipitation-confirmed binding, reduces LMO2 expression, and activates the WNT/β-catenin signaling pathway to promote breast cancer cell invasion and metastasis. Chromatin immunoprecipitation (ChIP), Western blot, cell counting kit-8, Transwell invasion assay, tumor xenograft in nude mice; KDM3B-ETF1 overexpression and knockdown Cancer gene therapy Medium 33828234

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy. The Journal of cell biology 83 12186856
2020 Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity. Neuron 70 32059759
2016 miR-150 regulates obesity-associated insulin resistance by controlling B cell functions. Scientific reports 63 26833392
2016 Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class III phosphatidylinositol 3-kinase. Autophagy 61 27541856
1991 Identification of a novel, N-ethylmaleimide-sensitive cytosolic factor required for vesicular transport from endosomes to the trans-Golgi network in vitro. The Journal of cell biology 58 1999460
2021 Iron robbery by intracellular pathogen via bacterial effector-induced ferritinophagy. Proceedings of the National Academy of Sciences of the United States of America 46 34074773
2007 Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 45 17982254
2017 Role and Function of the Type IV Secretion System in Anaplasma and Ehrlichia Species. Current topics in microbiology and immunology 39 29536364
2016 A novel infection- and inflammation-associated molecular signature in peripheral blood of myasthenia gravis patients. Immunobiology 39 27387891
2001 Temporal effect of human oviductal cell and its derived embryotrophic factors on mouse embryo development. Biology of reproduction 38 11673265
1992 Identification of a human cDNA with high homology to yeast omnipotent suppressor 45. Gene 32 1537561
1991 Functional properties of guinea pig eosinophil leukotriene B4 receptor. Journal of immunology (Baltimore, Md. : 1950) 32 1655904
2021 An intracellular nanobody targeting T4SS effector inhibits Ehrlichia infection. Proceedings of the National Academy of Sciences of the United States of America 31 33903242
2011 UG repeats/TDP-43 interactions near 5' splice sites exert unpredictable effects on splicing modulation. Journal of molecular biology 28 22100394
2009 Fibroblast growth factor 2-induced cytoplasmic asparaginyl-tRNA synthetase promotes survival of osteoblasts by regulating anti-apoptotic PI3K/Akt signaling. Bone 28 19631775
2022 The "Biological Weapons" of Ehrlichia chaffeensis: Novel Molecules and Mechanisms to Subjugate Host Cells. Frontiers in cellular and infection microbiology 25 35155275
2020 Host membrane lipids are trafficked to membranes of intravacuolar bacterium Ehrlichia chaffeensis. Proceedings of the National Academy of Sciences of the United States of America 25 32193339
2016 Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies. The international journal of neuropsychopharmacology 23 27450446
2019 mRNA levels are buffered upon knockdown of RNA decay and translation factors via adjustment of transcription rates in human HepG2 cells. RNA biology 22 31116665
2017 Peptide Nucleic Acid Knockdown and Intra-host Cell Complementation of Ehrlichia Type IV Secretion System Effector. Frontiers in cellular and infection microbiology 19 28638803
2002 Evaluation of ETF1/eRF1, mapping to 5q31, as a candidate myeloid tumor suppressor gene. Cancer genetics and cytogenetics 19 11996793
2009 Correlation of Notch1 expression and activation to cisplatin-sensitivity of head and neck squamous cell carcinoma. Ai zheng = Aizheng = Chinese journal of cancer 16 19550121
2012 Subdivision of molecularly-classified groups by new gene signatures in breast cancer patients. Oncology reports 14 22961600
2022 Identification of Four Biomarkers of Human Skin Aging by Comprehensive Single Cell Transcriptome, Transcriptome, and Proteomics. Frontiers in genetics 13 36081986
2017 Blocking of stromal interaction molecule 1 expression influence cell proliferation and promote cell apoptosis in vitro and inhibit tumor growth in vivo in head and neck squamous cell carcinoma. PloS one 13 28494008
2023 Relocalization of Translation Termination and Ribosome Recycling Factors to Stress Granules Coincides with Elevated Stop-Codon Readthrough and Reinitiation Rates upon Oxidative Stress. Cells 12 36672194
2018 Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network. Renal failure 12 29532746
2021 KDM3B-ETF1 fusion gene downregulates LMO2 via the WNT/β-catenin signaling pathway, promoting metastasis of invasive ductal carcinoma. Cancer gene therapy 11 33828234
2022 Differential proteomic analysis demonstrates follicle fluid participate immune reaction and protein translation in yak. BMC veterinary research 9 35031034
2020 A Novel Signature Based on mTORC1 Pathway in Hepatocellular Carcinoma. Journal of oncology 9 33014055
2023 Inhibition of Ehrlichia chaffeensis infection by cell-permeable macrocyclic peptides that bind type IV secretion effector Etf-1. PNAS nexus 8 36874272
2021 Identifying age-specific gene signatures of the human cerebral cortex with joint analysis of transcriptomes and functional connectomes. Briefings in bioinformatics 8 33367491
2003 Promoter analysis of the human translation termination factor 1 gene. Gene 8 14563555
1995 Cloning and identification of genes differentially expressed in metastatic and non-metastatic rat rhabdomyosarcoma cell lines. Clinical & experimental metastasis 8 7543834
2020 Computational analysis and verification of molecular genetic targets for glioblastoma. Bioscience reports 7 32469390
2022 miR-195 Inhibits Proliferation and Enhances Apoptosis of OSCC Cells via Targeting TLR4. Journal of healthcare engineering 6 35310196
1992 Chromosomal localization of a human cDNA containing a DIDS binding domain and demonstrating high homology to yeast omnipotent suppressor 45. Somatic cell and molecular genetics 6 1546371
2021 Comprehensive analyses of microRNA and mRNA expression in colorectal serrated lesions and colorectal cancer with a microsatellite instability phenotype. Genes, chromosomes & cancer 5 34846081
2000 Eukaryotic translation termination factor gene (ETF1/eRF1) maps at D5S500 in a commonly deleted region of chromosome 5q31 in malignant myeloid diseases. Cytogenetics and cell genetics 5 10773672
2019 Identification of Gli1-interacting proteins during simvastatin-stimulated osteogenic differentiation of bone marrow mesenchymal stem cells. Journal of cellular biochemistry 4 31245876
2018 Large-Scale Proteomic Identification of Targets of Cellular miR-197 Downregulated by Enterovirus A71. Journal of proteome research 4 30336044
2025 Bidirectional Hypoxic Extracellular Vesicle Signaling Between Müller Glia and Retinal Pigment Epithelium Regulates Retinal Metabolism and Barrier Function. Biology 2 40906190
2025 Integrated phenotypic screening and chemical proteomics identifies ETF1 ligands that modulate viral translation and replication. bioRxiv : the preprint server for biology 2 40909472
2024 Functional Activity of Isoform 2 of Human eRF1. International journal of molecular sciences 2 39063238
2011 [Anti-sense miRNA-21 oligonucleotide inhibits Tb 3.1 human tongue squamous cell carcinoma growth in vitro]. Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology 1 21426775
2025 Neuroprotective Effects of Black Raspberry Extract Against β-Amyloid-Induced Cytotoxicity in HT-22 Cells. Food science & nutrition 0 40918171
2016 [Construction of epithelial membrane protein 1 eukaryotic expression vector and its influence on migration and invasion of human oral tongue squamous carcinoma cells]. Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology 0 28317360

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