{"gene":"EEF1G","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2025,"finding":"EEF1G acts as a sensor of oxidized glutathione that couples cellular redox state to translation elongation rate. Under oxidative stress, EEF1G sensing of oxidized glutathione slows translation elongation, which reduces ribosome collisions at inefficiently decoded selenocysteine codons and thereby enhances production of detoxifying selenoproteins (GPX1, GPX4) to restore homeostasis.","method":"Genome-wide CRISPR knockout screens using GPX1/GPX4 selenoprotein reporters, combined with functional assays measuring translation elongation rate and ribosome collision frequency upon EEF1G perturbation under oxidative stress conditions","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide functional screen with mechanistic follow-up (ribosome collision assay, selenoprotein reporter), single lab, preprint not yet peer-reviewed","pmids":["41279241"],"is_preprint":true},{"year":2012,"finding":"eEF1G (along with eEF1A) is a critical cofactor of the HIV-1 reverse transcription complex (RTC). eEF1G co-immunoprecipitates with the p51 subunit of reverse transcriptase and integrase, associates with purified RTCs, and co-localizes with reverse transcriptase following cell infection. siRNA-mediated knockdown of eEF1G sharply down-regulates reverse transcription in cells by reducing RTC levels, indicating eEF1G is required for RTC stability.","method":"Protein fractionation with endogenous reverse transcription assay, co-immunoprecipitation, siRNA knockdown with quantification of RTCs and reverse transcription products, confocal co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional in vitro assay, siRNA knockdown with defined phenotype, and co-localization; multiple orthogonal methods in a single rigorous study","pmids":["22628567"],"is_preprint":false},{"year":2018,"finding":"eEF1G plays a strain-specific role in the translation of influenza A virus (IAV) proteins. In eEF1G-knockout cells generated by CRISPR/Cas9, A/WSN/33 (H1N1) virus growth and protein expression were significantly suppressed without reduction in viral mRNA, vRNA, or cRNA, indicating eEF1G acts post-transcriptionally at the translation step. The PB2 and PA proteins of WSN virus were identified as responsible for this eEF1G-dependent replication. In contrast, A/California/04/2009 (H1N1pdm) replication was unaffected.","method":"CRISPR/Cas9 knockout of eEF1G in cell lines, viral titration, protein expression analysis, viral RNA quantification (mRNA/vRNA/cRNA), strain comparison experiments","journal":"Frontiers in microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined cellular phenotype, multiple readouts (protein, RNA, viral titer), strain-specificity controls; single lab but multiple orthogonal methods","pmids":["30008712"],"is_preprint":false},{"year":2017,"finding":"eEF1G interacts with the FMDV nonstructural protein 2B. The interaction involves amino acids 208–437 in the C-terminal region of eEF1G and was identified by split-ubiquitin yeast two-hybrid screening and confirmed by co-immunoprecipitation of 2B and eEF1G in HEK293T cells.","method":"Split-ubiquitin yeast two-hybrid system with FMDV-infected tissue cDNA library, confirmed by co-immunoprecipitation in HEK293T cells","journal":"Microbial pathogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus confirmatory Co-IP; two methods but both are binding assays without functional follow-up; single lab","pmids":["28942178"],"is_preprint":false},{"year":2025,"finding":"eEF1G is a host restriction factor that inhibits porcine deltacoronavirus (PDCoV) replication. eEF1G directly binds PDCoV Nsp12 (the RdRp) and also binds PDCoV genomic RNA, competitively disrupting the Nsp12–viral RNA interaction and thereby impairing RdRp activity. siRNA knockdown of eEF1G significantly enhanced viral replication and negative-stranded RNA synthesis, while overexpression did not affect viral proliferation.","method":"Immunoprecipitation-coupled mass spectrometry, co-immunoprecipitation, pull-down assays, confocal microscopy, siRNA knockdown and overexpression with viral titration, strand-specific RT-qPCR, RNA immunoprecipitation assays","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IP-MS, Co-IP, pulldown, RIP, strand-specific qPCR, KD with defined phenotype) in a single rigorous study establishing direct molecular mechanism","pmids":["41157639"],"is_preprint":false},{"year":2023,"finding":"The cytosolic hCdc73–eEF1G (eEF1Bγ) complex controls the stability of p53 mRNA. Under arsenic stress, cytosolic hCdc73 is selectively sequestered into stress granules, but eEF1G (EEF1G) is not sequestered with it, leading to a transient increase in p53 mRNA at the post-transcriptional level. This indicates eEF1G participates in a cytosolic complex that negatively regulates p53 mRNA stability under normal conditions.","method":"Stress granule imaging (translocation assays), selective protein/mRNA sequestration analysis under arsenic stress, previously established cytosolic hCdc73-eEF1Bγ interaction referenced as prior work","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization/sequestration experiments under stress with functional mRNA stability readout; the eEF1G–hCdc73 complex is described as previously established, and this paper extends it to stress conditions with a defined post-transcriptional consequence; single lab","pmids":["37350228"],"is_preprint":false},{"year":2018,"finding":"EEF1G is a component of the eEF1 elongation factor complex that interacts with TCTP (translationally controlled tumor protein) in NF1-deficient malignant tumor cells. Affinity purification–mass spectrometry (AP-DIA/SWATH) identified EEF1G as part of the TCTP-interacting complex alongside EF1A2, EF1B, EF1D, and valyl-tRNA synthetase, suggesting eEF1G participates in a TCTP-coordinated translational machinery.","method":"Sequential affinity purification coupled with data-independent mass spectrometry acquisition (AP-DIA/SWATH) in NF1-deficient malignant tumor cells","journal":"Molecular & cellular proteomics : MCP","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single AP-MS experiment identifying EEF1G as part of a complex; no direct functional validation of eEF1G specifically within the complex; single lab","pmids":["30381327"],"is_preprint":false},{"year":2024,"finding":"YTHDF1, a m6A reader protein, promotes EEF1G translation in a m6A-dependent manner in lung adenocarcinoma (LUAD). YTHDF1 binds to m6A-modified EEF1G mRNA (validated by RIP-qPCR, Co-IP, and Co-IF), accelerating its translation. EEF1G overexpression partially counteracts tumor suppression induced by YTHDF1 silencing, confirming the regulatory relationship.","method":"RNA-seq, MeRIP-seq, RIP-seq, RIP-qPCR, Co-IP, Co-IF; functional rescue/knockdown experiments in LUAD cell lines and xenograft models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP-seq, RIP-qPCR, Co-IP, rescue experiments) establishing m6A-dependent translational regulation; preprint, single lab","pmids":["bio_10.1101_2024.09.13.612607"],"is_preprint":true},{"year":2013,"finding":"TRAP1 associates with ribosomes and with eEF1G (along with other translation factors such as eIF4A, eIF4E, eEF1A) in colon carcinoma cells, and TRAP1 is co-upregulated with eEF1G in human colorectal cancers. TRAP1 regulates global protein synthesis rate, and eEF1G is identified as a component of the translational apparatus associated with TRAP1.","method":"Co-immunoprecipitation of TRAP1 with ribosomal fractions and translation factors in colon carcinoma cells; correlation analysis in human colorectal cancer specimens","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying association; no direct functional validation of eEF1G's role within the TRAP1-ribosome complex; single lab","pmids":["24113185"],"is_preprint":false},{"year":2015,"finding":"eEF1G undergoes ubiquitination during oncogene-induced senescence (OIS). Global ubiquitinome profiling of primary human fibroblasts expressing oncogenic RAS identified eEF1G as one of the elongation factors with significantly changed ubiquitination sites during OIS, suggesting ubiquitination of the translation machinery including eEF1G as a regulatory mechanism during senescence.","method":"Ubiquitinated peptide enrichment by immune affinity purification followed by LC-MS/MS in RAS-induced OIS primary human fibroblasts; total proteome MS for normalization","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mass spectrometry-based identification of ubiquitination site on eEF1G in a pan-ubiquitinome screen; no direct functional validation of the modification's consequence on eEF1G activity; single lab","pmids":["25785348"],"is_preprint":false}],"current_model":"EEF1G (eEF1Bγ), a subunit of the eukaryotic elongation factor 1 complex, functions in translation elongation and additionally acts as a redox sensor: it detects oxidized glutathione under oxidative stress to slow translation elongation and enhance selenoprotein production; it stabilizes the HIV-1 reverse transcription complex; it restricts porcine deltacoronavirus replication by competing with Nsp12 for viral genomic RNA binding; it participates in a cytosolic complex with hCdc73 that negatively regulates p53 mRNA stability; and its own mRNA is subject to m6A-dependent translational upregulation by the YTHDF1 reader protein in lung adenocarcinoma cells."},"narrative":{"mechanistic_narrative":"EEF1G (eEF1Bγ) is a subunit of the eukaryotic elongation factor 1 complex that participates in translation elongation as part of a TCTP-coordinated translational machinery alongside eEF1A2, eEF1B, eEF1D, and valyl-tRNA synthetase [PMID:30381327]. Beyond its canonical elongation role, EEF1G couples cellular redox state to elongation: it senses oxidized glutathione under oxidative stress and slows elongation, reducing ribosome collisions at selenocysteine codons and enhancing production of the detoxifying selenoproteins GPX1 and GPX4 [PMID:41279241]. EEF1G is recurrently appropriated or opposed at the host–pathogen interface — it is required for HIV-1 reverse transcription complex stability, co-immunoprecipitating with the p51 reverse transcriptase subunit and integrase [PMID:22628567]; supports strain-specific translation of influenza A virus PB2/PA proteins [PMID:30008712]; and conversely acts as a restriction factor against porcine deltacoronavirus by directly binding the Nsp12 RdRp and competing for viral genomic RNA [PMID:41157639]. In the cytosol, EEF1G partners with hCdc73 in a complex that negatively regulates p53 mRNA stability [PMID:37350228]. EEF1G expression is itself controlled post-transcriptionally, its m6A-modified mRNA being translationally upregulated by the reader YTHDF1 in lung adenocarcinoma [PMID:bio_10.1101_2024.09.13.612607].","teleology":[{"year":2012,"claim":"Established that beyond translation, eEF1G is physically and functionally co-opted by a virus, defining it as a host cofactor required for HIV-1 reverse transcription complex stability.","evidence":"Reciprocal Co-IP with reverse transcriptase p51 and integrase, endogenous RT assays, siRNA knockdown, and confocal co-localization in infected cells","pmids":["22628567"],"confidence":"High","gaps":["Does not define the structural basis or binding interface of eEF1G–RTC association","Does not establish whether elongation-factor activity is required for the RTC role"]},{"year":2013,"claim":"Placed eEF1G within a TRAP1-associated translational apparatus linked to global protein synthesis in cancer, hinting at regulatory coupling to the elongation machinery.","evidence":"Co-IP of TRAP1 with ribosomal fractions and translation factors in colon carcinoma cells, plus tumor correlation analysis","pmids":["24113185"],"confidence":"Low","gaps":["Single Co-IP without functional validation of eEF1G's specific role","Association does not establish direct binding to TRAP1"]},{"year":2015,"claim":"Identified eEF1G as a target of regulatory ubiquitination during oncogene-induced senescence, implying post-translational control of the translation machinery.","evidence":"Ubiquitinome LC-MS/MS profiling of RAS-induced senescent primary human fibroblasts","pmids":["25785348"],"confidence":"Low","gaps":["Functional consequence of the ubiquitination on eEF1G activity unknown","Responsible E3 ligase not identified"]},{"year":2017,"claim":"Mapped a discrete viral protein interaction to the eEF1G C-terminus, narrowing the structural region engaged by a pathogen.","evidence":"Split-ubiquitin yeast two-hybrid with FMDV cDNA library and confirmatory Co-IP in HEK293T cells","pmids":["28942178"],"confidence":"Medium","gaps":["No functional consequence of the FMDV 2B interaction tested","Binding assays only, no reconstitution"]},{"year":2018,"claim":"Showed eEF1G acts post-transcriptionally at the translation step for select viral proteins, establishing strain-specific functional dependency rather than a generic role.","evidence":"CRISPR/Cas9 eEF1G knockout cells with viral titration, protein expression, and mRNA/vRNA/cRNA quantification across IAV strains","pmids":["30008712"],"confidence":"High","gaps":["Molecular basis for PB2/PA strain specificity unresolved","Whether eEF1G directly engages viral mRNA not shown"]},{"year":2018,"claim":"Defined eEF1G as a component of a TCTP-coordinated eEF1 translational complex in tumor cells, anchoring its canonical elongation context.","evidence":"Sequential affinity purification with data-independent MS (AP-DIA/SWATH) in NF1-deficient malignant tumor cells","pmids":["30381327"],"confidence":"Low","gaps":["Single AP-MS without functional validation of eEF1G in the complex","Direct vs. indirect TCTP association not distinguished"]},{"year":2023,"claim":"Revealed a moonlighting cytosolic role: eEF1G in complex with hCdc73 negatively regulates p53 mRNA stability, with stress-induced differential sequestration relieving this control.","evidence":"Stress-granule imaging and selective protein/mRNA sequestration analysis under arsenic stress, building on a prior eEF1G–hCdc73 interaction","pmids":["37350228"],"confidence":"Medium","gaps":["Mechanism by which the complex destabilizes p53 mRNA not defined","Direct RNA binding by eEF1G not demonstrated"]},{"year":2024,"claim":"Established that eEF1G's own expression is under m6A control, with YTHDF1 accelerating its translation to drive a tumor-promoting program.","evidence":"MeRIP-seq, RIP-qPCR, Co-IP/Co-IF, and rescue/knockdown in LUAD cell lines and xenografts (preprint)","pmids":["bio_10.1101_2024.09.13.612607"],"confidence":"Medium","gaps":["Specific m6A sites on EEF1G mRNA not pinpointed","Downstream effectors of EEF1G in LUAD not defined"]},{"year":2025,"claim":"Defined a redox-sensing function: eEF1G detects oxidized glutathione to slow elongation and boost selenoprotein output, linking translation speed to oxidative homeostasis.","evidence":"Genome-wide CRISPR knockout screens with GPX1/GPX4 selenoprotein reporters, elongation-rate and ribosome-collision assays (preprint)","pmids":["41279241"],"confidence":"Medium","gaps":["Molecular mechanism of oxidized-glutathione sensing by eEF1G not structurally resolved","Not yet peer-reviewed"]},{"year":2025,"claim":"Demonstrated eEF1G acts as an antiviral restriction factor that directly competes with a viral polymerase for genomic RNA.","evidence":"IP-MS, Co-IP, pull-down, RNA-IP, strand-specific RT-qPCR, and knockdown/overexpression with viral titration for PDCoV Nsp12","pmids":["41157639"],"confidence":"High","gaps":["Why overexpression fails to further restrict replication unexplained","RNA-binding determinants on eEF1G not mapped"]},{"year":null,"claim":"How eEF1G integrates its canonical elongation function with its redox-sensing, RNA-binding, and host–pathogen roles at the molecular and structural level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking elongation activity to moonlighting functions","Direct RNA-binding interface uncharacterized","Regulatory post-translational modifications not functionally dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,4]}],"complexes":["eEF1 elongation factor complex"],"partners":["EEF1A2","HCDC73","TCTP","TRAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26641","full_name":"Elongation factor 1-gamma","aliases":["eEF-1B gamma"],"length_aa":437,"mass_kda":50.1,"function":"Probably plays a role in anchoring the complex to other cellular components","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P26641/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EEF1G","classification":"Common Essential","n_dependent_lines":1157,"n_total_lines":1208,"dependency_fraction":0.9577814569536424},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000254772","cell_line_id":"CID001749","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"er","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"EEF1B2","stoichiometry":10.0},{"gene":"VARS","stoichiometry":10.0},{"gene":"EEF1D","stoichiometry":10.0},{"gene":"EEF1A1;EEF1A1P5","stoichiometry":10.0},{"gene":"CDCA8","stoichiometry":0.2},{"gene":"CARS","stoichiometry":0.2},{"gene":"EEF1A2","stoichiometry":0.2},{"gene":"AP3S1","stoichiometry":0.2},{"gene":"RRBP1","stoichiometry":0.2},{"gene":"KTN1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001749","total_profiled":1310},"omim":[{"mim_id":"600655","title":"EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, BETA-2; EEF1B2","url":"https://www.omim.org/entry/600655"},{"mim_id":"138295","title":"GLUTAMYL-PROLYL-tRNA SYNTHETASE 1; EPRS1","url":"https://www.omim.org/entry/138295"},{"mim_id":"130593","title":"EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, GAMMA; EEF1G","url":"https://www.omim.org/entry/130593"},{"mim_id":"130592","title":"EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, DELTA; EEF1D","url":"https://www.omim.org/entry/130592"},{"mim_id":"130590","title":"EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, ALPHA-1; EEF1A1","url":"https://www.omim.org/entry/130590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EEF1G"},"hgnc":{"alias_symbol":["EF1G"],"prev_symbol":[]},"alphafold":{"accession":"P26641","domains":[{"cath_id":"3.40.30.10","chopping":"2-80","consensus_level":"high","plddt":97.4129,"start":2,"end":80},{"cath_id":"1.20.1050.10","chopping":"85-203","consensus_level":"high","plddt":96.1396,"start":85,"end":203},{"cath_id":"3.30.70.1010","chopping":"289-435","consensus_level":"high","plddt":90.8329,"start":289,"end":435}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26641","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26641-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26641-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EEF1G","jax_strain_url":"https://www.jax.org/strain/search?query=EEF1G"},"sequence":{"accession":"P26641","fasta_url":"https://rest.uniprot.org/uniprotkb/P26641.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26641/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26641"}},"corpus_meta":[{"pmid":"24113185","id":"PMC_24113185","title":"Translational 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Manner","date":"2024-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.13.612607","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24681,"output_tokens":3125,"usd":0.060459,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10538,"output_tokens":3232,"usd":0.066745,"stage2_stop_reason":"end_turn"},"total_usd":0.127204,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"EEF1G acts as a sensor of oxidized glutathione that couples cellular redox state to translation elongation rate. Under oxidative stress, EEF1G sensing of oxidized glutathione slows translation elongation, which reduces ribosome collisions at inefficiently decoded selenocysteine codons and thereby enhances production of detoxifying selenoproteins (GPX1, GPX4) to restore homeostasis.\",\n      \"method\": \"Genome-wide CRISPR knockout screens using GPX1/GPX4 selenoprotein reporters, combined with functional assays measuring translation elongation rate and ribosome collision frequency upon EEF1G perturbation under oxidative stress conditions\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide functional screen with mechanistic follow-up (ribosome collision assay, selenoprotein reporter), single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41279241\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"eEF1G (along with eEF1A) is a critical cofactor of the HIV-1 reverse transcription complex (RTC). eEF1G co-immunoprecipitates with the p51 subunit of reverse transcriptase and integrase, associates with purified RTCs, and co-localizes with reverse transcriptase following cell infection. siRNA-mediated knockdown of eEF1G sharply down-regulates reverse transcription in cells by reducing RTC levels, indicating eEF1G is required for RTC stability.\",\n      \"method\": \"Protein fractionation with endogenous reverse transcription assay, co-immunoprecipitation, siRNA knockdown with quantification of RTCs and reverse transcription products, confocal co-localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional in vitro assay, siRNA knockdown with defined phenotype, and co-localization; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"22628567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"eEF1G plays a strain-specific role in the translation of influenza A virus (IAV) proteins. In eEF1G-knockout cells generated by CRISPR/Cas9, A/WSN/33 (H1N1) virus growth and protein expression were significantly suppressed without reduction in viral mRNA, vRNA, or cRNA, indicating eEF1G acts post-transcriptionally at the translation step. The PB2 and PA proteins of WSN virus were identified as responsible for this eEF1G-dependent replication. In contrast, A/California/04/2009 (H1N1pdm) replication was unaffected.\",\n      \"method\": \"CRISPR/Cas9 knockout of eEF1G in cell lines, viral titration, protein expression analysis, viral RNA quantification (mRNA/vRNA/cRNA), strain comparison experiments\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with defined cellular phenotype, multiple readouts (protein, RNA, viral titer), strain-specificity controls; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30008712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"eEF1G interacts with the FMDV nonstructural protein 2B. The interaction involves amino acids 208–437 in the C-terminal region of eEF1G and was identified by split-ubiquitin yeast two-hybrid screening and confirmed by co-immunoprecipitation of 2B and eEF1G in HEK293T cells.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid system with FMDV-infected tissue cDNA library, confirmed by co-immunoprecipitation in HEK293T cells\",\n      \"journal\": \"Microbial pathogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus confirmatory Co-IP; two methods but both are binding assays without functional follow-up; single lab\",\n      \"pmids\": [\"28942178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"eEF1G is a host restriction factor that inhibits porcine deltacoronavirus (PDCoV) replication. eEF1G directly binds PDCoV Nsp12 (the RdRp) and also binds PDCoV genomic RNA, competitively disrupting the Nsp12–viral RNA interaction and thereby impairing RdRp activity. siRNA knockdown of eEF1G significantly enhanced viral replication and negative-stranded RNA synthesis, while overexpression did not affect viral proliferation.\",\n      \"method\": \"Immunoprecipitation-coupled mass spectrometry, co-immunoprecipitation, pull-down assays, confocal microscopy, siRNA knockdown and overexpression with viral titration, strand-specific RT-qPCR, RNA immunoprecipitation assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IP-MS, Co-IP, pulldown, RIP, strand-specific qPCR, KD with defined phenotype) in a single rigorous study establishing direct molecular mechanism\",\n      \"pmids\": [\"41157639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The cytosolic hCdc73–eEF1G (eEF1Bγ) complex controls the stability of p53 mRNA. Under arsenic stress, cytosolic hCdc73 is selectively sequestered into stress granules, but eEF1G (EEF1G) is not sequestered with it, leading to a transient increase in p53 mRNA at the post-transcriptional level. This indicates eEF1G participates in a cytosolic complex that negatively regulates p53 mRNA stability under normal conditions.\",\n      \"method\": \"Stress granule imaging (translocation assays), selective protein/mRNA sequestration analysis under arsenic stress, previously established cytosolic hCdc73-eEF1Bγ interaction referenced as prior work\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization/sequestration experiments under stress with functional mRNA stability readout; the eEF1G–hCdc73 complex is described as previously established, and this paper extends it to stress conditions with a defined post-transcriptional consequence; single lab\",\n      \"pmids\": [\"37350228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EEF1G is a component of the eEF1 elongation factor complex that interacts with TCTP (translationally controlled tumor protein) in NF1-deficient malignant tumor cells. Affinity purification–mass spectrometry (AP-DIA/SWATH) identified EEF1G as part of the TCTP-interacting complex alongside EF1A2, EF1B, EF1D, and valyl-tRNA synthetase, suggesting eEF1G participates in a TCTP-coordinated translational machinery.\",\n      \"method\": \"Sequential affinity purification coupled with data-independent mass spectrometry acquisition (AP-DIA/SWATH) in NF1-deficient malignant tumor cells\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single AP-MS experiment identifying EEF1G as part of a complex; no direct functional validation of eEF1G specifically within the complex; single lab\",\n      \"pmids\": [\"30381327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF1, a m6A reader protein, promotes EEF1G translation in a m6A-dependent manner in lung adenocarcinoma (LUAD). YTHDF1 binds to m6A-modified EEF1G mRNA (validated by RIP-qPCR, Co-IP, and Co-IF), accelerating its translation. EEF1G overexpression partially counteracts tumor suppression induced by YTHDF1 silencing, confirming the regulatory relationship.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP-seq, RIP-qPCR, Co-IP, Co-IF; functional rescue/knockdown experiments in LUAD cell lines and xenograft models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP-seq, RIP-qPCR, Co-IP, rescue experiments) establishing m6A-dependent translational regulation; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.09.13.612607\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRAP1 associates with ribosomes and with eEF1G (along with other translation factors such as eIF4A, eIF4E, eEF1A) in colon carcinoma cells, and TRAP1 is co-upregulated with eEF1G in human colorectal cancers. TRAP1 regulates global protein synthesis rate, and eEF1G is identified as a component of the translational apparatus associated with TRAP1.\",\n      \"method\": \"Co-immunoprecipitation of TRAP1 with ribosomal fractions and translation factors in colon carcinoma cells; correlation analysis in human colorectal cancer specimens\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying association; no direct functional validation of eEF1G's role within the TRAP1-ribosome complex; single lab\",\n      \"pmids\": [\"24113185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"eEF1G undergoes ubiquitination during oncogene-induced senescence (OIS). Global ubiquitinome profiling of primary human fibroblasts expressing oncogenic RAS identified eEF1G as one of the elongation factors with significantly changed ubiquitination sites during OIS, suggesting ubiquitination of the translation machinery including eEF1G as a regulatory mechanism during senescence.\",\n      \"method\": \"Ubiquitinated peptide enrichment by immune affinity purification followed by LC-MS/MS in RAS-induced OIS primary human fibroblasts; total proteome MS for normalization\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mass spectrometry-based identification of ubiquitination site on eEF1G in a pan-ubiquitinome screen; no direct functional validation of the modification's consequence on eEF1G activity; single lab\",\n      \"pmids\": [\"25785348\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EEF1G (eEF1Bγ), a subunit of the eukaryotic elongation factor 1 complex, functions in translation elongation and additionally acts as a redox sensor: it detects oxidized glutathione under oxidative stress to slow translation elongation and enhance selenoprotein production; it stabilizes the HIV-1 reverse transcription complex; it restricts porcine deltacoronavirus replication by competing with Nsp12 for viral genomic RNA binding; it participates in a cytosolic complex with hCdc73 that negatively regulates p53 mRNA stability; and its own mRNA is subject to m6A-dependent translational upregulation by the YTHDF1 reader protein in lung adenocarcinoma cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EEF1G (eEF1Bγ) is a subunit of the eukaryotic elongation factor 1 complex that participates in translation elongation as part of a TCTP-coordinated translational machinery alongside eEF1A2, eEF1B, eEF1D, and valyl-tRNA synthetase [#6]. Beyond its canonical elongation role, EEF1G couples cellular redox state to elongation: it senses oxidized glutathione under oxidative stress and slows elongation, reducing ribosome collisions at selenocysteine codons and enhancing production of the detoxifying selenoproteins GPX1 and GPX4 [#0]. EEF1G is recurrently appropriated or opposed at the host–pathogen interface — it is required for HIV-1 reverse transcription complex stability, co-immunoprecipitating with the p51 reverse transcriptase subunit and integrase [#1]; supports strain-specific translation of influenza A virus PB2/PA proteins [#2]; and conversely acts as a restriction factor against porcine deltacoronavirus by directly binding the Nsp12 RdRp and competing for viral genomic RNA [#4]. In the cytosol, EEF1G partners with hCdc73 in a complex that negatively regulates p53 mRNA stability [#5]. EEF1G expression is itself controlled post-transcriptionally, its m6A-modified mRNA being translationally upregulated by the reader YTHDF1 in lung adenocarcinoma [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that beyond translation, eEF1G is physically and functionally co-opted by a virus, defining it as a host cofactor required for HIV-1 reverse transcription complex stability.\",\n      \"evidence\": \"Reciprocal Co-IP with reverse transcriptase p51 and integrase, endogenous RT assays, siRNA knockdown, and confocal co-localization in infected cells\",\n      \"pmids\": [\"22628567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the structural basis or binding interface of eEF1G–RTC association\", \"Does not establish whether elongation-factor activity is required for the RTC role\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed eEF1G within a TRAP1-associated translational apparatus linked to global protein synthesis in cancer, hinting at regulatory coupling to the elongation machinery.\",\n      \"evidence\": \"Co-IP of TRAP1 with ribosomal fractions and translation factors in colon carcinoma cells, plus tumor correlation analysis\",\n      \"pmids\": [\"24113185\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without functional validation of eEF1G's specific role\", \"Association does not establish direct binding to TRAP1\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified eEF1G as a target of regulatory ubiquitination during oncogene-induced senescence, implying post-translational control of the translation machinery.\",\n      \"evidence\": \"Ubiquitinome LC-MS/MS profiling of RAS-induced senescent primary human fibroblasts\",\n      \"pmids\": [\"25785348\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional consequence of the ubiquitination on eEF1G activity unknown\", \"Responsible E3 ligase not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped a discrete viral protein interaction to the eEF1G C-terminus, narrowing the structural region engaged by a pathogen.\",\n      \"evidence\": \"Split-ubiquitin yeast two-hybrid with FMDV cDNA library and confirmatory Co-IP in HEK293T cells\",\n      \"pmids\": [\"28942178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the FMDV 2B interaction tested\", \"Binding assays only, no reconstitution\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed eEF1G acts post-transcriptionally at the translation step for select viral proteins, establishing strain-specific functional dependency rather than a generic role.\",\n      \"evidence\": \"CRISPR/Cas9 eEF1G knockout cells with viral titration, protein expression, and mRNA/vRNA/cRNA quantification across IAV strains\",\n      \"pmids\": [\"30008712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for PB2/PA strain specificity unresolved\", \"Whether eEF1G directly engages viral mRNA not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined eEF1G as a component of a TCTP-coordinated eEF1 translational complex in tumor cells, anchoring its canonical elongation context.\",\n      \"evidence\": \"Sequential affinity purification with data-independent MS (AP-DIA/SWATH) in NF1-deficient malignant tumor cells\",\n      \"pmids\": [\"30381327\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single AP-MS without functional validation of eEF1G in the complex\", \"Direct vs. indirect TCTP association not distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a moonlighting cytosolic role: eEF1G in complex with hCdc73 negatively regulates p53 mRNA stability, with stress-induced differential sequestration relieving this control.\",\n      \"evidence\": \"Stress-granule imaging and selective protein/mRNA sequestration analysis under arsenic stress, building on a prior eEF1G–hCdc73 interaction\",\n      \"pmids\": [\"37350228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the complex destabilizes p53 mRNA not defined\", \"Direct RNA binding by eEF1G not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that eEF1G's own expression is under m6A control, with YTHDF1 accelerating its translation to drive a tumor-promoting program.\",\n      \"evidence\": \"MeRIP-seq, RIP-qPCR, Co-IP/Co-IF, and rescue/knockdown in LUAD cell lines and xenografts (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.13.612607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on EEF1G mRNA not pinpointed\", \"Downstream effectors of EEF1G in LUAD not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a redox-sensing function: eEF1G detects oxidized glutathione to slow elongation and boost selenoprotein output, linking translation speed to oxidative homeostasis.\",\n      \"evidence\": \"Genome-wide CRISPR knockout screens with GPX1/GPX4 selenoprotein reporters, elongation-rate and ribosome-collision assays (preprint)\",\n      \"pmids\": [\"41279241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of oxidized-glutathione sensing by eEF1G not structurally resolved\", \"Not yet peer-reviewed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated eEF1G acts as an antiviral restriction factor that directly competes with a viral polymerase for genomic RNA.\",\n      \"evidence\": \"IP-MS, Co-IP, pull-down, RNA-IP, strand-specific RT-qPCR, and knockdown/overexpression with viral titration for PDCoV Nsp12\",\n      \"pmids\": [\"41157639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why overexpression fails to further restrict replication unexplained\", \"RNA-binding determinants on eEF1G not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How eEF1G integrates its canonical elongation function with its redox-sensing, RNA-binding, and host–pathogen roles at the molecular and structural level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking elongation activity to moonlighting functions\", \"Direct RNA-binding interface uncharacterized\", \"Regulatory post-translational modifications not functionally dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"complexes\": [\"eEF1 elongation factor complex\"],\n    \"partners\": [\"EEF1A2\", \"hCdc73\", \"TCTP\", \"TRAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":4,"faith_pct":50.0}}