{"gene":"EIF6","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2007,"finding":"Human RISC associates with a multiprotein complex containing MOV10 and proteins of the 60S ribosome subunit, including the anti-association factor eIF6 (ITGB4BP/p27BBP). Depletion of eIF6 in human cells and C. elegans specifically abrogates miRNA-mediated regulation of target protein and mRNA levels, establishing an evolutionarily conserved function of eIF6 in miRNA-mediated post-transcriptional silencing by preventing productive 80S ribosome assembly.","method":"Biochemical co-purification, functional depletion assays in human cells and C. elegans, assessment of miRNA target protein and mRNA levels","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical isolation of RISC-eIF6 complex plus loss-of-function in two independent organisms (human cells and C. elegans) with specific phenotypic readouts","pmids":["17507929"],"is_preprint":false},{"year":2001,"finding":"p27BBP/eIF6 (ITGB4BP) protein is expressed in a cell-specific fashion in vivo despite constitutive expression in cultured cells; mRNA and protein levels vary among different organs and even among cells within the same tissue, indicating regulation by tissue-specific factors and protein synthesis pathways.","method":"Immunohistochemistry, qRT-PCR, serum starvation and heat-shock treatment in cultured cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization and expression experiments in vivo and in vitro, single lab, multiple methods but no functional manipulation","pmids":["11290417"],"is_preprint":false},{"year":2012,"finding":"ITGB4BP (eIF6) was identified as a direct interaction partner of the 8 kDa protein P311, confirmed by yeast two-hybrid screening, FRET in pulmonary adenocarcinoma tissue, and co-immunoprecipitation in HEK293 cells.","method":"Yeast two-hybrid, FRET, co-immunoprecipitation (Co-IP)","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — three orthogonal methods (Y2H, FRET, Co-IP) from a single lab confirming the interaction, but no downstream functional mechanism established","pmids":["22365962"],"is_preprint":false},{"year":2024,"finding":"The N106S mutant of eIF6, which disrupts eIF6 interaction with the 60S subunit, leads to an increase in vacant 80S ribosomes, demonstrating that eIF6's anti-association activity on 60S is distinct from its role in 60S biogenesis. Limiting active ribosomal pools via this mutant markedly deregulates translation during mitosis, causing chromosome segregation defects, mitotic exit delays, and mitotic catastrophe. Ribo-Seq analysis showed significant downregulation in translation efficiencies of mitotic factors and transcripts with long 3′UTRs. The nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions.","method":"N106S point mutant of eIF6, ribosome sedimentation assays, Ribo-Seq, live-cell imaging for mitotic phenotypes, subcellular localization analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutant separation-of-function with multiple orthogonal readouts (ribosome profiling, Ribo-Seq, imaging), single preprint lab, not yet peer-reviewed","pmids":["bio_10.1101_2024.06.24.600220"],"is_preprint":true},{"year":2024,"finding":"Under oxidative stress (menadione treatment), inhibition of EIF6 complex formation occurs as part of the cellular translational inhibition response, as detected by DIA-MS-based redox proteomics identifying elevated cysteine oxidation on EIF6.","method":"Data-independent acquisition mass spectrometry (DIA-MS)-based label-free redox proteomics (DIALRP) in DU145 prostate cancer cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomic screen, single lab, no direct functional validation of the EIF6 complex disruption mechanism","pmids":["bio_10.1101_2024.12.16.626735"],"is_preprint":true},{"year":2024,"finding":"The lncRNA CRNDE UCE binds to eIF6 through a sequence element adjacent to its ultraconserved element (UCE), facilitating delivery of eIF6 to the nucleolus as part of 60S ribosomal subunit biogenesis.","method":"CRISPRi screens, nucleolar localization assays, RNA-protein binding assays for CRNDE UCE–eIF6 interaction","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, binding interaction described but mechanistic details of eIF6 delivery remain incompletely characterized in the abstract","pmids":["bio_10.1101_2024.07.23.604857"],"is_preprint":true}],"current_model":"EIF6 (p27BBP/ITGB4BP) is a ribosome anti-association factor that binds the 60S subunit to prevent 80S assembly; its release from 60S is required for productive translation, its anti-association activity is separable from its role in 60S biogenesis, it is recruited to RISC to mediate miRNA-dependent translational silencing, it is delivered to the nucleolus via interaction with lncRNA CRNDE UCE during ribosome biogenesis, it physically interacts with P311, and its modulation of 80S availability is specifically critical for accurate translation of mitotic factors and for proper chromosome segregation and mitotic exit."},"narrative":{"mechanistic_narrative":"EIF6 (p27BBP/ITGB4BP) is a 60S ribosomal subunit-binding factor whose control over 80S ribosome assembly couples ribosome biogenesis to the regulation of translation [PMID:17507929, PMID:bio_10.1101_2024.06.24.600220]. As an anti-association factor, eIF6 occupies the 60S subunit to block productive 80S formation, and a separation-of-function mutant (N106S) that disrupts eIF6–60S binding increases vacant 80S ribosomes, establishing that its anti-association activity is mechanistically distinct from its role in 60S biogenesis [PMID:bio_10.1101_2024.06.24.600220]. By limiting the active ribosomal pool, eIF6 governs accurate translation of mitotic factors and transcripts with long 3′UTRs; its dysregulation causes chromosome segregation defects, mitotic exit delays, and mitotic catastrophe [PMID:bio_10.1101_2024.06.24.600220]. The same anti-association property underlies a conserved role in miRNA-mediated silencing: eIF6 co-purifies with human RISC alongside MOV10 and 60S subunit proteins, and its depletion in human cells and C. elegans abrogates miRNA-mediated repression of target protein and mRNA levels [PMID:17507929]. eIF6 is delivered to the nucleolus through binding of the lncRNA CRNDE UCE during 60S biogenesis [PMID:bio_10.1101_2024.07.23.604857], and it physically interacts with the small protein P311 [PMID:22365962].","teleology":[{"year":2001,"claim":"Before functional studies, it was unclear whether eIF6 was a uniform housekeeping factor; this work showed its expression is cell-specific in vivo despite constitutive expression in culture, implying regulation by tissue-specific and protein-synthesis-linked factors.","evidence":"Immunohistochemistry, qRT-PCR, and serum-starvation/heat-shock treatment of cultured cells","pmids":["11290417"],"confidence":"Medium","gaps":["No functional manipulation linking expression level to translation or biogenesis","Regulatory factors driving tissue specificity not identified"]},{"year":2007,"claim":"Addressed how a ribosome anti-association factor participates in gene silencing by showing eIF6 is a RISC-associated component required for miRNA-mediated repression, extending its anti-80S-assembly function to post-transcriptional control.","evidence":"Biochemical co-purification of RISC with MOV10 and 60S proteins plus eIF6 depletion in human cells and C. elegans with miRNA target readouts","pmids":["17507929"],"confidence":"High","gaps":["Direct molecular mechanism by which eIF6 within RISC blocks 80S assembly on target mRNAs not resolved","Whether eIF6's silencing role is identical to its biogenesis pool unclear"]},{"year":2012,"claim":"Identified a physical partner of eIF6 outside the ribosome, linking it to the small protein P311, though without a downstream functional mechanism.","evidence":"Yeast two-hybrid, FRET in pulmonary adenocarcinoma tissue, and co-immunoprecipitation in HEK293 cells","pmids":["22365962"],"confidence":"Medium","gaps":["Functional consequence of the eIF6–P311 interaction unknown","No structural or stoichiometric characterization of the interaction"]},{"year":2024,"claim":"Resolved whether eIF6's anti-association activity is separable from 60S biogenesis and connected ribosome availability to mitosis, using a binding-disruptive mutant to show increased vacant 80S, deregulated mitotic-factor translation, and mitotic defects.","evidence":"N106S point mutant, ribosome sedimentation, Ribo-Seq, and live-cell imaging of mitotic phenotypes (preprint)","pmids":["bio_10.1101_2024.06.24.600220"],"confidence":"Medium","gaps":["Single preprint, not peer-reviewed","Mechanism coupling 80S availability specifically to mitotic transcript selection not fully defined"]},{"year":2024,"claim":"Began to define how eIF6 reaches its site of action, showing the lncRNA CRNDE UCE binds eIF6 and facilitates its nucleolar delivery during 60S biogenesis.","evidence":"CRISPRi screens, nucleolar localization assays, and CRNDE UCE–eIF6 RNA-protein binding assays (preprint)","pmids":["bio_10.1101_2024.07.23.604857"],"confidence":"Low","gaps":["Single preprint; mechanistic details of delivery incompletely characterized","Binding element mapped only adjacent to the UCE without structural detail"]},{"year":2024,"claim":"Began to connect eIF6 to stress-responsive translational control, with redox proteomics detecting cysteine oxidation on eIF6 and inferred complex disruption under oxidative stress.","evidence":"DIA-MS-based redox proteomics (DIALRP) in DU145 prostate cancer cells (preprint)","pmids":["bio_10.1101_2024.12.16.626735"],"confidence":"Low","gaps":["Single proteomic screen without functional validation","Direct effect of cysteine oxidation on eIF6–60S binding not demonstrated"]},{"year":null,"claim":"How eIF6 release from the 60S subunit is triggered and coordinated between its biogenesis, silencing, and mitotic-control functions remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No molecular trigger for eIF6 release defined in the corpus","Whether distinct eIF6 pools serve RISC versus biogenesis is unknown","Structural basis of the anti-association mechanism not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5]}],"complexes":["RISC","60S ribosomal subunit"],"partners":["MOV10","P311"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56537","full_name":"Eukaryotic translation initiation factor 6","aliases":["B(2)GCN homolog","B4 integrin interactor","CAB","p27(BBP)"],"length_aa":245,"mass_kda":26.6,"function":"Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm (PubMed:10085284, PubMed:14654845, PubMed:21536732, PubMed:32669547). Behaves as a stimulatory translation initiation factor downstream insulin/growth factors. Is also involved in ribosome biogenesis. Associates with pre-60S subunits in the nucleus and is involved in its nuclear export. Cytoplasmic release of TIF6 from 60S subunits and nuclear relocalization is promoted by a RACK1 (RACK1)-dependent protein kinase C activity (PubMed:10085284, PubMed:14654845, PubMed:21536732). In tissues responsive to insulin, controls fatty acid synthesis and glycolysis by exerting translational control of adipogenic transcription factors such as CEBPB, CEBPD and ATF4 that have G/C rich or uORF in their 5'UTR. Required for ROS-dependent megakaryocyte maturation and platelets formation, controls the expression of mitochondrial respiratory chain genes involved in reactive oxygen species (ROS) synthesis (By similarity). Involved in miRNA-mediated gene silencing by the RNA-induced silencing complex (RISC). Required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC (PubMed:17507929). Modulates cell cycle progression and global translation of pre-B cells, its activation seems to be rate-limiting in tumorigenesis and tumor growth (By similarity)","subcellular_location":"Cytoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P56537/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF6","classification":"Common Essential","n_dependent_lines":1183,"n_total_lines":1208,"dependency_fraction":0.9793046357615894},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NPM1","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"SRP19","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF6","total_profiled":1310},"omim":[{"mim_id":"619089","title":"GIPC PDZ DOMAIN-CONTAINING FAMILY, MEMBER 2; GIPC2","url":"https://www.omim.org/entry/619089"},{"mim_id":"617941","title":"SHWACHMAN-DIAMOND SYNDROME 2; SDS2","url":"https://www.omim.org/entry/617941"},{"mim_id":"617538","title":"ELONGATION FACTOR-LIKE GTPase 1; EFL1","url":"https://www.omim.org/entry/617538"},{"mim_id":"607444","title":"SBDS RIBOSOME MATURATION FACTOR; SBDS","url":"https://www.omim.org/entry/607444"},{"mim_id":"602912","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 6; EIF6","url":"https://www.omim.org/entry/602912"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF6"},"hgnc":{"alias_symbol":["p27BBP","b(2)gcn"],"prev_symbol":["EIF3A","ITGB4BP"]},"alphafold":{"accession":"P56537","domains":[{"cath_id":"3.75.10.10","chopping":"1-242","consensus_level":"medium","plddt":91.4426,"start":1,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56537","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56537-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56537-F1-predicted_aligned_error_v6.png","plddt_mean":91.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF6","jax_strain_url":"https://www.jax.org/strain/search?query=EIF6"},"sequence":{"accession":"P56537","fasta_url":"https://rest.uniprot.org/uniprotkb/P56537.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56537/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56537"}},"corpus_meta":[{"pmid":"17507929","id":"PMC_17507929","title":"MicroRNA silencing through RISC recruitment of eIF6.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17507929","citation_count":368,"is_preprint":false},{"pmid":"17284669","id":"PMC_17284669","title":"Identification of reference genes for quantitative real-time PCR in the bovine mammary gland during the lactation cycle.","date":"2007","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17284669","citation_count":250,"is_preprint":false},{"pmid":"11290417","id":"PMC_11290417","title":"The human ITGB4BP gene is constitutively expressed in vitro, but highly modulated in vivo.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11290417","citation_count":21,"is_preprint":false},{"pmid":"34830804","id":"PMC_34830804","title":"Dysregulation of Translation Factors EIF2S1, EIF5A and EIF6 in Intestinal-Type Adenocarcinoma (ITAC).","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34830804","citation_count":14,"is_preprint":false},{"pmid":"22365962","id":"PMC_22365962","title":"Identification of ITGB4BP as a new interaction protein of P311.","date":"2012","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22365962","citation_count":10,"is_preprint":false},{"pmid":"21029697","id":"PMC_21029697","title":"[Expression and significance of P311 and ITGB4BP in non-small cell lung cancer].","date":"2010","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/21029697","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.24.600220","title":"Modulation of ribosomal subunit associations by eIF6 is critical for mitotic exit and cancer progression","date":"2024-06-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.24.600220","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.16.626735","title":"Data-Independent Acquisition (DIA)-Based Label-Free Redox Proteomics (DIALRP) Reveals Novel Oxidative Stress Responsive Translation Factors","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.626735","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.23.604857","title":"An ultraconserved snoRNA-like element in long noncoding RNA  <i>CRNDE</i>  promotes ribosome biogenesis and cell proliferation","date":"2024-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604857","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6045,"output_tokens":1662,"usd":0.021532,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8458,"output_tokens":2481,"usd":0.052158,"stage2_stop_reason":"end_turn"},"total_usd":0.07369,"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\": 2007,\n      \"finding\": \"Human RISC associates with a multiprotein complex containing MOV10 and proteins of the 60S ribosome subunit, including the anti-association factor eIF6 (ITGB4BP/p27BBP). Depletion of eIF6 in human cells and C. elegans specifically abrogates miRNA-mediated regulation of target protein and mRNA levels, establishing an evolutionarily conserved function of eIF6 in miRNA-mediated post-transcriptional silencing by preventing productive 80S ribosome assembly.\",\n      \"method\": \"Biochemical co-purification, functional depletion assays in human cells and C. elegans, assessment of miRNA target protein and mRNA levels\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical isolation of RISC-eIF6 complex plus loss-of-function in two independent organisms (human cells and C. elegans) with specific phenotypic readouts\",\n      \"pmids\": [\"17507929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"p27BBP/eIF6 (ITGB4BP) protein is expressed in a cell-specific fashion in vivo despite constitutive expression in cultured cells; mRNA and protein levels vary among different organs and even among cells within the same tissue, indicating regulation by tissue-specific factors and protein synthesis pathways.\",\n      \"method\": \"Immunohistochemistry, qRT-PCR, serum starvation and heat-shock treatment in cultured cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization and expression experiments in vivo and in vitro, single lab, multiple methods but no functional manipulation\",\n      \"pmids\": [\"11290417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ITGB4BP (eIF6) was identified as a direct interaction partner of the 8 kDa protein P311, confirmed by yeast two-hybrid screening, FRET in pulmonary adenocarcinoma tissue, and co-immunoprecipitation in HEK293 cells.\",\n      \"method\": \"Yeast two-hybrid, FRET, co-immunoprecipitation (Co-IP)\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — three orthogonal methods (Y2H, FRET, Co-IP) from a single lab confirming the interaction, but no downstream functional mechanism established\",\n      \"pmids\": [\"22365962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The N106S mutant of eIF6, which disrupts eIF6 interaction with the 60S subunit, leads to an increase in vacant 80S ribosomes, demonstrating that eIF6's anti-association activity on 60S is distinct from its role in 60S biogenesis. Limiting active ribosomal pools via this mutant markedly deregulates translation during mitosis, causing chromosome segregation defects, mitotic exit delays, and mitotic catastrophe. Ribo-Seq analysis showed significant downregulation in translation efficiencies of mitotic factors and transcripts with long 3′UTRs. The nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions.\",\n      \"method\": \"N106S point mutant of eIF6, ribosome sedimentation assays, Ribo-Seq, live-cell imaging for mitotic phenotypes, subcellular localization analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutant separation-of-function with multiple orthogonal readouts (ribosome profiling, Ribo-Seq, imaging), single preprint lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.24.600220\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under oxidative stress (menadione treatment), inhibition of EIF6 complex formation occurs as part of the cellular translational inhibition response, as detected by DIA-MS-based redox proteomics identifying elevated cysteine oxidation on EIF6.\",\n      \"method\": \"Data-independent acquisition mass spectrometry (DIA-MS)-based label-free redox proteomics (DIALRP) in DU145 prostate cancer cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomic screen, single lab, no direct functional validation of the EIF6 complex disruption mechanism\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.626735\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The lncRNA CRNDE UCE binds to eIF6 through a sequence element adjacent to its ultraconserved element (UCE), facilitating delivery of eIF6 to the nucleolus as part of 60S ribosomal subunit biogenesis.\",\n      \"method\": \"CRISPRi screens, nucleolar localization assays, RNA-protein binding assays for CRNDE UCE–eIF6 interaction\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, binding interaction described but mechanistic details of eIF6 delivery remain incompletely characterized in the abstract\",\n      \"pmids\": [\"bio_10.1101_2024.07.23.604857\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EIF6 (p27BBP/ITGB4BP) is a ribosome anti-association factor that binds the 60S subunit to prevent 80S assembly; its release from 60S is required for productive translation, its anti-association activity is separable from its role in 60S biogenesis, it is recruited to RISC to mediate miRNA-dependent translational silencing, it is delivered to the nucleolus via interaction with lncRNA CRNDE UCE during ribosome biogenesis, it physically interacts with P311, and its modulation of 80S availability is specifically critical for accurate translation of mitotic factors and for proper chromosome segregation and mitotic exit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF6 (p27BBP/ITGB4BP) is a 60S ribosomal subunit-binding factor whose control over 80S ribosome assembly couples ribosome biogenesis to the regulation of translation [#0, #3]. As an anti-association factor, eIF6 occupies the 60S subunit to block productive 80S formation, and a separation-of-function mutant (N106S) that disrupts eIF6–60S binding increases vacant 80S ribosomes, establishing that its anti-association activity is mechanistically distinct from its role in 60S biogenesis [#3]. By limiting the active ribosomal pool, eIF6 governs accurate translation of mitotic factors and transcripts with long 3′UTRs; its dysregulation causes chromosome segregation defects, mitotic exit delays, and mitotic catastrophe [#3]. The same anti-association property underlies a conserved role in miRNA-mediated silencing: eIF6 co-purifies with human RISC alongside MOV10 and 60S subunit proteins, and its depletion in human cells and C. elegans abrogates miRNA-mediated repression of target protein and mRNA levels [#0]. eIF6 is delivered to the nucleolus through binding of the lncRNA CRNDE UCE during 60S biogenesis [#5], and it physically interacts with the small protein P311 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Before functional studies, it was unclear whether eIF6 was a uniform housekeeping factor; this work showed its expression is cell-specific in vivo despite constitutive expression in culture, implying regulation by tissue-specific and protein-synthesis-linked factors.\",\n      \"evidence\": \"Immunohistochemistry, qRT-PCR, and serum-starvation/heat-shock treatment of cultured cells\",\n      \"pmids\": [\"11290417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional manipulation linking expression level to translation or biogenesis\", \"Regulatory factors driving tissue specificity not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Addressed how a ribosome anti-association factor participates in gene silencing by showing eIF6 is a RISC-associated component required for miRNA-mediated repression, extending its anti-80S-assembly function to post-transcriptional control.\",\n      \"evidence\": \"Biochemical co-purification of RISC with MOV10 and 60S proteins plus eIF6 depletion in human cells and C. elegans with miRNA target readouts\",\n      \"pmids\": [\"17507929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular mechanism by which eIF6 within RISC blocks 80S assembly on target mRNAs not resolved\", \"Whether eIF6's silencing role is identical to its biogenesis pool unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a physical partner of eIF6 outside the ribosome, linking it to the small protein P311, though without a downstream functional mechanism.\",\n      \"evidence\": \"Yeast two-hybrid, FRET in pulmonary adenocarcinoma tissue, and co-immunoprecipitation in HEK293 cells\",\n      \"pmids\": [\"22365962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the eIF6–P311 interaction unknown\", \"No structural or stoichiometric characterization of the interaction\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved whether eIF6's anti-association activity is separable from 60S biogenesis and connected ribosome availability to mitosis, using a binding-disruptive mutant to show increased vacant 80S, deregulated mitotic-factor translation, and mitotic defects.\",\n      \"evidence\": \"N106S point mutant, ribosome sedimentation, Ribo-Seq, and live-cell imaging of mitotic phenotypes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.24.600220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single preprint, not peer-reviewed\", \"Mechanism coupling 80S availability specifically to mitotic transcript selection not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Began to define how eIF6 reaches its site of action, showing the lncRNA CRNDE UCE binds eIF6 and facilitates its nucleolar delivery during 60S biogenesis.\",\n      \"evidence\": \"CRISPRi screens, nucleolar localization assays, and CRNDE UCE–eIF6 RNA-protein binding assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.23.604857\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single preprint; mechanistic details of delivery incompletely characterized\", \"Binding element mapped only adjacent to the UCE without structural detail\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Began to connect eIF6 to stress-responsive translational control, with redox proteomics detecting cysteine oxidation on eIF6 and inferred complex disruption under oxidative stress.\",\n      \"evidence\": \"DIA-MS-based redox proteomics (DIALRP) in DU145 prostate cancer cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.626735\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single proteomic screen without functional validation\", \"Direct effect of cysteine oxidation on eIF6–60S binding not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How eIF6 release from the 60S subunit is triggered and coordinated between its biogenesis, silencing, and mitotic-control functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular trigger for eIF6 release defined in the corpus\", \"Whether distinct eIF6 pools serve RISC versus biogenesis is unknown\", \"Structural basis of the anti-association mechanism not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"RISC\", \"60S ribosomal subunit\"],\n    \"partners\": [\"MOV10\", \"P311\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}