{"gene":"EIF3M","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2005,"finding":"Fission yeast has two distinct eIF3 complexes that share common core subunits but are distinguished by the PCI proteins eIF3e and eIF3m. eIF3m is an essential gene required for global cellular protein synthesis and polysome formation, unlike eIF3e. Using a ribonomic approach, the eIF3m complex was shown to associate with the bulk of cellular mRNAs, whereas the eIF3e complex associates with a far more restricted mRNA set, indicating that PCI proteins eIF3e and eIF3m define distinct eIF3 complexes that assist in translation of different mRNA sets.","method":"Genetic deletion (eif3m essential vs. eif3e non-essential), polysome analysis, ribonomics/microarray with RT-PCR validation, biochemical fractionation","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, polysome profiling, ribonomics) with corroboration across 14 mRNAs; replicated within same study","pmids":["15904532"],"is_preprint":false},{"year":2010,"finding":"In human colon cancer cells (HCT-116), siRNA-mediated silencing of eIF3m impairs cell proliferation, cell cycle progression, and induces cell death. Ribonomics identified a subset of eIF3m-associated mRNAs including MIF and MT2A; eIF3m knockdown reduced expression of MT2A downstream effector CDC25A, linking eIF3m to cell cycle control via mRNA-specific translational regulation.","method":"siRNA knockdown, cell proliferation/cell cycle/apoptosis assays, ribonomics approach (mRNA immunoprecipitation), RT-PCR validation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with defined cellular phenotypes and ribonomic pathway placement, single lab","pmids":["20838379"],"is_preprint":false},{"year":2013,"finding":"Drosophila Tango7 (ortholog of EIF3M) collaborates with the Drosophila apoptosome to drive caspase-dependent cellular remodeling required to resolve individual sperm from a syncytium. Tango7 localizes to the active apoptosome compartment via its C terminus and directly stimulates the activity of this complex in vitro, specifying the apoptosome as an effector of cellular remodeling rather than cell death.","method":"Genetic loss-of-function, in vitro caspase activity assay, C-terminal domain truncation/localization analysis, co-localization imaging","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of activity stimulation combined with genetic loss-of-function and domain mapping","pmids":["23913920"],"is_preprint":false},{"year":2017,"finding":"Drosophila Tango7 (EIF3M ortholog) regulates cortical caspase (dronc) activity in living salivary glands independently of the canonical Apaf-1 adaptor Dark. Tango7-dependent cortical dronc activity enables F-actin dismantling at the cortex, allowing glands to stretch as they accumulate secreted products, demonstrating that Tango7 and Dark define mutually exclusive subcellular domains of caspase activity.","method":"Genetic loss-of-function (tango7 and dark mutants), live imaging, F-actin staining, cortical caspase activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with orthogonal imaging and activity assays establishing distinct subcellular caspase domains","pmids":["28928435"],"is_preprint":false},{"year":2019,"finding":"In vivo RNAi-mediated knockdown of eIF3m in mouse liver causes transcriptional upregulation of ribosomal protein genes and inhibition of rRNA processing (decoupling rRNA synthesis from ribosomal protein gene transcription), with broad metabolic gene expression changes but few detectable differences in translation of specific mRNAs. In vitro, reduced eIF3m protein levels are associated with induction of the mTOR pathway, an effect not observed in vivo.","method":"In vivo RNAi knockdown, transcriptome sequencing, ribosome profiling, whole proteome and phosphoproteome mass spectrometry, rRNA processing analysis","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal omics methods (ribosome profiling, proteomics, transcriptomics, phosphoproteomics) in vivo","pmids":["31855834"],"is_preprint":false},{"year":2021,"finding":"EIF3m binds directly to the 5'UTR of CAPRIN1 mRNA and positively regulates its expression at the post-transcriptional level. EIF3m protein stability in lung adenocarcinoma cells is maintained through interaction with the deubiquitinase UCHL5, which stabilizes EIF3m via deubiquitination. The UCHL5/EIF3m/CAPRIN1 axis promotes malignant phenotypes in vitro and in vivo.","method":"RNA immunoprecipitation (RIP) of 5'UTR, co-immunoprecipitation (EIF3m-UCHL5 interaction), gain- and loss-of-function assays, in vivo xenograft models","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP for protein interaction, RIP for RNA binding, functional rescue experiments; single lab","pmids":["33791168"],"is_preprint":false},{"year":2026,"finding":"USP34 deubiquitinase maintains EIF3m protein stability through deubiquitination in TNBC cells. EIF3m in turn binds directly to the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function (membrane potential and network structure). Disruption of this USP34/eIF3m/MTCH2 axis impairs mitochondrial function and inhibits TNBC cell proliferation.","method":"Co-immunoprecipitation, GST pull-down, RNA immunoprecipitation, RNA pull-down, JC-1 mitochondrial membrane potential assay, MitoSOX/MitoTracker imaging, siRNA knockdown","journal":"Journal of histotechnology","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple biochemical methods (Co-IP, GST pulldown, RIP, RNA pulldown) converging on mechanism; single lab, recent publication","pmids":["42023842"],"is_preprint":false},{"year":2026,"finding":"EIF3m, particularly its C-terminal domain, physically interacts with ORF1B, a non-structural protein of fowl adenovirus serotype 4 (FAdV-4), as identified by co-immunoprecipitation/mass spectrometry. The two proteins co-localize in the cytoplasm. Overexpression of EIF3m promotes FAdV-4 replication while EIF3m knockdown suppresses it, indicating that the virus hijacks EIF3m to facilitate replication.","method":"Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), domain mapping (C-terminal truncation), co-localization imaging, overexpression and knockdown functional assays","journal":"Poultry science","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP/MS for interaction identification with domain mapping and functional gain/loss-of-function; non-mammalian virus model","pmids":["41637784"],"is_preprint":false}],"current_model":"EIF3M is an essential PCI-domain subunit of the eIF3 translation initiation complex that defines a distinct eIF3 sub-complex responsible for bulk mRNA translation; it binds specific mRNA 5'UTRs to post-transcriptionally regulate targets (including CAPRIN1 and MTCH2), its protein stability is controlled by deubiquitination via UCHL5/USP34, and its Drosophila ortholog (Tango7) additionally functions as an apoptosome co-activator that specifies subcellular domains of non-apoptotic caspase activity for cellular remodeling."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that eIF3m defines a distinct eIF3 sub-complex essential for bulk mRNA translation resolved the question of whether PCI-domain subunits were functionally interchangeable within eIF3.","evidence":"Genetic deletion, polysome profiling, and ribonomics in fission yeast","pmids":["15904532"],"confidence":"High","gaps":["Mechanism by which eIF3m selects the bulk mRNA pool versus the eIF3e-restricted pool was not determined","Whether the two-complex architecture is conserved in mammals was untested"]},{"year":2010,"claim":"Demonstrating that eIF3m knockdown impairs human cancer cell proliferation and cycle progression through mRNA-specific translational regulation (e.g., MT2A–CDC25A axis) extended eIF3m's mRNA-selective role to mammalian cells.","evidence":"siRNA knockdown, ribonomics, cell cycle/apoptosis assays in HCT-116 cells","pmids":["20838379"],"confidence":"Medium","gaps":["Direct binding of eIF3m to identified mRNAs was not shown","Single cell line with no in vivo validation"]},{"year":2013,"claim":"Discovery that Drosophila Tango7 directly stimulates the apoptosome to drive non-apoptotic caspase-dependent cellular remodeling revealed an unexpected translation-independent function for the eIF3m ortholog.","evidence":"Genetic loss-of-function, in vitro caspase reconstitution, C-terminal domain mapping in Drosophila spermatogenesis","pmids":["23913920"],"confidence":"High","gaps":["Whether the apoptosome co-activator function is conserved in mammals was not tested","Structural basis of Tango7 C-terminal interaction with the apoptosome is unresolved"]},{"year":2017,"claim":"Showing that Tango7 activates cortical dronc independently of canonical adaptor Dark established that eIF3m ortholog defines a spatially distinct, non-apoptotic caspase activation mechanism for tissue remodeling.","evidence":"Genetic epistasis between tango7 and dark mutants, live imaging, cortical caspase and F-actin assays in Drosophila salivary glands","pmids":["28928435"],"confidence":"High","gaps":["Molecular basis of Dark-independent caspase activation by Tango7 is unknown","Whether this cortical function requires eIF3 translation activity was not dissected"]},{"year":2019,"claim":"In vivo eIF3m knockdown in mouse liver revealed that reduced eIF3m decouples ribosomal protein gene transcription from rRNA processing, linking eIF3m to ribosome biogenesis quality control beyond its direct role in translation initiation.","evidence":"In vivo RNAi, ribosome profiling, proteomics, phosphoproteomics, and rRNA processing analysis in mouse liver","pmids":["31855834"],"confidence":"High","gaps":["Whether rRNA processing perturbation is a direct or indirect consequence of eIF3m loss is unclear","mTOR pathway induction seen in vitro was not recapitulated in vivo, leaving the in vitro relevance uncertain"]},{"year":2021,"claim":"Identification of direct EIF3M binding to the CAPRIN1 5′UTR and stabilization of EIF3M by deubiquitinase UCHL5 established the first molecularly defined mRNA target and upstream stability mechanism for EIF3M in human cells.","evidence":"RNA immunoprecipitation of 5′UTR, reciprocal co-immunoprecipitation of EIF3M–UCHL5, functional rescue, xenograft models in lung adenocarcinoma","pmids":["33791168"],"confidence":"Medium","gaps":["Structural determinants of EIF3M 5′UTR recognition are undefined","Whether UCHL5-mediated stabilization is specific to cancer contexts or generalizable was not addressed"]},{"year":2026,"claim":"Demonstration that USP34 deubiquitinates EIF3M and that EIF3M binds the MTCH2 5′UTR to sustain mitochondrial function revealed a second deubiquitinase–EIF3M–target mRNA axis, linking EIF3M translational control to mitochondrial homeostasis.","evidence":"Co-IP, GST pull-down, RIP, RNA pull-down, mitochondrial membrane potential and morphology assays in TNBC cells","pmids":["42023842"],"confidence":"Medium","gaps":["Whether USP34 and UCHL5 act redundantly or in distinct contexts is unknown","No structural or transcriptome-wide mapping of EIF3M RNA-binding specificity has been performed"]},{"year":2026,"claim":"Finding that FAdV-4 ORF1B protein binds the EIF3M C-terminal domain to promote viral replication demonstrated that EIF3M is a host factor co-opted by a pathogen, consistent with its central role in translation initiation.","evidence":"Co-IP/MS, C-terminal domain mapping, overexpression/knockdown in avian cells","pmids":["41637784"],"confidence":"Medium","gaps":["Non-mammalian virus system; relevance to mammalian viral infections is untested","Whether ORF1B binding competes with eIF3 complex assembly or translation function is unknown"]},{"year":null,"claim":"A transcriptome-wide map of EIF3M direct RNA targets and the structural basis of its 5′UTR selectivity remain undefined, as does whether the Drosophila apoptosome co-activator function is conserved in mammals.","evidence":"","pmids":[],"confidence":"High","gaps":["No CLIP-seq or equivalent unbiased RNA-binding map exists for EIF3M","Structural mechanism of 5′UTR recognition is unresolved","Mammalian relevance of non-apoptotic caspase co-activation is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,5,6]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1,4,5,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4,5,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]}],"complexes":["eIF3"],"partners":["UCHL5","USP34","DARK","DRONC"],"other_free_text":[]},"mechanistic_narrative":"EIF3M is a PCI-domain subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that is essential for bulk cellular protein synthesis and polysome formation, distinguishing a functionally distinct eIF3 sub-complex from the eIF3e-containing complex [PMID:15904532]. Beyond its role in global translation, EIF3M binds specific mRNA 5′UTRs—including those of CAPRIN1 and MTCH2—to post-transcriptionally regulate their expression, coupling translational control to cell proliferation and mitochondrial homeostasis [PMID:33791168, PMID:42023842]. EIF3M protein stability is maintained by deubiquitinases UCHL5 and USP34, and its loss perturbs ribosomal protein gene expression and rRNA processing in vivo [PMID:31855834, PMID:33791168, PMID:42023842]. In Drosophila, the ortholog Tango7 additionally functions as an apoptosome co-activator that specifies subcellular domains of non-apoptotic caspase activity for cellular remodeling [PMID:23913920, PMID:28928435]."},"prefetch_data":{"uniprot":{"accession":"Q7L2H7","full_name":"Eukaryotic translation initiation factor 3 subunit M","aliases":["Fetal lung protein B5","hFL-B5","PCI domain-containing protein 1"],"length_aa":374,"mass_kda":42.5,"function":"Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17403899, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17403899). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773) (Microbial infection) May favor virus entry in case of infection with herpes simplex virus 1 (HSV1) or herpes simplex virus 2 (HSV2)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q7L2H7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3M","classification":"Common Essential","n_dependent_lines":1177,"n_total_lines":1208,"dependency_fraction":0.9743377483443708},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000149100","cell_line_id":"CID001740","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3I","stoichiometry":10.0},{"gene":"EIF3K","stoichiometry":10.0},{"gene":"EIF3E","stoichiometry":10.0},{"gene":"EIF3A","stoichiometry":10.0},{"gene":"EIF3L","stoichiometry":10.0},{"gene":"EIF3CL","stoichiometry":10.0},{"gene":"EIF3H","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":10.0},{"gene":"ABCE1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001740","total_profiled":1310},"omim":[{"mim_id":"612294","title":"DEP DOMAIN-CONTAINING PROTEIN 7; DEPDC7","url":"https://www.omim.org/entry/612294"},{"mim_id":"609641","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT M; EIF3M","url":"https://www.omim.org/entry/609641"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3M"},"hgnc":{"alias_symbol":["hfl-B5","FLJ29030","GA17","TANGO7"],"prev_symbol":["PCID1"]},"alphafold":{"accession":"Q7L2H7","domains":[{"cath_id":"1.10.10.10","chopping":"274-340","consensus_level":"medium","plddt":60.6387,"start":274,"end":340},{"cath_id":"1.20.5","chopping":"342-374","consensus_level":"medium","plddt":73.793,"start":342,"end":374}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L2H7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L2H7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L2H7-F1-predicted_aligned_error_v6.png","plddt_mean":55.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3M","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3M"},"sequence":{"accession":"Q7L2H7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L2H7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L2H7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L2H7"}},"corpus_meta":[{"pmid":"15904532","id":"PMC_15904532","title":"PCI proteins eIF3e and eIF3m define distinct translation initiation factor 3 complexes.","date":"2005","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/15904532","citation_count":120,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20838379","id":"PMC_20838379","title":"eIF3m expression influences the regulation of tumorigenesis-related genes in human colon cancer.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20838379","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28928435","id":"PMC_28928435","title":"Tango7 regulates cortical activity of caspases during reaper-triggered changes in tissue elasticity.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28928435","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23913920","id":"PMC_23913920","title":"Tango7 directs cellular remodeling by the Drosophila apoptosome.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/23913920","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33791168","id":"PMC_33791168","title":"EIF3m promotes the malignant phenotype of lung adenocarcinoma by the up-regulation of oncogene CAPRIN1.","date":"2021","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33791168","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32368187","id":"PMC_32368187","title":"Roles of eIF3m in the tumorigenesis of triple negative breast cancer.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32368187","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31855834","id":"PMC_31855834","title":"In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation.","date":"2019","source":"Molecular therapy. 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16920360","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28611215","id":"PMC_28611215","title":"Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28611215","citation_count":282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22678362","id":"PMC_22678362","title":"MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22678362","citation_count":230,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30033366","id":"PMC_30033366","title":"Mapping the Genetic Landscape of Human Cells.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30033366","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6373,"output_tokens":1430,"usd":0.020285},"stage2":{"model":"claude-opus-4-6","input_tokens":4665,"output_tokens":1941,"usd":0.107775},"total_usd":0.309681,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":17350,"output_tokens":3119,"usd":0.049418},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5842,"output_tokens":2357,"usd":0.132203}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"EIF3M (eIF3m) is a PCI-domain protein that defines a distinct eIF3 complex separate from the eIF3e-containing complex; both complexes share common core subunits but associate with different sets of cellular mRNAs, with the eIF3m complex associating with the bulk of cellular mRNAs while the eIF3e complex associates with a restricted set.\",\n      \"method\": \"Biochemical fractionation, ribonomic/microarray analysis of mRNA co-purification, RT-PCR validation, genetic analysis in fission yeast (eif3m deletion)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical fractionation, ribonomics, RT-PCR, genetics) in a highly cited foundational study\",\n      \"pmids\": [\"15904532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EIF3M is essential for global cellular protein synthesis and polysome formation, as deletion of eif3m in fission yeast abolishes these activities, whereas eIF3e is non-essential for global translation.\",\n      \"method\": \"Genetic deletion in fission yeast, polysome profiling\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular phenotype (polysome profiling), replicated by ribonomic analysis\",\n      \"pmids\": [\"15904532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EIF3M knockdown in human colon cancer cells (HCT-116) by siRNA reduces cell proliferation, alters cell cycle progression, and promotes cell death; EIF3M influences expression of tumorigenesis-related genes MIF and MT2 at the mRNA level, and regulates downstream CDC25A protein levels.\",\n      \"method\": \"siRNA knockdown, ribonomics, cell cycle analysis, western blotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — siRNA KD with cellular phenotype and ribonomic pathway placement, single lab\",\n      \"pmids\": [\"20838379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In vivo RNAi-mediated knockdown of eIF3m in mouse liver leads to inhibition of rRNA processing and upregulation of ribosomal protein gene transcription (ribosome biogenesis response), as well as alterations in lipid, amino acid, and nucleic acid metabolism, but has limited impact on translation of specific mRNAs.\",\n      \"method\": \"In vivo RNAi knockdown in mouse liver, transcriptome sequencing, ribosome profiling, whole proteome and phosphoproteome analysis\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal genome-wide methods (ribosome profiling, transcriptomics, proteomics) in vivo\",\n      \"pmids\": [\"31855834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EIF3M binds to the 5'UTR of CAPRIN1 mRNA and positively regulates CAPRIN1 expression at the post-transcriptional level; EIF3M also interacts with the deubiquitinase UCHL5, which stabilizes EIF3M protein and promotes its accumulation in lung adenocarcinoma cells.\",\n      \"method\": \"RNA immunoprecipitation (binding to 5'UTR), Co-immunoprecipitation (EIF3M-UCHL5 interaction), gain- and loss-of-function assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — reciprocal Co-IP and RNA-IP with functional validation, single lab\",\n      \"pmids\": [\"33791168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP34 deubiquitinates EIF3M to maintain its protein stability; EIF3M in turn binds the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function in triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, RNA immunoprecipitation, RNA-pulldown, JC-1 assay, MitoSOX assay\",\n      \"journal\": \"Journal of histotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods (Co-IP, GST-pulldown, RNA-IP, RNA-pulldown) with functional rescue, single lab\",\n      \"pmids\": [\"42023842\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3M is a PCI-domain subunit that defines a distinct eIF3 translation initiation complex required for global protein synthesis and polysome formation; it associates with the bulk of cellular mRNAs via their 5'UTRs to regulate their translation post-transcriptionally, its protein stability is controlled by deubiquitination (by UCHL5 or USP34), and its knockdown disrupts ribosome biogenesis (rRNA processing) and broadly alters cellular metabolism without strongly affecting translation of specific individual mRNAs.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries from KEPT papers only.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:15904532 — Directly about eIF3m/EIF3M in fission yeast → **KEEP**\n2. PMID:20838379 — Directly about EIF3m in human colon cancer → **KEEP**\n3. PMID:28928435 — Tango7/Drosophila caspases — Tango7 is an alias for EIF3M in Drosophila (TANGO7 = EIF3M ortholog). The paper is about caspase regulation, but Tango7 is the Drosophila ortholog of EIF3M → **KEEP** (ortholog)\n4. PMID:23913920 — Tango7 in Drosophila apoptosome/sperm remodeling — same as above, Tango7 = EIF3M ortholog → **KEEP** (ortholog)\n5. PMID:33791168 — EIF3m in lung adenocarcinoma → **KEEP**\n6. PMID:32368187 — EIF3m in TNBC → **KEEP**\n7. PMID:31855834 — eIF3m knockdown in mouse liver → **KEEP**\n8. PMID:39556433 — eIF3m in prostate cancer → **KEEP**\n9. PMID:42023842 — USP34/eIF3m/MTCH2 axis in TNBC → **KEEP**\n10. PMID:41637784 — eIF3m interaction with FAdV-4 ORF1B → **KEEP**\n11. PMID:15214079 — Crystal chemistry of Yb-Fe-Ga alloy → **EXCLUDE** (completely unrelated)\n\nGene2pubmed curated papers:\n- Most are large interactome/proteome resource papers (PMID:16169070, 12477932, 19615732, 26777405, 26186194, 28514442, 26496610, 25416956, 32296183, 29507755, 14702039, 17353931, 33961781, 22939629, 21873635, 32680882, 30232453, 22190034, 29395067, 33060197, 8125298, 35271311, 20360068, 26344197, 25849773, 16920360, 28611215, 22863883, 22678362, 30033366) — These are large-scale resource papers that may contain EIF3M as one of thousands of proteins detected, but do not provide mechanistic findings about EIF3M specifically. **EXCLUDE** from discovery extraction (no specific mechanistic findings about EIF3M).\n\nException: PMID:25849773 (eIF3 targets cell-proliferation mRNAs) — describes eIF3 complex function broadly, not EIF3M subunit specifically → **EXCLUDE** from EIF3M-specific discoveries.\n\nPMID:16920360 (eIF3 review) — general eIF3 review → **EXCLUDE** from EIF3M-specific discoveries.\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Fission yeast has two distinct eIF3 complexes that share common core subunits but are distinguished by the PCI proteins eIF3e and eIF3m. eIF3m is an essential gene required for global cellular protein synthesis and polysome formation, unlike eIF3e. Using a ribonomic approach, the eIF3m complex was shown to associate with the bulk of cellular mRNAs, whereas the eIF3e complex associates with a far more restricted mRNA set, indicating that PCI proteins eIF3e and eIF3m define distinct eIF3 complexes that assist in translation of different mRNA sets.\",\n      \"method\": \"Genetic deletion (eif3m essential vs. eif3e non-essential), polysome analysis, ribonomics/microarray with RT-PCR validation, biochemical fractionation\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, polysome profiling, ribonomics) with corroboration across 14 mRNAs; replicated within same study\",\n      \"pmids\": [\"15904532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In human colon cancer cells (HCT-116), siRNA-mediated silencing of eIF3m impairs cell proliferation, cell cycle progression, and induces cell death. Ribonomics identified a subset of eIF3m-associated mRNAs including MIF and MT2A; eIF3m knockdown reduced expression of MT2A downstream effector CDC25A, linking eIF3m to cell cycle control via mRNA-specific translational regulation.\",\n      \"method\": \"siRNA knockdown, cell proliferation/cell cycle/apoptosis assays, ribonomics approach (mRNA immunoprecipitation), RT-PCR validation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with defined cellular phenotypes and ribonomic pathway placement, single lab\",\n      \"pmids\": [\"20838379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Tango7 (ortholog of EIF3M) collaborates with the Drosophila apoptosome to drive caspase-dependent cellular remodeling required to resolve individual sperm from a syncytium. Tango7 localizes to the active apoptosome compartment via its C terminus and directly stimulates the activity of this complex in vitro, specifying the apoptosome as an effector of cellular remodeling rather than cell death.\",\n      \"method\": \"Genetic loss-of-function, in vitro caspase activity assay, C-terminal domain truncation/localization analysis, co-localization imaging\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of activity stimulation combined with genetic loss-of-function and domain mapping\",\n      \"pmids\": [\"23913920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila Tango7 (EIF3M ortholog) regulates cortical caspase (dronc) activity in living salivary glands independently of the canonical Apaf-1 adaptor Dark. Tango7-dependent cortical dronc activity enables F-actin dismantling at the cortex, allowing glands to stretch as they accumulate secreted products, demonstrating that Tango7 and Dark define mutually exclusive subcellular domains of caspase activity.\",\n      \"method\": \"Genetic loss-of-function (tango7 and dark mutants), live imaging, F-actin staining, cortical caspase activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with orthogonal imaging and activity assays establishing distinct subcellular caspase domains\",\n      \"pmids\": [\"28928435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In vivo RNAi-mediated knockdown of eIF3m in mouse liver causes transcriptional upregulation of ribosomal protein genes and inhibition of rRNA processing (decoupling rRNA synthesis from ribosomal protein gene transcription), with broad metabolic gene expression changes but few detectable differences in translation of specific mRNAs. In vitro, reduced eIF3m protein levels are associated with induction of the mTOR pathway, an effect not observed in vivo.\",\n      \"method\": \"In vivo RNAi knockdown, transcriptome sequencing, ribosome profiling, whole proteome and phosphoproteome mass spectrometry, rRNA processing analysis\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal omics methods (ribosome profiling, proteomics, transcriptomics, phosphoproteomics) in vivo\",\n      \"pmids\": [\"31855834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EIF3m binds directly to the 5'UTR of CAPRIN1 mRNA and positively regulates its expression at the post-transcriptional level. EIF3m protein stability in lung adenocarcinoma cells is maintained through interaction with the deubiquitinase UCHL5, which stabilizes EIF3m via deubiquitination. The UCHL5/EIF3m/CAPRIN1 axis promotes malignant phenotypes in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of 5'UTR, co-immunoprecipitation (EIF3m-UCHL5 interaction), gain- and loss-of-function assays, in vivo xenograft models\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP for protein interaction, RIP for RNA binding, functional rescue experiments; single lab\",\n      \"pmids\": [\"33791168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP34 deubiquitinase maintains EIF3m protein stability through deubiquitination in TNBC cells. EIF3m in turn binds directly to the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function (membrane potential and network structure). Disruption of this USP34/eIF3m/MTCH2 axis impairs mitochondrial function and inhibits TNBC cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, RNA immunoprecipitation, RNA pull-down, JC-1 mitochondrial membrane potential assay, MitoSOX/MitoTracker imaging, siRNA knockdown\",\n      \"journal\": \"Journal of histotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple biochemical methods (Co-IP, GST pulldown, RIP, RNA pulldown) converging on mechanism; single lab, recent publication\",\n      \"pmids\": [\"42023842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EIF3m, particularly its C-terminal domain, physically interacts with ORF1B, a non-structural protein of fowl adenovirus serotype 4 (FAdV-4), as identified by co-immunoprecipitation/mass spectrometry. The two proteins co-localize in the cytoplasm. Overexpression of EIF3m promotes FAdV-4 replication while EIF3m knockdown suppresses it, indicating that the virus hijacks EIF3m to facilitate replication.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), domain mapping (C-terminal truncation), co-localization imaging, overexpression and knockdown functional assays\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP/MS for interaction identification with domain mapping and functional gain/loss-of-function; non-mammalian virus model\",\n      \"pmids\": [\"41637784\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3M is an essential PCI-domain subunit of the eIF3 translation initiation complex that defines a distinct eIF3 sub-complex responsible for bulk mRNA translation; it binds specific mRNA 5'UTRs to post-transcriptionally regulate targets (including CAPRIN1 and MTCH2), its protein stability is controlled by deubiquitination via UCHL5/USP34, and its Drosophila ortholog (Tango7) additionally functions as an apoptosome co-activator that specifies subcellular domains of non-apoptotic caspase activity for cellular remodeling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EIF3M is a PCI-domain subunit that defines a distinct eIF3 translation initiation complex required for global protein synthesis and polysome formation [PMID:15904532]. The EIF3M-containing complex associates with the bulk of cellular mRNAs, in contrast to the eIF3e-containing complex which engages a restricted mRNA subset, and EIF3M binds specific mRNA 5′UTRs (e.g., CAPRIN1, MTCH2) to regulate their translation post-transcriptionally [PMID:15904532, PMID:33791168, PMID:42023842]. In vivo knockdown in mouse liver impairs rRNA processing and triggers a ribosome biogenesis stress response with broad metabolic reprogramming, yet has limited impact on the translational efficiency of individual mRNAs [PMID:31855834]. EIF3M protein stability is maintained through deubiquitination by UCHL5 and USP34 [PMID:33791168, PMID:42023842].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying EIF3M as the defining subunit of a distinct eIF3 complex resolved whether eIF3 exists as a single entity or as functionally separable subcomplexes with different mRNA clienteles.\",\n      \"evidence\": \"Biochemical fractionation, ribonomic/microarray analysis of co-purifying mRNAs, and RT-PCR validation in human cells and fission yeast\",\n      \"pmids\": [\"15904532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for the mutual exclusivity of eIF3m and eIF3e complexes is unknown\",\n        \"Determinants in mRNAs that dictate selectivity for the eIF3m versus eIF3e complex are uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic deletion of eif3m in fission yeast demonstrated that EIF3M is essential for global translation and polysome formation, establishing its non-redundant role relative to eIF3e.\",\n      \"evidence\": \"eif3m gene deletion in S. pombe with polysome profiling\",\n      \"pmids\": [\"15904532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian genetic knockout data are lacking\",\n        \"Whether EIF3M loss affects cap-dependent versus IRES-mediated translation differently is untested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"EIF3M knockdown in human cancer cells revealed that it influences cell proliferation and cell cycle progression, linking translational control by eIF3m to oncogenic pathways including CDC25A regulation.\",\n      \"evidence\": \"siRNA knockdown in HCT-116 colon cancer cells with ribonomics, cell cycle analysis, and western blotting\",\n      \"pmids\": [\"20838379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Observed effects on MIF, MT2, and CDC25A were from a single lab with siRNA, lacking genetic confirmation\",\n        \"Direct versus indirect effects on these targets are not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo knockdown in mouse liver showed that EIF3M is required for rRNA processing and ribosome biogenesis rather than for selective translational regulation of individual mRNAs, repositioning it as a global ribosome assembly factor.\",\n      \"evidence\": \"In vivo RNAi in mouse liver with ribosome profiling, RNA-seq, proteomics, and phosphoproteomics\",\n      \"pmids\": [\"31855834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which EIF3M participates in rRNA processing is unknown\",\n        \"Whether the metabolic alterations are direct consequences of translation defects or secondary adaptations is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that EIF3M binds the 5′UTR of CAPRIN1 mRNA and that UCHL5-mediated deubiquitination stabilizes EIF3M protein established the first post-translational regulatory axis controlling EIF3M abundance.\",\n      \"evidence\": \"RNA immunoprecipitation, Co-IP of EIF3M-UCHL5 interaction, and gain/loss-of-function assays in lung adenocarcinoma cells\",\n      \"pmids\": [\"33791168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitination sites on EIF3M and the responsible E3 ligase are unidentified\",\n        \"Whether UCHL5 regulation of EIF3M is conserved beyond lung adenocarcinoma cells is untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of USP34 as a second deubiquitinase stabilizing EIF3M, coupled with EIF3M binding the MTCH2 5′UTR to sustain mitochondrial function, extended the deubiquitination–EIF3M–5′UTR axis to mitochondrial homeostasis.\",\n      \"evidence\": \"Co-IP, GST-pulldown, RNA-IP, RNA-pulldown, and mitochondrial membrane potential/ROS assays in triple-negative breast cancer cells\",\n      \"pmids\": [\"42023842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication and in vivo validation are needed\",\n        \"Whether USP34 and UCHL5 act on the same or different ubiquitin chains on EIF3M is unknown\",\n        \"Full repertoire of 5′UTR targets directly regulated by EIF3M remains undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for EIF3M's role in rRNA processing, the identity of the E3 ubiquitin ligase(s) targeting EIF3M for degradation, and the complete set of mRNA 5′UTRs directly bound and translationally regulated by EIF3M remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of the EIF3M-specific eIF3 subcomplex exists\",\n        \"E3 ligase targeting EIF3M is unknown\",\n        \"Genome-wide CLIP or eCLIP map of EIF3M-bound 5′UTRs has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"eIF3 (eIF3m-containing subcomplex)\"],\n    \"partners\": [\"UCHL5\", \"USP34\", \"EIF3E\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EIF3M is a PCI-domain subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that is essential for bulk cellular protein synthesis and polysome formation, distinguishing a functionally distinct eIF3 sub-complex from the eIF3e-containing complex [PMID:15904532]. Beyond its role in global translation, EIF3M binds specific mRNA 5′UTRs—including those of CAPRIN1 and MTCH2—to post-transcriptionally regulate their expression, coupling translational control to cell proliferation and mitochondrial homeostasis [PMID:33791168, PMID:42023842]. EIF3M protein stability is maintained by deubiquitinases UCHL5 and USP34, and its loss perturbs ribosomal protein gene expression and rRNA processing in vivo [PMID:31855834, PMID:33791168, PMID:42023842]. In Drosophila, the ortholog Tango7 additionally functions as an apoptosome co-activator that specifies subcellular domains of non-apoptotic caspase activity for cellular remodeling [PMID:23913920, PMID:28928435].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that eIF3m defines a distinct eIF3 sub-complex essential for bulk mRNA translation resolved the question of whether PCI-domain subunits were functionally interchangeable within eIF3.\",\n      \"evidence\": \"Genetic deletion, polysome profiling, and ribonomics in fission yeast\",\n      \"pmids\": [\"15904532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which eIF3m selects the bulk mRNA pool versus the eIF3e-restricted pool was not determined\",\n        \"Whether the two-complex architecture is conserved in mammals was untested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that eIF3m knockdown impairs human cancer cell proliferation and cycle progression through mRNA-specific translational regulation (e.g., MT2A–CDC25A axis) extended eIF3m's mRNA-selective role to mammalian cells.\",\n      \"evidence\": \"siRNA knockdown, ribonomics, cell cycle/apoptosis assays in HCT-116 cells\",\n      \"pmids\": [\"20838379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of eIF3m to identified mRNAs was not shown\",\n        \"Single cell line with no in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that Drosophila Tango7 directly stimulates the apoptosome to drive non-apoptotic caspase-dependent cellular remodeling revealed an unexpected translation-independent function for the eIF3m ortholog.\",\n      \"evidence\": \"Genetic loss-of-function, in vitro caspase reconstitution, C-terminal domain mapping in Drosophila spermatogenesis\",\n      \"pmids\": [\"23913920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the apoptosome co-activator function is conserved in mammals was not tested\",\n        \"Structural basis of Tango7 C-terminal interaction with the apoptosome is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that Tango7 activates cortical dronc independently of canonical adaptor Dark established that eIF3m ortholog defines a spatially distinct, non-apoptotic caspase activation mechanism for tissue remodeling.\",\n      \"evidence\": \"Genetic epistasis between tango7 and dark mutants, live imaging, cortical caspase and F-actin assays in Drosophila salivary glands\",\n      \"pmids\": [\"28928435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of Dark-independent caspase activation by Tango7 is unknown\",\n        \"Whether this cortical function requires eIF3 translation activity was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo eIF3m knockdown in mouse liver revealed that reduced eIF3m decouples ribosomal protein gene transcription from rRNA processing, linking eIF3m to ribosome biogenesis quality control beyond its direct role in translation initiation.\",\n      \"evidence\": \"In vivo RNAi, ribosome profiling, proteomics, phosphoproteomics, and rRNA processing analysis in mouse liver\",\n      \"pmids\": [\"31855834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether rRNA processing perturbation is a direct or indirect consequence of eIF3m loss is unclear\",\n        \"mTOR pathway induction seen in vitro was not recapitulated in vivo, leaving the in vitro relevance uncertain\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of direct EIF3M binding to the CAPRIN1 5′UTR and stabilization of EIF3M by deubiquitinase UCHL5 established the first molecularly defined mRNA target and upstream stability mechanism for EIF3M in human cells.\",\n      \"evidence\": \"RNA immunoprecipitation of 5′UTR, reciprocal co-immunoprecipitation of EIF3M–UCHL5, functional rescue, xenograft models in lung adenocarcinoma\",\n      \"pmids\": [\"33791168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural determinants of EIF3M 5′UTR recognition are undefined\",\n        \"Whether UCHL5-mediated stabilization is specific to cancer contexts or generalizable was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstration that USP34 deubiquitinates EIF3M and that EIF3M binds the MTCH2 5′UTR to sustain mitochondrial function revealed a second deubiquitinase–EIF3M–target mRNA axis, linking EIF3M translational control to mitochondrial homeostasis.\",\n      \"evidence\": \"Co-IP, GST pull-down, RIP, RNA pull-down, mitochondrial membrane potential and morphology assays in TNBC cells\",\n      \"pmids\": [\"42023842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether USP34 and UCHL5 act redundantly or in distinct contexts is unknown\",\n        \"No structural or transcriptome-wide mapping of EIF3M RNA-binding specificity has been performed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Finding that FAdV-4 ORF1B protein binds the EIF3M C-terminal domain to promote viral replication demonstrated that EIF3M is a host factor co-opted by a pathogen, consistent with its central role in translation initiation.\",\n      \"evidence\": \"Co-IP/MS, C-terminal domain mapping, overexpression/knockdown in avian cells\",\n      \"pmids\": [\"41637784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Non-mammalian virus system; relevance to mammalian viral infections is untested\",\n        \"Whether ORF1B binding competes with eIF3 complex assembly or translation function is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A transcriptome-wide map of EIF3M direct RNA targets and the structural basis of its 5′UTR selectivity remain undefined, as does whether the Drosophila apoptosome co-activator function is conserved in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No CLIP-seq or equivalent unbiased RNA-binding map exists for EIF3M\",\n        \"Structural mechanism of 5′UTR recognition is unresolved\",\n        \"Mammalian relevance of non-apoptotic caspase co-activation is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\n      \"eIF3\"\n    ],\n    \"partners\": [\n      \"UCHL5\",\n      \"USP34\",\n      \"DARK\",\n      \"DRONC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}