{"gene":"EIF3M","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2005,"finding":"Fission yeast has two distinct eIF3 complexes sharing common core subunits but distinguished by the PCI proteins eIF3e and the novel eIF3m; eIF3m (unlike eIF3e) is an essential gene required for global cellular protein synthesis and polysome formation, and the eIF3m complex associates with the bulk of cellular mRNAs whereas the eIF3e complex associates with a far more restricted set.","method":"Genetic analysis (essential gene determination), polysome profiling, ribonomic/microarray approach, RT-PCR validation of 14 mRNAs","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (polysome profiling, ribonomics, RT-PCR), essential gene demonstrated by genetics, replicated across methods in single rigorous study","pmids":["15904532"],"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 is required for caspase activity, localizes to the active apoptosome compartment via its C terminus, and directly stimulates the activity of this complex in vitro.","method":"Genetic loss-of-function, in vitro apoptosome activity assay, C-terminal domain localization experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of apoptosome stimulation, domain-mapping of localization, and genetic phenotype in a single focused study","pmids":["23913920"],"is_preprint":false},{"year":2017,"finding":"Drosophila Tango7 (ortholog of EIF3M) regulates cortical (but not cytoplasmic) activity of the initiator caspase Dronc in living salivary gland cells, enabling F-actin dismantling and tissue stretching; this is distinct from the canonical Dark (Apaf-1) adaptor that governs cytoplasmic Dronc activity during cell death, defining mutually exclusive subcellular domains of caspase activity.","method":"Genetic loss-of-function in Drosophila salivary glands, live imaging of F-actin dynamics, subcellular fractionation/localization studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis between tango7 and dark defining distinct caspase compartments, combined with direct F-actin phenotype readout and localization data","pmids":["28928435"],"is_preprint":false},{"year":2010,"finding":"In human colon cancer cells, eIF3m silencing by siRNA affects cell proliferation, cell cycle progression, and cell death; a ribonomic approach identified that eIF3m influences the mRNA levels of MIF and MT2, and that eIF3m-dependent regulation of MT2A controls downstream CDC25A expression required for cell cycle progression.","method":"siRNA knockdown, ribonomics, RT-PCR, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ribonomic approach plus RT-PCR and functional cell-based assays, single lab, multiple methods but no in vitro reconstitution","pmids":["20838379"],"is_preprint":false},{"year":2019,"finding":"In vivo RNAi-mediated knockdown of eIF3m in mouse liver leads to inhibition of rRNA processing, increased transcription of ribosomal protein genes, and metabolic gene expression changes, but yields few detectable differences in translation of particular mRNAs; a similar reduction in eIF3m protein is associated with induction of the mTOR pathway in vitro but not in vivo.","method":"RNAi knockdown in mouse liver, ribosome profiling, transcriptome sequencing, whole proteome and phosphoproteome analyses","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal omics methods (ribosome profiling, transcriptomics, proteomics, phosphoproteomics) applied in vivo in a single comprehensive study","pmids":["31855834"],"is_preprint":false},{"year":2021,"finding":"EIF3m binds to the 5'UTR of CAPRIN1 mRNA and positively modulates its expression at the post-transcriptional level; additionally, EIF3m interacts with the deubiquitinase UCHL5, which stabilizes EIF3m protein and promotes its accumulation in lung adenocarcinoma cells.","method":"RNA immunoprecipitation (5'UTR binding), co-immunoprecipitation (UCHL5 interaction), gain- and loss-of-function assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-IP for 5'UTR binding and Co-IP for protein interaction, single lab, two orthogonal methods","pmids":["33791168"],"is_preprint":false},{"year":2026,"finding":"USP34 maintains eIF3m protein stability through deubiquitination; the stabilized eIF3m binds directly to the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function in triple-negative breast cancer cells.","method":"Co-immunoprecipitation, GST pull-down, RNA immunoprecipitation, RNA pull-down, JC-1 mitochondrial membrane potential assay, MitoSOX assay","journal":"Journal of histotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down for protein interaction, RNA-IP and RNA pull-down for 5'UTR binding, single lab, multiple orthogonal methods","pmids":["42023842"],"is_preprint":false},{"year":2026,"finding":"EIF3m, especially its C-terminal part, interacts with FAdV-4 ORF1B protein and co-localizes with it in the cytoplasm; overexpression of eIF3m promotes FAdV-4 replication while knockdown reduces it, indicating the virus hijacks eIF3m to facilitate infection.","method":"Co-immunoprecipitation coupled with mass spectrometry, domain mapping, co-localization imaging, overexpression and knockdown assays","journal":"Poultry science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS for interaction identification, domain mapping, and functional gain/loss-of-function, single lab, multiple methods","pmids":["41637784"],"is_preprint":false}],"current_model":"EIF3M (eIF3m/Tango7) is a PCI-domain subunit that defines a distinct eIF3 translation initiation complex responsible for global mRNA translation and polysome formation; it also binds the 5'UTR of specific mRNAs (e.g., CAPRIN1, MTCH2) to regulate their post-transcriptional expression, is stabilized by deubiquitinases USP34 and UCHL5, and—in Drosophila—functions as a caspase adaptor that directs the apoptosome to cortical subcellular compartments to drive non-apoptotic caspase activity and cellular remodeling independently of the canonical Apaf-1/Dark adaptor."},"narrative":{"mechanistic_narrative":"EIF3M (eIF3m) is a PCI-domain subunit that defines a distinct eIF3 translation initiation complex required for global cellular protein synthesis and polysome formation, as established in fission yeast where eIF3m is an essential gene and its complex associates with the bulk of cellular mRNAs, in contrast to the eIF3e complex that binds a far more restricted set [PMID:15904532]. Beyond its bulk-translation role, EIF3M acts as a sequence-specific post-transcriptional regulator by binding the 5'UTR of particular mRNAs, including CAPRIN1 and MTCH2, to upregulate their expression [PMID:33791168, PMID:42023842]; in mouse liver, eIF3m loss perturbs rRNA processing and ribosomal protein gene transcription with little effect on translation of individual mRNAs [PMID:31855834]. EIF3M protein levels are controlled by the deubiquitinases UCHL5 and USP34, which stabilize the protein and drive its accumulation in cancer cells, where it supports proliferation, cell-cycle progression, and mitochondrial function [PMID:20838379, PMID:33791168, PMID:42023842]. In Drosophila, the EIF3M ortholog Tango7 functions independently of its translation role as a caspase adaptor that directs and directly stimulates the apoptosome, localizing the active complex to cortical compartments via its C terminus to drive non-apoptotic caspase activity and cellular remodeling distinct from the canonical Dark/Apaf-1 adaptor [PMID:23913920, PMID:28928435]. EIF3M is also hijacked by fowl adenovirus 4, whose ORF1B protein interacts with the EIF3M C terminus to facilitate viral replication [PMID:41637784].","teleology":[{"year":2005,"claim":"Established that eIF3m is not interchangeable with other PCI subunits but defines a distinct, essential eIF3 complex driving bulk translation, answering whether eIF3 functional heterogeneity exists.","evidence":"Genetics, polysome profiling, and ribonomics/microarray in fission yeast","pmids":["15904532"],"confidence":"High","gaps":["Does not define which mRNA features partition transcripts to the eIF3m versus eIF3e complex","Mechanism of how eIF3m loss abolishes polysome formation not resolved at structural level"]},{"year":2010,"claim":"Showed that eIF3m couples to cancer cell-cycle control, linking it to specific transcript regulation (MT2A) and downstream CDC25A rather than only global translation.","evidence":"siRNA knockdown, ribonomics, RT-PCR, and cell-cycle analysis in human colon cancer cells","pmids":["20838379"],"confidence":"Medium","gaps":["Whether the MT2A/CDC25A effect is direct or a downstream consequence of altered global translation is unclear","No in vitro reconstitution of transcript-specific regulation"]},{"year":2013,"claim":"Revealed a translation-independent moonlighting function: the EIF3M ortholog Tango7 acts as a caspase adaptor that directly stimulates apoptosome activity, answering how non-apoptotic caspase activity is targeted.","evidence":"Genetic loss-of-function, in vitro apoptosome activity assay, and C-terminal localization in Drosophila spermatid individualization","pmids":["23913920"],"confidence":"High","gaps":["Whether the mammalian EIF3M ortholog retains caspase-adaptor function is untested","Molecular basis of C-terminal targeting to the apoptosome compartment not defined"]},{"year":2017,"claim":"Defined that Tango7 and the canonical Dark adaptor govern mutually exclusive subcellular domains of caspase activity, establishing spatial control as the mechanism for non-apoptotic versus apoptotic caspase output.","evidence":"Genetic epistasis, live F-actin imaging, and subcellular localization in Drosophila salivary glands","pmids":["28928435"],"confidence":"High","gaps":["How Tango7 is restricted to the cell cortex is not resolved","Whether cortical caspase substrates beyond F-actin regulators exist is unknown"]},{"year":2019,"claim":"Tested the in vivo translational role of eIF3m in mammals, finding its loss reshapes ribosome biogenesis and metabolism more than individual mRNA translation, refining the bulk-translation model.","evidence":"In vivo RNAi in mouse liver with ribosome profiling, transcriptomics, proteomics, and phosphoproteomics","pmids":["31855834"],"confidence":"High","gaps":["Discrepancy between mTOR induction in vitro versus in vivo unexplained","Does not identify mRNAs translationally dependent on eIF3m in vivo"]},{"year":2021,"claim":"Identified a direct 5'UTR-binding, transcript-specific regulatory mode (CAPRIN1) and the first deubiquitinase (UCHL5) controlling EIF3M protein stability.","evidence":"RNA immunoprecipitation and co-immunoprecipitation with gain/loss-of-function in lung adenocarcinoma cells","pmids":["33791168"],"confidence":"Medium","gaps":["Whether 5'UTR binding occurs within the canonical eIF3 complex or independently is unclear","Direct ubiquitination sites on EIF3M not mapped"]},{"year":2026,"claim":"Extended the deubiquitinase-stabilization/5'UTR-binding axis to USP34 and MTCH2, linking EIF3M to mitochondrial maintenance in cancer.","evidence":"Reciprocal Co-IP, GST pull-down, RNA-IP/RNA pull-down, and mitochondrial function assays in triple-negative breast cancer cells","pmids":["42023842"],"confidence":"Medium","gaps":["Whether USP34 and UCHL5 act redundantly or in different contexts is unresolved","Direct versus indirect contribution of MTCH2 upregulation to mitochondrial phenotype not separated"]},{"year":2026,"claim":"Showed EIF3M is exploited by a viral pathogen, with FAdV-4 ORF1B binding the EIF3M C terminus to promote replication.","evidence":"Co-IP/MS, domain mapping, co-localization, and overexpression/knockdown assays","pmids":["41637784"],"confidence":"Medium","gaps":["Whether the virus co-opts EIF3M's translation function or another activity is unknown","Single-system finding not generalized to other viruses"]},{"year":null,"claim":"How EIF3M switches between its bulk-translation role, transcript-specific 5'UTR-binding role, and (in Drosophila) caspase-adaptor role remains unresolved, as does whether mammalian EIF3M retains the apoptosome-targeting function.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model distinguishing complex-bound versus free EIF3M activities","Mammalian counterpart of the Drosophila caspase-adaptor role untested","Determinants of transcript selectivity for 5'UTR binding undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,6]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2]}],"complexes":["eIF3"],"partners":["UCHL5","USP34","CAPRIN1","MTCH2"],"other_free_text":[]}},"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":121,"is_preprint":false},{"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":47,"is_preprint":false},{"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},{"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},{"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":19,"is_preprint":false},{"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":15,"is_preprint":false},{"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. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/31855834","citation_count":13,"is_preprint":false},{"pmid":"39556433","id":"PMC_39556433","title":"Exploring the role of eIF3m in prostate cancer: regulation of c-Myc signaling pathway and therapeutic implications.","date":"2024","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/39556433","citation_count":2,"is_preprint":false},{"pmid":"42023842","id":"PMC_42023842","title":"USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis.","date":"2026","source":"Journal of histotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/42023842","citation_count":0,"is_preprint":false},{"pmid":"41637784","id":"PMC_41637784","title":"eIF3m promotes fowl adenovirus serotype 4 replication via interacting with ORF1B protein.","date":"2026","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/41637784","citation_count":0,"is_preprint":false},{"pmid":"15214079","id":"PMC_15214079","title":"Chemical heterogeneity of a crystal built of nanoscale coherently twinned Yb(2-x)(Fe,Ga)(17+2x) polytypes.","date":"2004","source":"Chemistry (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/15214079","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7151,"output_tokens":2104,"usd":0.026506,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9099,"output_tokens":3003,"usd":0.060285,"stage2_stop_reason":"end_turn"},"total_usd":0.086791,"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\": 2005,\n      \"finding\": \"Fission yeast has two distinct eIF3 complexes sharing common core subunits but distinguished by the PCI proteins eIF3e and the novel eIF3m; eIF3m (unlike eIF3e) is an essential gene required for global cellular protein synthesis and polysome formation, and the eIF3m complex associates with the bulk of cellular mRNAs whereas the eIF3e complex associates with a far more restricted set.\",\n      \"method\": \"Genetic analysis (essential gene determination), polysome profiling, ribonomic/microarray approach, RT-PCR validation of 14 mRNAs\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (polysome profiling, ribonomics, RT-PCR), essential gene demonstrated by genetics, replicated across methods in single rigorous study\",\n      \"pmids\": [\"15904532\"],\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 is required for caspase activity, localizes to the active apoptosome compartment via its C terminus, and directly stimulates the activity of this complex in vitro.\",\n      \"method\": \"Genetic loss-of-function, in vitro apoptosome activity assay, C-terminal domain localization experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of apoptosome stimulation, domain-mapping of localization, and genetic phenotype in a single focused study\",\n      \"pmids\": [\"23913920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila Tango7 (ortholog of EIF3M) regulates cortical (but not cytoplasmic) activity of the initiator caspase Dronc in living salivary gland cells, enabling F-actin dismantling and tissue stretching; this is distinct from the canonical Dark (Apaf-1) adaptor that governs cytoplasmic Dronc activity during cell death, defining mutually exclusive subcellular domains of caspase activity.\",\n      \"method\": \"Genetic loss-of-function in Drosophila salivary glands, live imaging of F-actin dynamics, subcellular fractionation/localization studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis between tango7 and dark defining distinct caspase compartments, combined with direct F-actin phenotype readout and localization data\",\n      \"pmids\": [\"28928435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In human colon cancer cells, eIF3m silencing by siRNA affects cell proliferation, cell cycle progression, and cell death; a ribonomic approach identified that eIF3m influences the mRNA levels of MIF and MT2, and that eIF3m-dependent regulation of MT2A controls downstream CDC25A expression required for cell cycle progression.\",\n      \"method\": \"siRNA knockdown, ribonomics, RT-PCR, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ribonomic approach plus RT-PCR and functional cell-based assays, single lab, multiple methods but no in vitro reconstitution\",\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, increased transcription of ribosomal protein genes, and metabolic gene expression changes, but yields few detectable differences in translation of particular mRNAs; a similar reduction in eIF3m protein is associated with induction of the mTOR pathway in vitro but not in vivo.\",\n      \"method\": \"RNAi knockdown in mouse liver, ribosome profiling, transcriptome sequencing, whole proteome and phosphoproteome analyses\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal omics methods (ribosome profiling, transcriptomics, proteomics, phosphoproteomics) applied in vivo in a single comprehensive study\",\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 modulates its expression at the post-transcriptional level; additionally, EIF3m interacts with the deubiquitinase UCHL5, which stabilizes EIF3m protein and promotes its accumulation in lung adenocarcinoma cells.\",\n      \"method\": \"RNA immunoprecipitation (5'UTR binding), co-immunoprecipitation (UCHL5 interaction), gain- and loss-of-function assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-IP for 5'UTR binding and Co-IP for protein interaction, single lab, two orthogonal methods\",\n      \"pmids\": [\"33791168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP34 maintains eIF3m protein stability through deubiquitination; the stabilized eIF3m binds directly to 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 pull-down, RNA immunoprecipitation, RNA pull-down, JC-1 mitochondrial membrane potential assay, MitoSOX assay\",\n      \"journal\": \"Journal of histotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down for protein interaction, RNA-IP and RNA pull-down for 5'UTR binding, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42023842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EIF3m, especially its C-terminal part, interacts with FAdV-4 ORF1B protein and co-localizes with it in the cytoplasm; overexpression of eIF3m promotes FAdV-4 replication while knockdown reduces it, indicating the virus hijacks eIF3m to facilitate infection.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry, domain mapping, co-localization imaging, overexpression and knockdown assays\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS for interaction identification, domain mapping, and functional gain/loss-of-function, single lab, multiple methods\",\n      \"pmids\": [\"41637784\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3M (eIF3m/Tango7) is a PCI-domain subunit that defines a distinct eIF3 translation initiation complex responsible for global mRNA translation and polysome formation; it also binds the 5'UTR of specific mRNAs (e.g., CAPRIN1, MTCH2) to regulate their post-transcriptional expression, is stabilized by deubiquitinases USP34 and UCHL5, and—in Drosophila—functions as a caspase adaptor that directs the apoptosome to cortical subcellular compartments to drive non-apoptotic caspase activity and cellular remodeling independently of the canonical Apaf-1/Dark adaptor.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3M (eIF3m) is a PCI-domain subunit that defines a distinct eIF3 translation initiation complex required for global cellular protein synthesis and polysome formation, as established in fission yeast where eIF3m is an essential gene and its complex associates with the bulk of cellular mRNAs, in contrast to the eIF3e complex that binds a far more restricted set [#0]. Beyond its bulk-translation role, EIF3M acts as a sequence-specific post-transcriptional regulator by binding the 5'UTR of particular mRNAs, including CAPRIN1 and MTCH2, to upregulate their expression [#5, #6]; in mouse liver, eIF3m loss perturbs rRNA processing and ribosomal protein gene transcription with little effect on translation of individual mRNAs [#4]. EIF3M protein levels are controlled by the deubiquitinases UCHL5 and USP34, which stabilize the protein and drive its accumulation in cancer cells, where it supports proliferation, cell-cycle progression, and mitochondrial function [#3, #5, #6]. In Drosophila, the EIF3M ortholog Tango7 functions independently of its translation role as a caspase adaptor that directs and directly stimulates the apoptosome, localizing the active complex to cortical compartments via its C terminus to drive non-apoptotic caspase activity and cellular remodeling distinct from the canonical Dark/Apaf-1 adaptor [#1, #2]. EIF3M is also hijacked by fowl adenovirus 4, whose ORF1B protein interacts with the EIF3M C terminus to facilitate viral replication [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that eIF3m is not interchangeable with other PCI subunits but defines a distinct, essential eIF3 complex driving bulk translation, answering whether eIF3 functional heterogeneity exists.\",\n      \"evidence\": \"Genetics, polysome profiling, and ribonomics/microarray in fission yeast\",\n      \"pmids\": [\"15904532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define which mRNA features partition transcripts to the eIF3m versus eIF3e complex\", \"Mechanism of how eIF3m loss abolishes polysome formation not resolved at structural level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that eIF3m couples to cancer cell-cycle control, linking it to specific transcript regulation (MT2A) and downstream CDC25A rather than only global translation.\",\n      \"evidence\": \"siRNA knockdown, ribonomics, RT-PCR, and cell-cycle analysis in human colon cancer cells\",\n      \"pmids\": [\"20838379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the MT2A/CDC25A effect is direct or a downstream consequence of altered global translation is unclear\", \"No in vitro reconstitution of transcript-specific regulation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a translation-independent moonlighting function: the EIF3M ortholog Tango7 acts as a caspase adaptor that directly stimulates apoptosome activity, answering how non-apoptotic caspase activity is targeted.\",\n      \"evidence\": \"Genetic loss-of-function, in vitro apoptosome activity assay, and C-terminal localization in Drosophila spermatid individualization\",\n      \"pmids\": [\"23913920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mammalian EIF3M ortholog retains caspase-adaptor function is untested\", \"Molecular basis of C-terminal targeting to the apoptosome compartment not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined that Tango7 and the canonical Dark adaptor govern mutually exclusive subcellular domains of caspase activity, establishing spatial control as the mechanism for non-apoptotic versus apoptotic caspase output.\",\n      \"evidence\": \"Genetic epistasis, live F-actin imaging, and subcellular localization in Drosophila salivary glands\",\n      \"pmids\": [\"28928435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Tango7 is restricted to the cell cortex is not resolved\", \"Whether cortical caspase substrates beyond F-actin regulators exist is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested the in vivo translational role of eIF3m in mammals, finding its loss reshapes ribosome biogenesis and metabolism more than individual mRNA translation, refining the bulk-translation model.\",\n      \"evidence\": \"In vivo RNAi in mouse liver with ribosome profiling, transcriptomics, proteomics, and phosphoproteomics\",\n      \"pmids\": [\"31855834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy between mTOR induction in vitro versus in vivo unexplained\", \"Does not identify mRNAs translationally dependent on eIF3m in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a direct 5'UTR-binding, transcript-specific regulatory mode (CAPRIN1) and the first deubiquitinase (UCHL5) controlling EIF3M protein stability.\",\n      \"evidence\": \"RNA immunoprecipitation and co-immunoprecipitation with gain/loss-of-function in lung adenocarcinoma cells\",\n      \"pmids\": [\"33791168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether 5'UTR binding occurs within the canonical eIF3 complex or independently is unclear\", \"Direct ubiquitination sites on EIF3M not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the deubiquitinase-stabilization/5'UTR-binding axis to USP34 and MTCH2, linking EIF3M to mitochondrial maintenance in cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pull-down, RNA-IP/RNA pull-down, and mitochondrial function assays in triple-negative breast cancer cells\",\n      \"pmids\": [\"42023842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether USP34 and UCHL5 act redundantly or in different contexts is unresolved\", \"Direct versus indirect contribution of MTCH2 upregulation to mitochondrial phenotype not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed EIF3M is exploited by a viral pathogen, with FAdV-4 ORF1B binding the EIF3M C terminus to promote replication.\",\n      \"evidence\": \"Co-IP/MS, domain mapping, co-localization, and overexpression/knockdown assays\",\n      \"pmids\": [\"41637784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the virus co-opts EIF3M's translation function or another activity is unknown\", \"Single-system finding not generalized to other viruses\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EIF3M switches between its bulk-translation role, transcript-specific 5'UTR-binding role, and (in Drosophila) caspase-adaptor role remains unresolved, as does whether mammalian EIF3M retains the apoptosome-targeting function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model distinguishing complex-bound versus free EIF3M activities\", \"Mammalian counterpart of the Drosophila caspase-adaptor role untested\", \"Determinants of transcript selectivity for 5'UTR binding undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"eIF3\"],\n    \"partners\": [\"UCHL5\", \"USP34\", \"CAPRIN1\", \"MTCH2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}