{"gene":"EIF3H","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2018,"finding":"METTL3 directly interacts with eIF3h, and this interaction is required for enhanced translation of oncogenic mRNAs (including BRD4) via mRNA looping that brings the 3' stop codon region into proximity with 5' cap-binding proteins, facilitating ribosome recycling and translational control. Electron microscopy revealed METTL3 foci near 5' cap-binding proteins within polyribosomes. The METTL3-eIF3h interaction is required for formation of densely packed polyribosomes and oncogenic transformation.","method":"Co-IP, electron microscopy of polyribosomes, tethering assays, loss-of-function (METTL3 depletion), reporter translation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (EM, Co-IP, functional tethering, polysome profiling) in a single high-impact study with >600 citations","pmids":["30232453"],"is_preprint":false},{"year":2020,"finding":"EIF3H functions as a deubiquitylating enzyme (belonging to the JAMM superfamily) that catalyzes deubiquitylation of YAP, preventing its proteasomal degradation and stabilizing it to promote tumor invasion and metastasis. Structure-based modeling and biochemical characterization identified a catalytic triad (Asp90, Asp91, Gln121) and showed that Trp119 and Tyr140 on EIF3H interact with the N-terminal region of YAP1 to form a complex required for deubiquitylation.","method":"Structure-based molecular modeling and simulation, biochemical characterization, ubiquitination assays, site-directed mutagenesis, breast cancer invasion/metastasis models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — structural modeling coupled with mutagenesis of catalytic residues and biochemical assays, orthogonal validation in cell and animal models","pmids":["32269044"],"is_preprint":false},{"year":2020,"finding":"EIF3H acts as a deubiquitinating enzyme for Snail, interacting with and stabilizing Snail through deubiquitination, thereby promoting Snail-mediated EMT in esophageal squamous cell carcinoma. EIF3H co-localizes with Snail as demonstrated by reciprocal co-IP and immunofluorescence, and CHX pulse-chase and ubiquitination assays confirmed EIF3H's role in Snail stability.","method":"Co-IP with mass spectrometry, reciprocal Co-IP, immunofluorescence co-localization, cycloheximide pulse-chase assay, ubiquitination assay, in vitro and in vivo tumor models","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reciprocal Co-IP, MS, CHX chase, ubiquitination assay) with in vivo validation","pmids":["32867821"],"is_preprint":false},{"year":2024,"finding":"EIF3H functions as a deubiquitinase for HAX1, stabilizing HAX1 by antagonizing βTrCP-mediated ubiquitination, which in turn enhances the interaction between RAF1, MEK1, and ERK1, potentiating phosphorylation of ERK1/2 to promote colorectal cancer progression. Wnt/β-catenin signaling induces EIF3H expression. Conditional Eif3h deletion suppresses colorectal tumorigenesis in an AOM/DSS mouse model.","method":"Co-IP, ubiquitination assay, conditional knockout mouse model (AOM/DSS), orthotopic cancer model, patient-derived xenografts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assays, in vivo conditional KO, and PDX models providing strong mechanistic evidence","pmids":["38514606"],"is_preprint":false},{"year":2023,"finding":"EIF3H deubiquitylates and stabilizes OGT (O-GlcNAc transferase) in hepatocellular carcinoma by removing K48-linked ubiquitin chains from OGT. EIF3H interacts with the GT domain of OGT via its JAB/MPN domain. Loss of EIF3H reduces OGT protein expression, inhibits cell proliferation and invasion, induces G1/S arrest, and promotes ferroptosis.","method":"Co-IP, ubiquitination assay, domain mapping, knockdown/overexpression with cell proliferation and apoptosis readouts, HCC cell lines","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping and ubiquitination assay in a single study","pmids":["37559097"],"is_preprint":false},{"year":2022,"finding":"EIF3H deubiquitylates and stabilizes CCND1 (Cyclin D1), preventing its proteasomal degradation via the ubiquitin-proteasome system, thereby promoting proliferation and migration in intrahepatic cholangiocarcinoma.","method":"Knockdown experiments, Western blot for CCND1 degradation, ubiquitin-proteasome pathway analysis in iCCA cell lines and in vivo","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic claim supported by KD and protein degradation assays but limited orthogonal methods","pmids":["36350008"],"is_preprint":false},{"year":2025,"finding":"EIF3H deubiquitylates and stabilizes β-catenin by removing K48-linked ubiquitin chains via binding to the N-terminal tails of β-catenin, thereby activating Wnt/β-catenin signaling. EIF3H expression in anaplastic thyroid cancer is regulated by m6A modification in the 3'UTR read by the m6A reader IGF2BP2.","method":"Co-IP, ubiquitination assay, knockdown studies, m6A reader identification (IGF2BP2), ATC cell lines","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and ubiquitination assay with domain-level detail, but single study","pmids":["39984062"],"is_preprint":false},{"year":2007,"finding":"Measles virus nucleocapsid protein (N) binds directly to eIF3-p40 (EIF3H). GST-fused MV-N inhibits translation of reporter mRNAs in rabbit reticulocyte lysate in a dose-dependent manner, including IRES-dependent translation requiring canonical initiation factors, but does not affect PSIV intergenic region-mediated translation that bypasses canonical factors. In vivo expression of MV-N inhibits overall and reporter protein synthesis.","method":"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, in vitro translation assay with GST-N, Cre/loxP inducible in vivo expression","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — yeast two-hybrid identification confirmed by mammalian Co-IP, in vitro reconstituted translation assay, and in vivo validation","pmids":["17686838"],"is_preprint":false},{"year":2010,"finding":"The 8q23.3 risk SNP rs16888589 acts as an allele-specific transcriptional repressor that interacts with the EIF3H promoter (confirmed by chromosome conformation capture/3C analysis), and increased EIF3H expression increases colorectal cancer cell growth and invasiveness.","method":"Chromosome conformation capture (3C), reporter gene assays, CRC cell growth and invasion assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — 3C for promoter interaction and reporter assays for functional consequence, single study","pmids":["20862326"],"is_preprint":false},{"year":2008,"finding":"Fission yeast eIF3h (ortholog of human EIF3H) physically associates with the 40S ribosomal particles as part of the eIF3 holocomplex consisting of all five core (eIF3a, b, c, g, i) and five non-core subunits (eIF3d, e, f, h, m). Deletion of eif3h+ does not abolish general translation initiation or disrupt the eIF3 complex. Distinct forms of eIF3 differing in non-core subunit composition were observed. Human eIF3h functionally complements the yeast eif3h deletion. eif3hΔ cells are defective in meiosis/sporulation.","method":"TAP-tag affinity purification, polysome profile analysis, genetic deletion, complementation with human eIF3h, 40S ribosomal particle association assay","journal":"Yeast","confidence":"High","confidence_rationale":"Tier 1–2 — affinity purification, genetic complementation with human ortholog, polysome profiling in fission yeast ortholog","pmids":["19061185"],"is_preprint":false},{"year":2004,"finding":"Arabidopsis eIF3h (plant ortholog) is required for efficient translation of specific mRNAs containing upstream open reading frames (uORFs) in their 5' leaders (e.g., ATB2/AtbZip11), as shown by polysome fractionation and transient expression assays in eif3h mutants. eIF3h physically interacts with subunits of the COP9 signalosome. The eif3h mutant does not affect general translation but selectively impairs translation reinitiation at uORF-containing mRNAs.","method":"Polysome fractionation, transient expression assays, yeast two-hybrid/physical interaction with COP9 signalosome subunits, eif3h mutant analysis","journal":"The Plant cell","confidence":"High","confidence_rationale":"Tier 2 — polysome fractionation, transient expression assays, and protein interaction data in a plant ortholog study","pmids":["15548739"],"is_preprint":false},{"year":2013,"finding":"In zebrafish embryos, eIF3h (eif3ha isoform) controls translation of a specific cohort of mRNAs required for neural and lens development; genome-wide polysome profiling in eif3ha morphants identified lens-associated crystallin mRNAs that are lost from polysomes upon eif3ha depletion. Both UTR sequences of targeted crystallin mRNAs are necessary but not sufficient for regulation by eif3ha, implicating additional sequence/structural determinants.","method":"Morpholino knockdown, genome-wide polysome profiling in WT vs. morphant zebrafish embryos, UTR functional analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — genome-wide polysome profiling in vivo in vertebrate embryos, with UTR dissection experiments","pmids":["23716667"],"is_preprint":false},{"year":2006,"finding":"Overexpression of EIF3S3 (EIF3H) in NIH 3T3 fibroblasts promotes faster growth, anchorage-independent growth in soft agar, and increased S-phase fraction with Rb phosphorylation. siRNA-mediated knockdown inhibits growth of breast and prostate cancer cell lines.","method":"Inducible Tet-Off overexpression system, soft agar colony formation, flow cytometry, siRNA knockdown, cell viability assays","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function and loss-of-function experiments with multiple cellular readouts, single lab","pmids":["16652384"],"is_preprint":false},{"year":2020,"finding":"EIF3H interacts with PDCD4 (programmed cell death factor 4) in lung adenocarcinoma cells, as demonstrated by Co-IP and immunofluorescent co-localization. PDCD4 overexpression reduces EIF3H mRNA and protein levels by suppressing c-Jun-induced EIF3H transcription. EIF3H promotes LUAD cell migration, invasion, and EMT signaling, and these effects are abrogated by PDCD4 introduction.","method":"Co-IP combined with mass spectrometry, immunofluorescent co-localization, reporter/transcription assays for c-Jun, migration/invasion assays, EMT marker analysis, nude mouse metastasis model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP/MS and immunofluorescence with functional rescue, single lab","pmids":["32064160"],"is_preprint":false},{"year":2025,"finding":"Dephosphorylation of METTL3 at Ser2 disrupts the METTL3-eIF3H interaction, thereby suppressing translation of oncogenes BRD4 and SERPINE2 (involved in replication stress responses) and enhancing sensitivity to oxaliplatin in gastric cancer. Identified by high-throughput base editor screen in GC cell line AGS.","method":"High-throughput base editor screen, Co-IP to assess METTL3-eIF3H interaction, polysome/translation assays, GC cell line oxaliplatin sensitivity","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — base editor screen with biochemical validation of interaction disruption, single study","pmids":["41385641"],"is_preprint":false},{"year":2025,"finding":"EIF3H physically interacts with and deubiquitinates phosphorylated ERK (pERK), preventing its degradation and sustaining MAPK/ERK pathway activation in breast cancer cells, promoting proliferation, migration, and invasion.","method":"Co-IP, ubiquitination assay, functional overexpression/knockdown with proliferation and invasion readouts, clinical transcriptomic dataset analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint with Co-IP and ubiquitination assay, single lab, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"In the context of Src-driven tumor invasion, eIF3h (along with eIF3e and eIF3d) is essential for invadosome formation and extracellular matrix degradation. Src regulates eIF3h expression. eIF3h-containing eIF3 complexes associate with local mRNA translation activity at invadosomes.","method":"siRNA knockdown, invadosome formation assays, ECM degradation assays, expression analysis in HCC patient data","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, functional KD assays without full mechanistic dissection of eIF3h-specific contribution","pmids":[],"is_preprint":true}],"current_model":"EIF3H (eIF3 subunit h) is a multifunctional protein with two established biochemical activities: (1) as a non-core subunit of the eIF3 translation initiation complex, it selectively promotes translation reinitiation of mRNAs bearing upstream open reading frames (uORFs) and facilitates mRNA looping when partnered with METTL3 to enhance translation of m6A-modified oncogenic mRNAs near the stop codon via ribosome recycling; and (2) as a JAMM-family deubiquitylase, EIF3H catalyzes removal of K48-linked polyubiquitin chains from multiple substrates — including YAP, Snail, HAX1, OGT, CCND1, and β-catenin — stabilizing these oncoproteins to drive tumor invasion, EMT, and proliferation across multiple cancer types."},"narrative":{"teleology":[{"year":2004,"claim":"The first evidence that eIF3h is not required for general translation but selectively promotes reinitiation on uORF-containing mRNAs established its role as a transcript-specific translational regulator rather than a core initiation factor.","evidence":"Polysome fractionation and transient expression assays in Arabidopsis eif3h mutants showing selective loss of uORF-containing mRNA translation","pmids":["15548739"],"confidence":"High","gaps":["Mechanism of reinitiation promotion not resolved at the molecular level","Unclear whether the COP9 signalosome interaction is functionally relevant to translation"]},{"year":2006,"claim":"Gain- and loss-of-function experiments demonstrated that EIF3H overexpression is sufficient to drive oncogenic transformation, linking its translational activity to cell proliferation and cancer.","evidence":"Tet-Off overexpression in NIH 3T3 cells showing anchorage-independent growth; siRNA knockdown inhibiting breast and prostate cancer cell growth","pmids":["16652384"],"confidence":"Medium","gaps":["Mechanism was not distinguished between translation-dependent and deubiquitylase-dependent functions","Single lab study"]},{"year":2007,"claim":"Identification of measles virus N protein as a direct EIF3H-binding partner that inhibits translation established EIF3H as a viral target for host translational shutdown.","evidence":"Yeast two-hybrid, mammalian Co-IP, and in vitro translation inhibition with recombinant GST-N protein","pmids":["17686838"],"confidence":"High","gaps":["Relevance to natural MV infection pathogenesis not demonstrated","Whether other eIF3 subunits are co-targeted was not resolved"]},{"year":2008,"claim":"Biochemical purification of the fission yeast eIF3 complex showed that eIF3h is a non-core subunit dispensable for holocomplex integrity and general translation, but required for meiosis/sporulation, confirming its auxiliary regulatory role across eukaryotes.","evidence":"TAP-tag purification, polysome profiling, genetic deletion and human ortholog complementation in S. pombe","pmids":["19061185"],"confidence":"High","gaps":["Mechanism of meiotic defect not elucidated","Whether distinct eIF3 subcomplexes have separable functions was not resolved"]},{"year":2010,"claim":"A colorectal cancer risk SNP at 8q23.3 was shown to physically contact the EIF3H promoter via long-range chromatin interaction, directly linking genetic variation in EIF3H expression to cancer susceptibility.","evidence":"Chromosome conformation capture (3C) and reporter assays in CRC cell lines","pmids":["20862326"],"confidence":"Medium","gaps":["Causal variant not fine-mapped to single nucleotide resolution","Effect on endogenous EIF3H expression not quantified in patient tissue"]},{"year":2013,"claim":"Genome-wide polysome profiling in zebrafish embryos revealed that eIF3h controls translation of a specific mRNA cohort required for lens and neural development, extending its transcript-selective function to vertebrate organogenesis.","evidence":"Morpholino knockdown with genome-wide polysome profiling and UTR dissection in zebrafish","pmids":["23716667"],"confidence":"High","gaps":["cis-regulatory elements beyond UTRs not identified","Whether the deubiquitylase activity contributes to developmental phenotypes was not tested"]},{"year":2018,"claim":"Discovery that METTL3 directly binds eIF3h to promote mRNA looping between 3′ m6A sites and 5′ cap-binding complexes revealed the molecular mechanism by which m6A enhances translation through ribosome recycling, and established the METTL3-eIF3h axis as a driver of oncogenic translation.","evidence":"Co-IP, electron microscopy of polyribosomes, tethering assays, and reporter translation in human cells","pmids":["30232453"],"confidence":"High","gaps":["Structural basis of METTL3-eIF3h interface not determined at atomic resolution","Whether this mechanism operates on all m6A-containing mRNAs or a subset is unknown"]},{"year":2020,"claim":"Characterization of EIF3H as a JAMM-family deubiquitylase that removes K48-linked ubiquitin from YAP and Snail established a second biochemical activity independent of its translation initiation role, directly linking it to EMT and tumor invasion.","evidence":"Structure-based modeling with catalytic triad mutagenesis (D90/D91/Q121) and ubiquitination assays for YAP; reciprocal Co-IP/MS, CHX chase, and in vivo models for Snail","pmids":["32269044","32867821"],"confidence":"High","gaps":["No crystal structure of EIF3H DUB domain solved","Whether DUB activity occurs within or outside the eIF3 holocomplex is unknown","Catalytic mechanism details (zinc coordination, processivity) not biochemically characterized with purified enzyme"]},{"year":2023,"claim":"Extension of the DUB substrate repertoire to OGT and CCND1 showed that EIF3H stabilizes diverse oncoproteins across cancer types, broadening its role as a general oncoprotein stabilizer acting through K48-linked deubiquitylation.","evidence":"Co-IP with domain mapping (JAB/MPN–GT domain interaction for OGT); knockdown with CCND1 degradation assays in HCC and cholangiocarcinoma cells","pmids":["37559097","36350008"],"confidence":"Medium","gaps":["In vitro reconstitution with purified components not performed","Substrate selectivity determinants not defined","Whether CCND1 is a direct or indirect target needs clarification"]},{"year":2024,"claim":"Conditional Eif3h knockout in a mouse colorectal cancer model suppressed tumorigenesis and revealed that EIF3H deubiquitylates HAX1 to potentiate RAF1-MEK1-ERK signaling, while Wnt/β-catenin signaling induces EIF3H expression, establishing a feedforward oncogenic loop.","evidence":"Conditional knockout mouse (AOM/DSS model), Co-IP, ubiquitination assays, orthotopic and PDX models","pmids":["38514606"],"confidence":"High","gaps":["Whether EIF3H's translation and DUB functions are independently required for tumorigenesis was not dissected","Tissue specificity of the Wnt-EIF3H feedforward loop not determined"]},{"year":2025,"claim":"Phosphorylation of METTL3 at Ser2 was identified as a regulatory switch that disrupts the METTL3-eIF3H interaction, showing that the translational activity of the axis is dynamically regulated and targetable for chemosensitization.","evidence":"High-throughput base editor screen in gastric cancer cells with Co-IP validation of interaction disruption","pmids":["41385641"],"confidence":"Medium","gaps":["Kinase responsible for METTL3 Ser2 phosphorylation not identified","In vivo validation of chemosensitization limited"]},{"year":2025,"claim":"EIF3H was reported to deubiquitylate β-catenin, directly activating Wnt signaling in anaplastic thyroid cancer, with EIF3H expression itself regulated by m6A/IGF2BP2, closing a regulatory circuit between m6A RNA modification and Wnt pathway activation.","evidence":"Co-IP, ubiquitination assay, m6A reader identification in ATC cell lines","pmids":["39984062"],"confidence":"Medium","gaps":["Single study without in vivo validation","Whether β-catenin deubiquitylation is direct (purified enzyme) not shown"]},{"year":null,"claim":"Key unresolved questions include: (1) whether the translation initiation and deubiquitylase activities of EIF3H are structurally and functionally separable within the eIF3 holocomplex; (2) what determines substrate selectivity among the growing list of DUB substrates; and (3) whether a high-resolution structure of the EIF3H MPN/JAMM domain can be obtained to enable pharmacological targeting.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of EIF3H","No separation-of-function mutant distinguishing translation from DUB activity","No unbiased substrate screen (e.g., TUBE/diGly proteomics) performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,3,4,5,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,4,5,6]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,9,10,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,9,10,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,3,4,5,6,8]}],"complexes":["eIF3"],"partners":["METTL3","YAP1","SNAI1","HAX1","OGT","CTNNB1","PDCD4","CCND1"],"other_free_text":[]},"mechanistic_narrative":"EIF3H is a non-core subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that selectively promotes translation of mRNAs bearing upstream open reading frames (uORFs) and, through its interaction with METTL3, facilitates mRNA looping and ribosome recycling to enhance translation of m6A-modified transcripts [PMID:15548739, PMID:30232453, PMID:23716667]. As a JAMM/MPN-family deubiquitylase, EIF3H removes K48-linked polyubiquitin chains from multiple oncoproteins—including YAP, Snail, HAX1, OGT, CCND1, and β-catenin—thereby stabilizing them against proteasomal degradation and activating downstream signaling cascades such as MAPK/ERK and Wnt/β-catenin [PMID:32269044, PMID:32867821, PMID:38514606, PMID:37559097]. Within the eIF3 holocomplex, EIF3H associates with 40S ribosomal subunits and is dispensable for bulk translation but is required for transcript-specific translational control, including mRNAs critical for vertebrate lens and neural development [PMID:19061185, PMID:23716667]. Conditional deletion of Eif3h suppresses colorectal tumorigenesis in mouse models, and a colorectal cancer risk variant at 8q23.3 modulates EIF3H expression through long-range promoter interaction [PMID:38514606, PMID:20862326]."},"prefetch_data":{"uniprot":{"accession":"O15372","full_name":"Eukaryotic translation initiation factor 3 subunit H","aliases":["Eukaryotic translation initiation factor 3 subunit 3","eIF-3-gamma","eIF3 p40 subunit"],"length_aa":352,"mass_kda":39.9,"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:17581632, 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:17581632). 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)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O15372/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3H","classification":"Common Essential","n_dependent_lines":1094,"n_total_lines":1208,"dependency_fraction":0.9056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":10.0},{"gene":"EIF3M","stoichiometry":10.0},{"gene":"EIF3K","stoichiometry":4.0},{"gene":"RPL11","stoichiometry":4.0},{"gene":"RPL5","stoichiometry":4.0},{"gene":"RPS16","stoichiometry":4.0},{"gene":"SRP9","stoichiometry":4.0},{"gene":"ABCE1","stoichiometry":0.2},{"gene":"ATG13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF3H","total_profiled":1310},"omim":[{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"612231","title":"COLORECTAL CANCER, SUSCEPTIBILITY TO, 6; CRCS6","url":"https://www.omim.org/entry/612231"},{"mim_id":"608749","title":"BROMODOMAIN-CONTAINING PROTEIN 4; BRD4","url":"https://www.omim.org/entry/608749"},{"mim_id":"603912","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT H; EIF3H","url":"https://www.omim.org/entry/603912"}],"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/EIF3H"},"hgnc":{"alias_symbol":["eIF3-gamma","eIF3-p40"],"prev_symbol":["EIF3S3"]},"alphafold":{"accession":"O15372","domains":[{"cath_id":"3.40.140.10","chopping":"37-232","consensus_level":"high","plddt":77.2454,"start":37,"end":232},{"cath_id":"1.10.150","chopping":"252-291_306-350","consensus_level":"high","plddt":81.0174,"start":252,"end":350}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15372","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15372-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15372-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3H","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3H"},"sequence":{"accession":"O15372","fasta_url":"https://rest.uniprot.org/uniprotkb/O15372.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15372/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15372"}},"corpus_meta":[{"pmid":"30232453","id":"PMC_30232453","title":"mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30232453","citation_count":615,"is_preprint":false},{"pmid":"23524850","id":"PMC_23524850","title":"TOR and S6K1 promote translation reinitiation of uORF-containing mRNAs via phosphorylation of eIF3h.","date":"2013","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23524850","citation_count":227,"is_preprint":false},{"pmid":"35164758","id":"PMC_35164758","title":"Exosomal circLPAR1 functions in colorectal cancer diagnosis and tumorigenesis through suppressing BRD4 via METTL3-eIF3h interaction.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35164758","citation_count":185,"is_preprint":false},{"pmid":"11733359","id":"PMC_11733359","title":"Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer.","date":"2001","source":"The American journal of 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Electron microscopy revealed METTL3 foci near 5' cap-binding proteins within polyribosomes. The METTL3-eIF3h interaction is required for formation of densely packed polyribosomes and oncogenic transformation.\",\n      \"method\": \"Co-IP, electron microscopy of polyribosomes, tethering assays, loss-of-function (METTL3 depletion), reporter translation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (EM, Co-IP, functional tethering, polysome profiling) in a single high-impact study with >600 citations\",\n      \"pmids\": [\"30232453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF3H functions as a deubiquitylating enzyme (belonging to the JAMM superfamily) that catalyzes deubiquitylation of YAP, preventing its proteasomal degradation and stabilizing it to promote tumor invasion and metastasis. Structure-based modeling and biochemical characterization identified a catalytic triad (Asp90, Asp91, Gln121) and showed that Trp119 and Tyr140 on EIF3H interact with the N-terminal region of YAP1 to form a complex required for deubiquitylation.\",\n      \"method\": \"Structure-based molecular modeling and simulation, biochemical characterization, ubiquitination assays, site-directed mutagenesis, breast cancer invasion/metastasis models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural modeling coupled with mutagenesis of catalytic residues and biochemical assays, orthogonal validation in cell and animal models\",\n      \"pmids\": [\"32269044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF3H acts as a deubiquitinating enzyme for Snail, interacting with and stabilizing Snail through deubiquitination, thereby promoting Snail-mediated EMT in esophageal squamous cell carcinoma. EIF3H co-localizes with Snail as demonstrated by reciprocal co-IP and immunofluorescence, and CHX pulse-chase and ubiquitination assays confirmed EIF3H's role in Snail stability.\",\n      \"method\": \"Co-IP with mass spectrometry, reciprocal Co-IP, immunofluorescence co-localization, cycloheximide pulse-chase assay, ubiquitination assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reciprocal Co-IP, MS, CHX chase, ubiquitination assay) with in vivo validation\",\n      \"pmids\": [\"32867821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EIF3H functions as a deubiquitinase for HAX1, stabilizing HAX1 by antagonizing βTrCP-mediated ubiquitination, which in turn enhances the interaction between RAF1, MEK1, and ERK1, potentiating phosphorylation of ERK1/2 to promote colorectal cancer progression. Wnt/β-catenin signaling induces EIF3H expression. Conditional Eif3h deletion suppresses colorectal tumorigenesis in an AOM/DSS mouse model.\",\n      \"method\": \"Co-IP, ubiquitination assay, conditional knockout mouse model (AOM/DSS), orthotopic cancer model, patient-derived xenografts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assays, in vivo conditional KO, and PDX models providing strong mechanistic evidence\",\n      \"pmids\": [\"38514606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EIF3H deubiquitylates and stabilizes OGT (O-GlcNAc transferase) in hepatocellular carcinoma by removing K48-linked ubiquitin chains from OGT. EIF3H interacts with the GT domain of OGT via its JAB/MPN domain. Loss of EIF3H reduces OGT protein expression, inhibits cell proliferation and invasion, induces G1/S arrest, and promotes ferroptosis.\",\n      \"method\": \"Co-IP, ubiquitination assay, domain mapping, knockdown/overexpression with cell proliferation and apoptosis readouts, HCC cell lines\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping and ubiquitination assay in a single study\",\n      \"pmids\": [\"37559097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF3H deubiquitylates and stabilizes CCND1 (Cyclin D1), preventing its proteasomal degradation via the ubiquitin-proteasome system, thereby promoting proliferation and migration in intrahepatic cholangiocarcinoma.\",\n      \"method\": \"Knockdown experiments, Western blot for CCND1 degradation, ubiquitin-proteasome pathway analysis in iCCA cell lines and in vivo\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic claim supported by KD and protein degradation assays but limited orthogonal methods\",\n      \"pmids\": [\"36350008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EIF3H deubiquitylates and stabilizes β-catenin by removing K48-linked ubiquitin chains via binding to the N-terminal tails of β-catenin, thereby activating Wnt/β-catenin signaling. EIF3H expression in anaplastic thyroid cancer is regulated by m6A modification in the 3'UTR read by the m6A reader IGF2BP2.\",\n      \"method\": \"Co-IP, ubiquitination assay, knockdown studies, m6A reader identification (IGF2BP2), ATC cell lines\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and ubiquitination assay with domain-level detail, but single study\",\n      \"pmids\": [\"39984062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Measles virus nucleocapsid protein (N) binds directly to eIF3-p40 (EIF3H). GST-fused MV-N inhibits translation of reporter mRNAs in rabbit reticulocyte lysate in a dose-dependent manner, including IRES-dependent translation requiring canonical initiation factors, but does not affect PSIV intergenic region-mediated translation that bypasses canonical factors. In vivo expression of MV-N inhibits overall and reporter protein synthesis.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, in vitro translation assay with GST-N, Cre/loxP inducible in vivo expression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — yeast two-hybrid identification confirmed by mammalian Co-IP, in vitro reconstituted translation assay, and in vivo validation\",\n      \"pmids\": [\"17686838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The 8q23.3 risk SNP rs16888589 acts as an allele-specific transcriptional repressor that interacts with the EIF3H promoter (confirmed by chromosome conformation capture/3C analysis), and increased EIF3H expression increases colorectal cancer cell growth and invasiveness.\",\n      \"method\": \"Chromosome conformation capture (3C), reporter gene assays, CRC cell growth and invasion assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3C for promoter interaction and reporter assays for functional consequence, single study\",\n      \"pmids\": [\"20862326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fission yeast eIF3h (ortholog of human EIF3H) physically associates with the 40S ribosomal particles as part of the eIF3 holocomplex consisting of all five core (eIF3a, b, c, g, i) and five non-core subunits (eIF3d, e, f, h, m). Deletion of eif3h+ does not abolish general translation initiation or disrupt the eIF3 complex. Distinct forms of eIF3 differing in non-core subunit composition were observed. Human eIF3h functionally complements the yeast eif3h deletion. eif3hΔ cells are defective in meiosis/sporulation.\",\n      \"method\": \"TAP-tag affinity purification, polysome profile analysis, genetic deletion, complementation with human eIF3h, 40S ribosomal particle association assay\",\n      \"journal\": \"Yeast\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — affinity purification, genetic complementation with human ortholog, polysome profiling in fission yeast ortholog\",\n      \"pmids\": [\"19061185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Arabidopsis eIF3h (plant ortholog) is required for efficient translation of specific mRNAs containing upstream open reading frames (uORFs) in their 5' leaders (e.g., ATB2/AtbZip11), as shown by polysome fractionation and transient expression assays in eif3h mutants. eIF3h physically interacts with subunits of the COP9 signalosome. The eif3h mutant does not affect general translation but selectively impairs translation reinitiation at uORF-containing mRNAs.\",\n      \"method\": \"Polysome fractionation, transient expression assays, yeast two-hybrid/physical interaction with COP9 signalosome subunits, eif3h mutant analysis\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — polysome fractionation, transient expression assays, and protein interaction data in a plant ortholog study\",\n      \"pmids\": [\"15548739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In zebrafish embryos, eIF3h (eif3ha isoform) controls translation of a specific cohort of mRNAs required for neural and lens development; genome-wide polysome profiling in eif3ha morphants identified lens-associated crystallin mRNAs that are lost from polysomes upon eif3ha depletion. Both UTR sequences of targeted crystallin mRNAs are necessary but not sufficient for regulation by eif3ha, implicating additional sequence/structural determinants.\",\n      \"method\": \"Morpholino knockdown, genome-wide polysome profiling in WT vs. morphant zebrafish embryos, UTR functional analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide polysome profiling in vivo in vertebrate embryos, with UTR dissection experiments\",\n      \"pmids\": [\"23716667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpression of EIF3S3 (EIF3H) in NIH 3T3 fibroblasts promotes faster growth, anchorage-independent growth in soft agar, and increased S-phase fraction with Rb phosphorylation. siRNA-mediated knockdown inhibits growth of breast and prostate cancer cell lines.\",\n      \"method\": \"Inducible Tet-Off overexpression system, soft agar colony formation, flow cytometry, siRNA knockdown, cell viability assays\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function and loss-of-function experiments with multiple cellular readouts, single lab\",\n      \"pmids\": [\"16652384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF3H interacts with PDCD4 (programmed cell death factor 4) in lung adenocarcinoma cells, as demonstrated by Co-IP and immunofluorescent co-localization. PDCD4 overexpression reduces EIF3H mRNA and protein levels by suppressing c-Jun-induced EIF3H transcription. EIF3H promotes LUAD cell migration, invasion, and EMT signaling, and these effects are abrogated by PDCD4 introduction.\",\n      \"method\": \"Co-IP combined with mass spectrometry, immunofluorescent co-localization, reporter/transcription assays for c-Jun, migration/invasion assays, EMT marker analysis, nude mouse metastasis model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP/MS and immunofluorescence with functional rescue, single lab\",\n      \"pmids\": [\"32064160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dephosphorylation of METTL3 at Ser2 disrupts the METTL3-eIF3H interaction, thereby suppressing translation of oncogenes BRD4 and SERPINE2 (involved in replication stress responses) and enhancing sensitivity to oxaliplatin in gastric cancer. Identified by high-throughput base editor screen in GC cell line AGS.\",\n      \"method\": \"High-throughput base editor screen, Co-IP to assess METTL3-eIF3H interaction, polysome/translation assays, GC cell line oxaliplatin sensitivity\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — base editor screen with biochemical validation of interaction disruption, single study\",\n      \"pmids\": [\"41385641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EIF3H physically interacts with and deubiquitinates phosphorylated ERK (pERK), preventing its degradation and sustaining MAPK/ERK pathway activation in breast cancer cells, promoting proliferation, migration, and invasion.\",\n      \"method\": \"Co-IP, ubiquitination assay, functional overexpression/knockdown with proliferation and invasion readouts, clinical transcriptomic dataset analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint with Co-IP and ubiquitination assay, single lab, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the context of Src-driven tumor invasion, eIF3h (along with eIF3e and eIF3d) is essential for invadosome formation and extracellular matrix degradation. Src regulates eIF3h expression. eIF3h-containing eIF3 complexes associate with local mRNA translation activity at invadosomes.\",\n      \"method\": \"siRNA knockdown, invadosome formation assays, ECM degradation assays, expression analysis in HCC patient data\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, functional KD assays without full mechanistic dissection of eIF3h-specific contribution\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EIF3H (eIF3 subunit h) is a multifunctional protein with two established biochemical activities: (1) as a non-core subunit of the eIF3 translation initiation complex, it selectively promotes translation reinitiation of mRNAs bearing upstream open reading frames (uORFs) and facilitates mRNA looping when partnered with METTL3 to enhance translation of m6A-modified oncogenic mRNAs near the stop codon via ribosome recycling; and (2) as a JAMM-family deubiquitylase, EIF3H catalyzes removal of K48-linked polyubiquitin chains from multiple substrates — including YAP, Snail, HAX1, OGT, CCND1, and β-catenin — stabilizing these oncoproteins to drive tumor invasion, EMT, and proliferation across multiple cancer types.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EIF3H is a non-core subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that selectively promotes translation of mRNAs bearing upstream open reading frames (uORFs) and, through its interaction with METTL3, facilitates mRNA looping and ribosome recycling to enhance translation of m6A-modified transcripts [PMID:15548739, PMID:30232453, PMID:23716667]. As a JAMM/MPN-family deubiquitylase, EIF3H removes K48-linked polyubiquitin chains from multiple oncoproteins—including YAP, Snail, HAX1, OGT, CCND1, and β-catenin—thereby stabilizing them against proteasomal degradation and activating downstream signaling cascades such as MAPK/ERK and Wnt/β-catenin [PMID:32269044, PMID:32867821, PMID:38514606, PMID:37559097]. Within the eIF3 holocomplex, EIF3H associates with 40S ribosomal subunits and is dispensable for bulk translation but is required for transcript-specific translational control, including mRNAs critical for vertebrate lens and neural development [PMID:19061185, PMID:23716667]. Conditional deletion of Eif3h suppresses colorectal tumorigenesis in mouse models, and a colorectal cancer risk variant at 8q23.3 modulates EIF3H expression through long-range promoter interaction [PMID:38514606, PMID:20862326].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"The first evidence that eIF3h is not required for general translation but selectively promotes reinitiation on uORF-containing mRNAs established its role as a transcript-specific translational regulator rather than a core initiation factor.\",\n      \"evidence\": \"Polysome fractionation and transient expression assays in Arabidopsis eif3h mutants showing selective loss of uORF-containing mRNA translation\",\n      \"pmids\": [\"15548739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of reinitiation promotion not resolved at the molecular level\", \"Unclear whether the COP9 signalosome interaction is functionally relevant to translation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Gain- and loss-of-function experiments demonstrated that EIF3H overexpression is sufficient to drive oncogenic transformation, linking its translational activity to cell proliferation and cancer.\",\n      \"evidence\": \"Tet-Off overexpression in NIH 3T3 cells showing anchorage-independent growth; siRNA knockdown inhibiting breast and prostate cancer cell growth\",\n      \"pmids\": [\"16652384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism was not distinguished between translation-dependent and deubiquitylase-dependent functions\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of measles virus N protein as a direct EIF3H-binding partner that inhibits translation established EIF3H as a viral target for host translational shutdown.\",\n      \"evidence\": \"Yeast two-hybrid, mammalian Co-IP, and in vitro translation inhibition with recombinant GST-N protein\",\n      \"pmids\": [\"17686838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to natural MV infection pathogenesis not demonstrated\", \"Whether other eIF3 subunits are co-targeted was not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Biochemical purification of the fission yeast eIF3 complex showed that eIF3h is a non-core subunit dispensable for holocomplex integrity and general translation, but required for meiosis/sporulation, confirming its auxiliary regulatory role across eukaryotes.\",\n      \"evidence\": \"TAP-tag purification, polysome profiling, genetic deletion and human ortholog complementation in S. pombe\",\n      \"pmids\": [\"19061185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of meiotic defect not elucidated\", \"Whether distinct eIF3 subcomplexes have separable functions was not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A colorectal cancer risk SNP at 8q23.3 was shown to physically contact the EIF3H promoter via long-range chromatin interaction, directly linking genetic variation in EIF3H expression to cancer susceptibility.\",\n      \"evidence\": \"Chromosome conformation capture (3C) and reporter assays in CRC cell lines\",\n      \"pmids\": [\"20862326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal variant not fine-mapped to single nucleotide resolution\", \"Effect on endogenous EIF3H expression not quantified in patient tissue\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide polysome profiling in zebrafish embryos revealed that eIF3h controls translation of a specific mRNA cohort required for lens and neural development, extending its transcript-selective function to vertebrate organogenesis.\",\n      \"evidence\": \"Morpholino knockdown with genome-wide polysome profiling and UTR dissection in zebrafish\",\n      \"pmids\": [\"23716667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"cis-regulatory elements beyond UTRs not identified\", \"Whether the deubiquitylase activity contributes to developmental phenotypes was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that METTL3 directly binds eIF3h to promote mRNA looping between 3′ m6A sites and 5′ cap-binding complexes revealed the molecular mechanism by which m6A enhances translation through ribosome recycling, and established the METTL3-eIF3h axis as a driver of oncogenic translation.\",\n      \"evidence\": \"Co-IP, electron microscopy of polyribosomes, tethering assays, and reporter translation in human cells\",\n      \"pmids\": [\"30232453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of METTL3-eIF3h interface not determined at atomic resolution\", \"Whether this mechanism operates on all m6A-containing mRNAs or a subset is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Characterization of EIF3H as a JAMM-family deubiquitylase that removes K48-linked ubiquitin from YAP and Snail established a second biochemical activity independent of its translation initiation role, directly linking it to EMT and tumor invasion.\",\n      \"evidence\": \"Structure-based modeling with catalytic triad mutagenesis (D90/D91/Q121) and ubiquitination assays for YAP; reciprocal Co-IP/MS, CHX chase, and in vivo models for Snail\",\n      \"pmids\": [\"32269044\", \"32867821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of EIF3H DUB domain solved\", \"Whether DUB activity occurs within or outside the eIF3 holocomplex is unknown\", \"Catalytic mechanism details (zinc coordination, processivity) not biochemically characterized with purified enzyme\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extension of the DUB substrate repertoire to OGT and CCND1 showed that EIF3H stabilizes diverse oncoproteins across cancer types, broadening its role as a general oncoprotein stabilizer acting through K48-linked deubiquitylation.\",\n      \"evidence\": \"Co-IP with domain mapping (JAB/MPN–GT domain interaction for OGT); knockdown with CCND1 degradation assays in HCC and cholangiocarcinoma cells\",\n      \"pmids\": [\"37559097\", \"36350008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reconstitution with purified components not performed\", \"Substrate selectivity determinants not defined\", \"Whether CCND1 is a direct or indirect target needs clarification\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional Eif3h knockout in a mouse colorectal cancer model suppressed tumorigenesis and revealed that EIF3H deubiquitylates HAX1 to potentiate RAF1-MEK1-ERK signaling, while Wnt/β-catenin signaling induces EIF3H expression, establishing a feedforward oncogenic loop.\",\n      \"evidence\": \"Conditional knockout mouse (AOM/DSS model), Co-IP, ubiquitination assays, orthotopic and PDX models\",\n      \"pmids\": [\"38514606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EIF3H's translation and DUB functions are independently required for tumorigenesis was not dissected\", \"Tissue specificity of the Wnt-EIF3H feedforward loop not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Phosphorylation of METTL3 at Ser2 was identified as a regulatory switch that disrupts the METTL3-eIF3H interaction, showing that the translational activity of the axis is dynamically regulated and targetable for chemosensitization.\",\n      \"evidence\": \"High-throughput base editor screen in gastric cancer cells with Co-IP validation of interaction disruption\",\n      \"pmids\": [\"41385641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for METTL3 Ser2 phosphorylation not identified\", \"In vivo validation of chemosensitization limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"EIF3H was reported to deubiquitylate β-catenin, directly activating Wnt signaling in anaplastic thyroid cancer, with EIF3H expression itself regulated by m6A/IGF2BP2, closing a regulatory circuit between m6A RNA modification and Wnt pathway activation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, m6A reader identification in ATC cell lines\",\n      \"pmids\": [\"39984062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without in vivo validation\", \"Whether β-catenin deubiquitylation is direct (purified enzyme) not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) whether the translation initiation and deubiquitylase activities of EIF3H are structurally and functionally separable within the eIF3 holocomplex; (2) what determines substrate selectivity among the growing list of DUB substrates; and (3) whether a high-resolution structure of the EIF3H MPN/JAMM domain can be obtained to enable pharmacological targeting.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of EIF3H\", \"No separation-of-function mutant distinguishing translation from DUB activity\", \"No unbiased substrate screen (e.g., TUBE/diGly proteomics) performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 3, 4, 5, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 4, 5, 6]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 9, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 3, 4, 5, 6, 8]}\n    ],\n    \"complexes\": [\n      \"eIF3\"\n    ],\n    \"partners\": [\n      \"METTL3\",\n      \"YAP1\",\n      \"SNAI1\",\n      \"HAX1\",\n      \"OGT\",\n      \"CTNNB1\",\n      \"PDCD4\",\n      \"CCND1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}