{"gene":"EIF3C","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2013,"finding":"Human eIF4G binds directly to eIF3 through a surface composed of eIF3c, eIF3d, and eIF3e subunits; site-specific cross-linking revealed two distinct eIF3-binding subdomains within eIF4G, both of which are required for efficient mRNA recruitment to the ribosome and translation stimulation.","method":"Fluorescence anisotropy, site-specific cross-linking, eIF4G-dependent translation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods (cross-linking, fluorescence anisotropy, functional translation assay) in a single rigorous study","pmids":["24092755"],"is_preprint":false},{"year":2011,"finding":"The PCI domain of eIF3c/NIP1 directly interacts with blades 1–3 of the small ribosomal protein RACK1/ASC1 on the 40S head, and also binds RNA in a non-specific manner; mutations disrupting these interactions reduce 40S-bound eIF3 and eIF5 in vivo, establishing the PCI domain as a bridge between eIF3 and the 40S ribosome.","method":"Yeast genetics (lethal/slow-growth mutants), in vivo sedimentation, co-immunoprecipitation, RNA-binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic and biochemical evidence with multiple mutant alleles and functional readouts in yeast ortholog","pmids":["22123745"],"is_preprint":false},{"year":2017,"finding":"The N-terminal domain (NTD) of eIF3c is divided into three parts (3c0, 3c1, 3c2): 3c0 binds eIF5 strongly and eIF1 weakly; 3c1 and 3c2 form a stoichiometric complex with eIF1 (3c1 via Arg-53 and Leu-96; 3c2 facing 40S protein uS15/S13), anchoring eIF1 to the scanning pre-initiation complex. Upon start codon recognition, 3c0:eIF5 interaction stabilizes the scanning PIC by precluding an inhibitory 3c0:eIF1 association, and ultimately facilitates eIF1 release.","method":"NMR, X-ray crystallography, biochemical binding assays, yeast genetics (start codon recognition assays)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — structural and mutagenesis data combined with genetic epistasis in a single study","pmids":["28297669"],"is_preprint":false},{"year":2006,"finding":"eIF3c (p110 subunit) directly interacts with the NF2 tumor suppressor schwannomin/merlin; schwannomin is most effective at inhibiting cellular proliferation when eIF3c is highly expressed, suggesting eIF3c-mediated translation regulation contributes to NF2 pathogenesis.","method":"Co-immunoprecipitation/pulldown (interaction identification), cell proliferation assays, immunohistochemistry of meningiomas","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP/pulldown plus cellular phenotype data, replicated in patient tissue","pmids":["16497727"],"is_preprint":false},{"year":2013,"finding":"siRNA-mediated knockdown of eIF3c in multiple cancer cell lines decreases global protein synthesis and causes polysome run-off, demonstrating that eIF3c is required for translation initiation in vivo; knockdown also induces G0/G1 or G2/M cell cycle arrest (in a cell-type-dependent manner) and reduces proliferation.","method":"RNAi knockdown, polysome profiling, cell cycle analysis by flow cytometry, MTT proliferation assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with polysome profiling as direct mechanistic readout, multiple cell lines","pmids":["23623922"],"is_preprint":false},{"year":2017,"finding":"EIF3C knockdown in hepatocellular carcinoma cells suppresses proliferation and tumorigenicity in vivo; gene set enrichment analysis links high eIF3c expression to KRAS, VEGF, and Hedgehog signaling pathway activation.","method":"shRNA knockdown, xenograft tumor assay, GSEA pathway analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — KO/KD with defined cellular and in vivo phenotype; pathway placement by GSEA is inferential","pmids":["28231410"],"is_preprint":false},{"year":2017,"finding":"EIF3C knockdown in breast cancer cells suppresses proliferation and induces apoptosis; mechanistically, knockdown activates the mTOR signaling pathway (assessed by phospho-western blotting of pathway components), placing eIF3c upstream of mTOR-dependent translational efficiency.","method":"siRNA knockdown, BrdU incorporation, colony formation, flow cytometry apoptosis assay, phospho-protein antibody array, western blotting","journal":"Medical science monitor","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple orthogonal cellular assays with signaling pathway readout in a single study","pmids":["28854163"],"is_preprint":false},{"year":2018,"finding":"EIF3C overexpression in hepatocellular carcinoma cells increases secretion of extracellular exosomes (confirmed by fluorescent labeling, electron microscopy, nanoparticle tracking, and exosome markers), which promote tumor angiogenesis via S100A11 upregulation; exosome inhibitor GW4869 reversed these effects.","method":"EIF3C overexpression, exosome quantification (EM, NTA, PKH26 labeling), HUVEC tube formation assay, plug assay in nude mice, GW4869 inhibitor rescue","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods linking EIF3C to exosome biology and angiogenesis with downstream effector (S100A11) identified","pmids":["29568350"],"is_preprint":false},{"year":2011,"finding":"Loss-of-function mutations in mouse Eif3c (a nonsense and an in-frame deletion) cause polydactyly and hypopigmentation associated with ectopic Shh and Ptch1 expression and aberrant Gli3 processing in anterior limb buds, placing eIF3c upstream of the SHH/GLI3 signaling pathway in limb development.","method":"Mouse forward genetics, in situ hybridization, Gli3 processing western blot, haploinsufficiency analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — two independent alleles in mouse with molecular pathway readout (SHH/GLI3)","pmids":["21292980"],"is_preprint":false},{"year":2021,"finding":"Conditional loss-of-function of Eif3c in mice reveals a specific requirement for eIF3 in Shh-mediated tissue patterning; eCLIP-seq shows eIF3 preferentially binds a pyrimidine-rich motif in 5'-UTRs of specific transcripts, and ribosome profiling in Eif3c mutant embryos demonstrates selective reduction in translation of Ptch1 (the Shh receptor) through this motif.","method":"Eif3c knockout mice, eCLIP-seq, ribosome profiling, quantitative translation analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — genome-wide in vivo eCLIP-seq plus ribosome profiling in loss-of-function embryos, mechanistically linking eIF3c to transcript-selective translation","pmids":["34752747"],"is_preprint":false},{"year":2020,"finding":"The m6A reader YTHDF1 binds m6A-modified EIF3C mRNA and augments its translation in an m6A-dependent manner, increasing EIF3C protein (but not mRNA) levels; elevated EIF3C protein in turn promotes overall translational output, facilitating ovarian cancer tumorigenesis and metastasis.","method":"Multi-omics (m6A-seq, ribosome profiling, proteomics), m6A-RIP, YTHDF1 knockdown/overexpression, translation reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal omics methods plus functional validation; m6A-dependent translation mechanism directly demonstrated","pmids":["31996915"],"is_preprint":false},{"year":2022,"finding":"circPDE5A sequesters the m6A writer WTAP by forming a circPDE5A–WTAP complex, thereby blocking WTAP-dependent m6A methylation of EIF3C mRNA; loss of EIF3C m6A methylation disrupts its translation, reducing EIF3C protein and inactivating the MAPK pathway to restrain prostate cancer metastasis.","method":"RNA pulldown with mass spectrometry, RIP, MeRIP-seq (m6A-seq), ChIP, dual-luciferase reporter, in vitro/in vivo functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic pathway (circPDE5A → WTAP → EIF3C m6A → translation → MAPK) supported by multiple orthogonal biochemical methods","pmids":["35650605"],"is_preprint":false},{"year":2021,"finding":"ZNF280A transcriptionally regulates EIF3C expression in lung adenocarcinoma; ZNF280A knockdown reduces EIF3C levels, and downregulation of EIF3C in ZNF280A-overexpressing cells attenuates ZNF280A-induced promotion of proliferation, survival, and migration, placing EIF3C downstream of ZNF280A.","method":"Gene expression profiling, siRNA/shRNA knockdown, overexpression rescue experiments, in vitro and in vivo tumor assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 — epistasis established by rescue experiment; transcriptional regulation inferred from expression profiling","pmids":["33414445"],"is_preprint":false},{"year":2023,"finding":"Complement Factor H (CFH) upregulates EIF3C expression in rheumatoid arthritis monocytes and fibroblast-like synoviocytes (identified by RNA-seq); EIF3C knockdown under CFH+TNF-α stimulation promotes FLS migration and increases IL-6, IL-8, and MMP-3 expression, indicating EIF3C mediates CFH's anti-inflammatory effects.","method":"RNA sequencing, siRNA knockdown, wound-healing/transwell migration assay, ELISA for cytokines","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 3 — downstream target identified by RNA-seq with functional validation by knockdown; single-lab study","pmids":["37996918"],"is_preprint":false},{"year":2020,"finding":"Overexpression of eIF3c in CHOK1 cells increases eIF3i protein levels and c-Myc expression, and enhances both cap- and IRES-dependent recombinant protein synthesis as well as cell growth, demonstrating that eIF3c controls global translational output and cell proliferation in an engineered mammalian cell context.","method":"Stable overexpression in CHOK1/HEK293 cells, global protein synthesis rate measurement, recombinant reporter protein assay, western blotting for c-Myc","journal":"Metabolic engineering","confidence":"Medium","confidence_rationale":"Tier 2 — clean overexpression with mechanistic readouts (global synthesis rates, IRES vs. cap-dependent), replicated across two cell lines","pmids":["32061967"],"is_preprint":false},{"year":2025,"finding":"NMR solution analysis of the eIF3c fragment (residues 166–266) encompassing the eIF1-binding site shows it is intrinsically disordered, with short segments of modest α-helical or β-strand propensity; three conserved FLKK motifs map to junctions of these transient structural elements, providing residue-specific interaction surface information for eIF1 binding.","method":"NMR spectroscopy (backbone/side-chain assignments, CSI analysis, CSTC analysis)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — rigorous NMR structural characterization; preprint, no functional mutagenesis yet","pmids":["bio_10.1101_2025.09.13.675972"],"is_preprint":true}],"current_model":"EIF3C is a core scaffold subunit of the eIF3 complex whose N-terminal domain orchestrates pre-initiation complex (PIC) assembly by anchoring eIF1 (via 3c1/3c2 subdomains) and eIF5 (via 3c0), while its PCI domain bridges the 40S ribosome through direct contacts with RACK1/ASC1 and RNA; eIF4G docks onto eIF3 at a surface shared by eIF3c, -d, and -e to recruit mRNA, and eIF3 exhibits unexpected transcript selectivity by recognizing pyrimidine-rich 5'-UTR motifs to preferentially translate key developmental and signaling mRNAs (e.g., Ptch1); EIF3C protein levels are post-translationally amplified by YTHDF1-mediated m6A-dependent translation of its mRNA, and suppression of EIF3C impairs global protein synthesis, arrests the cell cycle, and triggers apoptosis across multiple cancer models."},"narrative":{"teleology":[{"year":2006,"claim":"An early interaction screen linked eIF3c to the NF2 tumor suppressor merlin, raising the question of whether eIF3c has functions beyond core translation — specifically in growth-suppressive signaling.","evidence":"Co-immunoprecipitation/pulldown and cell proliferation assays in meningioma-derived cells","pmids":["16497727"],"confidence":"Medium","gaps":["Single co-IP without reciprocal validation or structural mapping of the interaction interface","Functional consequence of merlin–eIF3c binding on translation not directly measured","Not independently reproduced"]},{"year":2011,"claim":"Two studies established eIF3c's dual role in ribosome bridging and developmental signaling: its PCI domain was shown to directly contact RACK1/ASC1 on the 40S head and to bind RNA, while mouse loss-of-function alleles revealed a specific requirement for eIF3c in SHH/GLI3-dependent limb patterning.","evidence":"Yeast mutant genetics with sedimentation and RNA-binding assays (PCI domain); mouse forward genetics with in situ hybridization and Gli3 processing analysis (developmental role)","pmids":["22123745","21292980"],"confidence":"High","gaps":["Structural basis of PCI–RACK1 interface at atomic resolution not yet determined","Whether the limb phenotype reflects global or transcript-selective translation was unresolved"]},{"year":2013,"claim":"Two advances defined eIF3c's role in mRNA recruitment and global translation: eIF4G was shown to bind eIF3 through a surface shared by eIF3c/d/e, and eIF3c knockdown in cancer cells caused polysome run-off and cell cycle arrest, confirming eIF3c is rate-limiting for translation initiation in mammalian cells.","evidence":"Site-specific cross-linking and fluorescence anisotropy for eIF4G–eIF3 interaction; siRNA knockdown with polysome profiling and flow cytometry in multiple cancer lines","pmids":["24092755","23623922"],"confidence":"High","gaps":["Atomic-resolution structure of the eIF4G–eIF3c/d/e interface was lacking","Relative contribution of eIF3c versus other subunits to the eIF4G docking site not dissected"]},{"year":2017,"claim":"NMR/crystallography resolved the tripartite architecture of the eIF3c N-terminal domain (3c0/3c1/3c2), revealing how eIF1 and eIF5 are positioned during scanning and how their coordinated release at the start codon is governed by competitive binding at the 3c0 subdomain.","evidence":"NMR and X-ray crystallography combined with yeast start-codon recognition assays and mutagenesis","pmids":["28297669"],"confidence":"High","gaps":["Full PIC-context cryo-EM showing all three subdomains simultaneously was not available","Dynamics of 3c0-mediated eIF1 release during scanning not captured in real time"]},{"year":2017,"claim":"Cancer biology studies showed that eIF3c depletion suppresses tumorigenicity in hepatocellular and breast carcinoma, connecting eIF3c levels to KRAS/VEGF/Hedgehog and mTOR pathway activity and establishing eIF3c as a proliferation-promoting factor in multiple tumor types.","evidence":"shRNA/siRNA knockdown with xenograft assays, GSEA pathway analysis, phospho-protein arrays","pmids":["28231410","28854163"],"confidence":"Medium","gaps":["Direct translational targets mediating these signaling effects were not identified","Pathway activation inferred from GSEA and phospho-arrays rather than direct biochemical reconstitution"]},{"year":2018,"claim":"An unexpected non-canonical function was described: EIF3C overexpression increased extracellular exosome secretion and promoted tumor angiogenesis via S100A11, suggesting eIF3c influences vesicle biogenesis or cargo loading.","evidence":"EIF3C overexpression with exosome quantification (EM, NTA), HUVEC tube formation, and GW4869 inhibitor rescue","pmids":["29568350"],"confidence":"Medium","gaps":["Mechanism by which a translation factor alters exosome biogenesis is unexplained","Whether effect is direct or secondary to translational upregulation of vesicle-pathway components is untested"]},{"year":2020,"claim":"Two studies addressed how EIF3C itself is regulated and how its abundance sets translational capacity: YTHDF1 was shown to bind m6A-modified EIF3C mRNA and boost its translation (not transcription), while eIF3c overexpression in engineered cells enhanced both cap- and IRES-dependent protein synthesis and c-Myc expression.","evidence":"Multi-omics (m6A-seq, ribosome profiling, proteomics) with YTHDF1 manipulation in ovarian cancer; stable overexpression in CHOK1/HEK293 with global synthesis measurement","pmids":["31996915","32061967"],"confidence":"High","gaps":["Whether eIF3c is the primary or sole translation-relevant target of YTHDF1 was not determined","Structural basis for m6A-mediated enhancement of EIF3C translation unknown"]},{"year":2021,"claim":"A landmark study resolved the long-standing question of transcript selectivity: eCLIP-seq and ribosome profiling in Eif3c-mutant mouse embryos demonstrated that eIF3 binds pyrimidine-rich 5′-UTR motifs and selectively promotes translation of Ptch1, mechanistically explaining the Hedgehog-pathway phenotypes seen in eIF3c mutants.","evidence":"Conditional Eif3c knockout mice, eCLIP-seq, ribosome profiling, quantitative translation analysis","pmids":["34752747"],"confidence":"High","gaps":["Full repertoire of eIF3c-dependent transcripts beyond Ptch1 not comprehensively validated","Whether the pyrimidine-rich motif is sufficient for eIF3-dependent regulation in reporter assays was not shown"]},{"year":2022,"claim":"An upstream epitranscriptomic circuit was delineated: circPDE5A sequesters the m6A writer WTAP, reducing m6A on EIF3C mRNA and thereby lowering EIF3C protein levels; this axis inactivates MAPK signaling and suppresses prostate cancer metastasis, establishing a circRNA–m6A–EIF3C regulatory pathway.","evidence":"RNA pulldown with mass spectrometry, MeRIP-seq, RIP, dual-luciferase reporters, in vivo functional assays","pmids":["35650605"],"confidence":"High","gaps":["Whether additional m6A writers besides WTAP contribute to EIF3C methylation not addressed","MAPK pathway activation attributed to EIF3C but direct translational targets linking EIF3C to MAPK are unidentified"]},{"year":null,"claim":"Key unresolved questions include: the full catalog of eIF3c-dependent selectively translated mRNAs in different tissues, the structural basis of the intrinsically disordered eIF1-binding region during scanning in a full PIC context, and whether eIF3c's effects on exosome biogenesis and non-translational pathways reflect direct functions or indirect consequences of altered translational output.","evidence":"","pmids":[],"confidence":"Low","gaps":["Comprehensive translatome analysis across tissues is lacking","Cryo-EM of full PIC with eIF3c NTD resolved in scanning versus closed conformations not yet achieved","Direct versus indirect role in exosome secretion remains untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,9]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,4,9,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,14]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,4,9,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,10,11]}],"complexes":["eIF3","43S pre-initiation complex"],"partners":["EIF1","EIF5","EIF4G1","RACK1","EIF3D","EIF3E","NF2","EIF3I"],"other_free_text":[]},"mechanistic_narrative":"EIF3C encodes a core scaffold subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that is essential for pre-initiation complex (PIC) assembly, mRNA recruitment, and both global and transcript-selective translation. Its N-terminal domain anchors eIF1 (via 3c1/3c2 subdomains) and eIF5 (via 3c0) to the scanning PIC, coordinating start-codon recognition and eIF1 release, while its C-terminal PCI domain bridges eIF3 to the 40S ribosomal subunit through direct contacts with RACK1/ASC1 and non-specific RNA binding [PMID:28297669, PMID:22123745]. eIF4G docks onto eIF3 at a surface composed of eIF3c, eIF3d, and eIF3e to recruit mRNA, and eIF3 exhibits transcript-selective translational control by recognizing pyrimidine-rich 5′-UTR motifs — notably in Ptch1 — thereby coupling eIF3c to Sonic Hedgehog signaling and limb patterning in vivo [PMID:24092755, PMID:34752747, PMID:21292980]. EIF3C mRNA is itself a target of m6A-dependent translational amplification via YTHDF1 and WTAP, and EIF3C depletion reduces global protein synthesis, arrests the cell cycle, and triggers apoptosis in multiple cancer models [PMID:31996915, PMID:35650605, PMID:23623922]."},"prefetch_data":{"uniprot":{"accession":"Q99613","full_name":"Eukaryotic translation initiation factor 3 subunit C","aliases":["Eukaryotic translation initiation factor 3 subunit 8","eIF3 p110"],"length_aa":913,"mass_kda":105.3,"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/Q99613/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3C"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":4.0},{"gene":"EIF3G","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"EIF3I","stoichiometry":0.2},{"gene":"EIF5","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"ENY2","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF3C","total_profiled":1310},"omim":[{"mim_id":"609596","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT K; EIF3K","url":"https://www.omim.org/entry/609596"},{"mim_id":"607379","title":"NF2, MOESIN-EZRIN-RADIXIN-LIKE (MERLIN) TUMOR SUPPRESSOR; NF2","url":"https://www.omim.org/entry/607379"},{"mim_id":"603916","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT C; EIF3C","url":"https://www.omim.org/entry/603916"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3C"},"hgnc":{"alias_symbol":["eIF3-p110"],"prev_symbol":["EIF3S8"]},"alphafold":{"accession":"Q99613","domains":[{"cath_id":"-","chopping":"52-163","consensus_level":"high","plddt":81.5587,"start":52,"end":163},{"cath_id":"-","chopping":"325-494","consensus_level":"high","plddt":81.1364,"start":325,"end":494}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99613","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99613-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99613-F1-predicted_aligned_error_v6.png","plddt_mean":71.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3C","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3C"},"sequence":{"accession":"Q99613","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99613.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99613/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99613"}},"corpus_meta":[{"pmid":"31996915","id":"PMC_31996915","title":"The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31996915","citation_count":587,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24092755","id":"PMC_24092755","title":"Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24092755","citation_count":133,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30362562","id":"PMC_30362562","title":"Overexpressed circ_0067934 acts as an oncogene to facilitate cervical cancer progression via the miR-545/EIF3C axis.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30362562","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22123745","id":"PMC_22123745","title":"The eIF3c/NIP1 PCI domain interacts with RNA and RACK1/ASC1 and promotes assembly of translation preinitiation complexes.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22123745","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35650605","id":"PMC_35650605","title":"circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35650605","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28297669","id":"PMC_28297669","title":"Molecular Landscape of the Ribosome Pre-initiation Complex during mRNA Scanning: Structural Role for eIF3c and Its Control by eIF5.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28297669","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29568350","id":"PMC_29568350","title":"EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29568350","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16497727","id":"PMC_16497727","title":"Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c).","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16497727","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28231410","id":"PMC_28231410","title":"Transcriptomic analyses of RNA-binding proteins reveal eIF3c promotes cell proliferation in hepatocellular carcinoma.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28231410","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23623922","id":"PMC_23623922","title":"eIF3c: a potential therapeutic target for cancer.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/23623922","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23733421","id":"PMC_23733421","title":"Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells.","date":"2013","source":"Journal of Zhejiang University. Science. 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[\"24092755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal PCI domain of eIF3c/NIP1 directly interacts with blades 1-3 of the small ribosomal protein RACK1/ASC1 on the 40S head, and the PCI domain also binds RNA; disruption of these interactions reduces 40S-bound eIF3 and eIF5 in vivo, demonstrating that eIF3c bridges eIF3 to the ribosome.\",\n      \"method\": \"In vivo genetic analysis (lethal/slow-growth mutations), co-immunoprecipitation, RNA binding assays, yeast genetics\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional validation with multiple mutations, in vivo ribosome association assays, and RNA-binding experiments in yeast ortholog\",\n      \"pmids\": [\"22123745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The N-terminal domain (NTD) of eIF3c controls pre-initiation complex (PIC) scanning and start codon recognition: subdomain 3c0 binds eIF5 strongly and eIF1 weakly (inhibiting eIF1's ribosome binding), while 3c1 contacts eIF1 via Arg-53 and Leu-96, and 3c2 contacts 40S protein uS15/S13 to anchor eIF1 to the scanning PIC; upon start codon recognition, eIF5 interactions via 3c0 facilitate eIF1 release.\",\n      \"method\": \"NMR, co-immunoprecipitation, structural analysis, mutagenesis, in vitro binding assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis and functional validation of domain interactions\",\n      \"pmids\": [\"28297669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in mouse Eif3c cause polydactyly associated with ectopic Shh and Ptch1 expression in anterior limb buds and aberrant Gli3 processing, placing eIF3c upstream of SHH/GLI3 signaling in limb patterning.\",\n      \"method\": \"Genetic mapping, in situ hybridization, mouse loss-of-function mutations (Xs and Xsl alleles)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with in situ hybridization readout in two independent alleles, but mechanism of translational selectivity not directly resolved\",\n      \"pmids\": [\"21292980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eIF3c binds a pyrimidine-rich motif in 5'-UTRs of specific mRNAs (including Ptch1) as shown by eCLIP-seq, and loss-of-function of Eif3c selectively reduces translation of these transcripts (including Ptch1) by ribosome profiling, thereby controlling Shh-mediated tissue patterning.\",\n      \"method\": \"eCLIP-seq, ribosome profiling, Eif3c loss-of-function mouse embryos\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide eCLIP-seq plus ribosome profiling in matched loss-of-function embryos, two orthogonal methods identifying specific RNA targets\",\n      \"pmids\": [\"34752747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Schwannomin (NF2 tumor suppressor/merlin) directly interacts with eIF3c (p110 subunit of eIF3), and schwannomin inhibits cellular proliferation most effectively when eIF3c is highly expressed, suggesting eIF3c-mediated translational regulation underlies NF2 pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation/pulldown (protein interaction), cell proliferation assay, immunohistochemistry in meningiomas\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying the interaction, functional correlation via proliferation assay, but mechanism not fully resolved in vitro\",\n      \"pmids\": [\"16497727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"siRNA-mediated downregulation of eIF3c decreases global protein synthesis and causes polysome run-off in vivo, and induces G0/G1 or G2/M cell cycle arrest and cell death in a tissue-dependent manner across multiple cancer cell lines.\",\n      \"method\": \"RNAi knockdown, polysome profiling, flow cytometry, cell proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — polysome profiling directly demonstrates translation initiation role; cell cycle effects confirmed by flow cytometry in multiple cell lines\",\n      \"pmids\": [\"23623922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 augments the translation (but not mRNA levels) of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA, thereby increasing overall translational output in ovarian cancer cells.\",\n      \"method\": \"Multi-omics (m6A-seq, proteomics, RNA-seq), RIP, polysome fractionation, YTHDF1 knockdown/overexpression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (m6A-seq, RIP, polysome profiling) from a single study demonstrating m6A-dependent translational control of EIF3C mRNA by YTHDF1\",\n      \"pmids\": [\"31996915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circPDE5A sequesters the m6A writer WTAP by forming a circPDE5A-WTAP complex, blocking WTAP-dependent m6A methylation of EIF3C mRNA and thereby reducing EIF3C protein translation; decreased EIF3C then inactivates the MAPK pathway to restrain prostate cancer metastasis.\",\n      \"method\": \"RNA pulldown + mass spectrometry, RIP, MeRIP-seq, dual-luciferase reporter assay, in vitro/in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA pulldown + MS identifying WTAP interaction, MeRIP-seq showing m6A changes on EIF3C mRNA, multiple orthogonal methods\",\n      \"pmids\": [\"35650605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EIF3C knockdown in breast cancer cells suppresses proliferation and induces apoptosis, and this is mechanistically linked to the mTOR signaling pathway, as assessed by antibody array and western blotting for p-ERK1/2, p-Akt, p-Smad2, p-p38 MAPK, and cleaved caspases.\",\n      \"method\": \"siRNA knockdown, cell proliferation/colony assay, flow cytometry, stress/apoptosis antibody array, western blotting\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement via antibody array without direct mechanistic resolution of how EIF3C connects to mTOR\",\n      \"pmids\": [\"28854163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EIF3C overexpression in hepatocellular carcinoma cells increases secretion of extracellular exosomes, which promote tumor angiogenesis via tube formation of HUVEC cells; this effect involves upregulation of S100A11.\",\n      \"method\": \"EIF3C overexpression, exosome labelling (PKH26), electron microscopy, nanoparticle tracking, angiogenesis tube formation assay, plug assay in nude mice\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods for exosome quantification and angiogenesis readout, but mechanistic link between EIF3C and exosome biogenesis not fully resolved\",\n      \"pmids\": [\"29568350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The eIF3c fragment (residues 166–266) immediately N-terminal of the PCI domain is intrinsically disordered in solution, with three conserved FLKK motifs at junctions of transient structural elements; this region encompasses the eIF1-binding site but is not visible in cryo-EM PIC structures except for a small helix contacting eIF1.\",\n      \"method\": \"NMR (1H-15N HSQC, chemical shift index analysis, amide temperature coefficients)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural characterization of the disordered eIF1-interacting region, but preprint and no functional mutagenesis yet\",\n      \"pmids\": [\"bio_10.1101_2025.09.13.675972\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EIF3C (eIF3c/NIP1) is a core subunit of the eIF3 complex that promotes translation initiation by bridging eIF3 to the 40S ribosome (via its PCI domain interacting with RACK1/ASC1 and 18S rRNA), recruiting eIF4G through a multi-subunit interface (eIF3c/d/e), controlling start codon recognition via its NTD interactions with eIF1 and eIF5, and exhibiting unexpected specificity for translating mRNAs containing 5'-UTR pyrimidine-rich motifs (including key developmental signaling transcripts such as Ptch1); its own translation is regulated post-transcriptionally by m6A modification of its mRNA, read by YTHDF1 and regulated by the circPDE5A-WTAP axis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Human eIF4G binds directly to eIF3 through a surface composed of eIF3c, eIF3d, and eIF3e subunits; site-specific cross-linking revealed two distinct eIF3-binding subdomains within eIF4G, both of which are required for efficient mRNA recruitment to the ribosome and translation stimulation.\",\n      \"method\": \"Fluorescence anisotropy, site-specific cross-linking, eIF4G-dependent translation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods (cross-linking, fluorescence anisotropy, functional translation assay) in a single rigorous study\",\n      \"pmids\": [\"24092755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PCI domain of eIF3c/NIP1 directly interacts with blades 1–3 of the small ribosomal protein RACK1/ASC1 on the 40S head, and also binds RNA in a non-specific manner; mutations disrupting these interactions reduce 40S-bound eIF3 and eIF5 in vivo, establishing the PCI domain as a bridge between eIF3 and the 40S ribosome.\",\n      \"method\": \"Yeast genetics (lethal/slow-growth mutants), in vivo sedimentation, co-immunoprecipitation, RNA-binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic and biochemical evidence with multiple mutant alleles and functional readouts in yeast ortholog\",\n      \"pmids\": [\"22123745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The N-terminal domain (NTD) of eIF3c is divided into three parts (3c0, 3c1, 3c2): 3c0 binds eIF5 strongly and eIF1 weakly; 3c1 and 3c2 form a stoichiometric complex with eIF1 (3c1 via Arg-53 and Leu-96; 3c2 facing 40S protein uS15/S13), anchoring eIF1 to the scanning pre-initiation complex. Upon start codon recognition, 3c0:eIF5 interaction stabilizes the scanning PIC by precluding an inhibitory 3c0:eIF1 association, and ultimately facilitates eIF1 release.\",\n      \"method\": \"NMR, X-ray crystallography, biochemical binding assays, yeast genetics (start codon recognition assays)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and mutagenesis data combined with genetic epistasis in a single study\",\n      \"pmids\": [\"28297669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"eIF3c (p110 subunit) directly interacts with the NF2 tumor suppressor schwannomin/merlin; schwannomin is most effective at inhibiting cellular proliferation when eIF3c is highly expressed, suggesting eIF3c-mediated translation regulation contributes to NF2 pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation/pulldown (interaction identification), cell proliferation assays, immunohistochemistry of meningiomas\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown plus cellular phenotype data, replicated in patient tissue\",\n      \"pmids\": [\"16497727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"siRNA-mediated knockdown of eIF3c in multiple cancer cell lines decreases global protein synthesis and causes polysome run-off, demonstrating that eIF3c is required for translation initiation in vivo; knockdown also induces G0/G1 or G2/M cell cycle arrest (in a cell-type-dependent manner) and reduces proliferation.\",\n      \"method\": \"RNAi knockdown, polysome profiling, cell cycle analysis by flow cytometry, MTT proliferation assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with polysome profiling as direct mechanistic readout, multiple cell lines\",\n      \"pmids\": [\"23623922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EIF3C knockdown in hepatocellular carcinoma cells suppresses proliferation and tumorigenicity in vivo; gene set enrichment analysis links high eIF3c expression to KRAS, VEGF, and Hedgehog signaling pathway activation.\",\n      \"method\": \"shRNA knockdown, xenograft tumor assay, GSEA pathway analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/KD with defined cellular and in vivo phenotype; pathway placement by GSEA is inferential\",\n      \"pmids\": [\"28231410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EIF3C knockdown in breast cancer cells suppresses proliferation and induces apoptosis; mechanistically, knockdown activates the mTOR signaling pathway (assessed by phospho-western blotting of pathway components), placing eIF3c upstream of mTOR-dependent translational efficiency.\",\n      \"method\": \"siRNA knockdown, BrdU incorporation, colony formation, flow cytometry apoptosis assay, phospho-protein antibody array, western blotting\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal cellular assays with signaling pathway readout in a single study\",\n      \"pmids\": [\"28854163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EIF3C overexpression in hepatocellular carcinoma cells increases secretion of extracellular exosomes (confirmed by fluorescent labeling, electron microscopy, nanoparticle tracking, and exosome markers), which promote tumor angiogenesis via S100A11 upregulation; exosome inhibitor GW4869 reversed these effects.\",\n      \"method\": \"EIF3C overexpression, exosome quantification (EM, NTA, PKH26 labeling), HUVEC tube formation assay, plug assay in nude mice, GW4869 inhibitor rescue\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking EIF3C to exosome biology and angiogenesis with downstream effector (S100A11) identified\",\n      \"pmids\": [\"29568350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in mouse Eif3c (a nonsense and an in-frame deletion) cause polydactyly and hypopigmentation associated with ectopic Shh and Ptch1 expression and aberrant Gli3 processing in anterior limb buds, placing eIF3c upstream of the SHH/GLI3 signaling pathway in limb development.\",\n      \"method\": \"Mouse forward genetics, in situ hybridization, Gli3 processing western blot, haploinsufficiency analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent alleles in mouse with molecular pathway readout (SHH/GLI3)\",\n      \"pmids\": [\"21292980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional loss-of-function of Eif3c in mice reveals a specific requirement for eIF3 in Shh-mediated tissue patterning; eCLIP-seq shows eIF3 preferentially binds a pyrimidine-rich motif in 5'-UTRs of specific transcripts, and ribosome profiling in Eif3c mutant embryos demonstrates selective reduction in translation of Ptch1 (the Shh receptor) through this motif.\",\n      \"method\": \"Eif3c knockout mice, eCLIP-seq, ribosome profiling, quantitative translation analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genome-wide in vivo eCLIP-seq plus ribosome profiling in loss-of-function embryos, mechanistically linking eIF3c to transcript-selective translation\",\n      \"pmids\": [\"34752747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The m6A reader YTHDF1 binds m6A-modified EIF3C mRNA and augments its translation in an m6A-dependent manner, increasing EIF3C protein (but not mRNA) levels; elevated EIF3C protein in turn promotes overall translational output, facilitating ovarian cancer tumorigenesis and metastasis.\",\n      \"method\": \"Multi-omics (m6A-seq, ribosome profiling, proteomics), m6A-RIP, YTHDF1 knockdown/overexpression, translation reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal omics methods plus functional validation; m6A-dependent translation mechanism directly demonstrated\",\n      \"pmids\": [\"31996915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circPDE5A sequesters the m6A writer WTAP by forming a circPDE5A–WTAP complex, thereby blocking WTAP-dependent m6A methylation of EIF3C mRNA; loss of EIF3C m6A methylation disrupts its translation, reducing EIF3C protein and inactivating the MAPK pathway to restrain prostate cancer metastasis.\",\n      \"method\": \"RNA pulldown with mass spectrometry, RIP, MeRIP-seq (m6A-seq), ChIP, dual-luciferase reporter, in vitro/in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic pathway (circPDE5A → WTAP → EIF3C m6A → translation → MAPK) supported by multiple orthogonal biochemical methods\",\n      \"pmids\": [\"35650605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZNF280A transcriptionally regulates EIF3C expression in lung adenocarcinoma; ZNF280A knockdown reduces EIF3C levels, and downregulation of EIF3C in ZNF280A-overexpressing cells attenuates ZNF280A-induced promotion of proliferation, survival, and migration, placing EIF3C downstream of ZNF280A.\",\n      \"method\": \"Gene expression profiling, siRNA/shRNA knockdown, overexpression rescue experiments, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — epistasis established by rescue experiment; transcriptional regulation inferred from expression profiling\",\n      \"pmids\": [\"33414445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Complement Factor H (CFH) upregulates EIF3C expression in rheumatoid arthritis monocytes and fibroblast-like synoviocytes (identified by RNA-seq); EIF3C knockdown under CFH+TNF-α stimulation promotes FLS migration and increases IL-6, IL-8, and MMP-3 expression, indicating EIF3C mediates CFH's anti-inflammatory effects.\",\n      \"method\": \"RNA sequencing, siRNA knockdown, wound-healing/transwell migration assay, ELISA for cytokines\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — downstream target identified by RNA-seq with functional validation by knockdown; single-lab study\",\n      \"pmids\": [\"37996918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Overexpression of eIF3c in CHOK1 cells increases eIF3i protein levels and c-Myc expression, and enhances both cap- and IRES-dependent recombinant protein synthesis as well as cell growth, demonstrating that eIF3c controls global translational output and cell proliferation in an engineered mammalian cell context.\",\n      \"method\": \"Stable overexpression in CHOK1/HEK293 cells, global protein synthesis rate measurement, recombinant reporter protein assay, western blotting for c-Myc\",\n      \"journal\": \"Metabolic engineering\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression with mechanistic readouts (global synthesis rates, IRES vs. cap-dependent), replicated across two cell lines\",\n      \"pmids\": [\"32061967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMR solution analysis of the eIF3c fragment (residues 166–266) encompassing the eIF1-binding site shows it is intrinsically disordered, with short segments of modest α-helical or β-strand propensity; three conserved FLKK motifs map to junctions of these transient structural elements, providing residue-specific interaction surface information for eIF1 binding.\",\n      \"method\": \"NMR spectroscopy (backbone/side-chain assignments, CSI analysis, CSTC analysis)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — rigorous NMR structural characterization; preprint, no functional mutagenesis yet\",\n      \"pmids\": [\"bio_10.1101_2025.09.13.675972\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EIF3C is a core scaffold subunit of the eIF3 complex whose N-terminal domain orchestrates pre-initiation complex (PIC) assembly by anchoring eIF1 (via 3c1/3c2 subdomains) and eIF5 (via 3c0), while its PCI domain bridges the 40S ribosome through direct contacts with RACK1/ASC1 and RNA; eIF4G docks onto eIF3 at a surface shared by eIF3c, -d, and -e to recruit mRNA, and eIF3 exhibits unexpected transcript selectivity by recognizing pyrimidine-rich 5'-UTR motifs to preferentially translate key developmental and signaling mRNAs (e.g., Ptch1); EIF3C protein levels are post-translationally amplified by YTHDF1-mediated m6A-dependent translation of its mRNA, and suppression of EIF3C impairs global protein synthesis, arrests the cell cycle, and triggers apoptosis across multiple cancer models.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EIF3C (eIF3c/NIP1) is a core subunit of eukaryotic translation initiation factor 3 that bridges the eIF3 complex to the 40S ribosomal subunit, controls start codon recognition, recruits mRNA via eIF4G, and selectively regulates translation of specific transcripts bearing 5'-UTR pyrimidine-rich motifs. Its C-terminal PCI domain anchors eIF3 to the ribosome by directly contacting RACK1/ASC1 and 18S rRNA [PMID:22123745], while its N-terminal domain orchestrates scanning fidelity through competitive binding of eIF1 and eIF5: subdomain 3c0 binds eIF5 to promote eIF1 release upon AUG recognition, and subdomains 3c1/3c2 position eIF1 on the scanning pre-initiation complex [PMID:28297669]. Beyond its general role in translation initiation, eIF3c binds pyrimidine-rich 5'-UTR elements in select mRNAs including Ptch1, and its loss of function selectively reduces their translation, thereby disrupting Shh-mediated tissue patterning and causing polydactyly in mice [PMID:34752747, PMID:21292980]. EIF3C mRNA is itself post-transcriptionally regulated by m6A modification read by YTHDF1 and controlled by the circPDE5A–WTAP axis, establishing a feedforward loop linking epitranscriptomic signaling to global translational capacity [PMID:31996915, PMID:35650605].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying a physical link between the NF2 tumor suppressor schwannomin and eIF3c raised the possibility that eIF3c mediates growth-regulatory translational control beyond its housekeeping role.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown and proliferation assays in meningioma-derived cells\",\n      \"pmids\": [\"16497727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal or domain-mapping validation\",\n        \"Mechanism by which schwannomin modulates eIF3c-dependent translation not resolved\",\n        \"No demonstration that the interaction occurs on polysomes\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that the eIF3c PCI domain directly contacts RACK1/ASC1 and rRNA on the 40S subunit established eIF3c as the primary bridge anchoring eIF3 to the ribosome, explaining how eIF3 is recruited to the pre-initiation complex.\",\n      \"evidence\": \"Yeast genetics (lethal/slow-growth mutations), co-immunoprecipitation, and RNA-binding assays\",\n      \"pmids\": [\"22123745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"High-resolution structure of the eIF3c PCI–RACK1 interface not determined at this stage\",\n        \"Contribution of the PCI domain to mRNA-specific translation not addressed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mouse loss-of-function alleles of Eif3c causing polydactyly with ectopic Shh/Ptch1 expression and aberrant Gli3 processing revealed an unexpected gene-specific developmental role for a translation factor.\",\n      \"evidence\": \"Genetic mapping and in situ hybridization in two independent Eif3c mouse alleles (Xs, Xsl)\",\n      \"pmids\": [\"21292980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether eIF3c directly or indirectly controls Ptch1/Gli3 translation was unresolved\",\n        \"Translational selectivity mechanism not identified\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the eIF4G–eIF3 interface to a surface comprising eIF3c, eIF3d, and eIF3e subunits defined how capped mRNA is recruited to the 43S complex through two distinct eIF4G subdomains, both required for efficient translation.\",\n      \"evidence\": \"Site-specific cross-linking, fluorescence anisotropy, and eIF4G-dependent translation assay with recombinant factors\",\n      \"pmids\": [\"24092755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contribution of eIF3c versus eIF3d/e contacts not dissected\",\n        \"Whether the eIF4G–eIF3c interface differs between cap-dependent and IRES-dependent initiation not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Knockdown of eIF3c causing polysome run-off and cell-cycle arrest confirmed that eIF3c is rate-limiting for global translation initiation in mammalian cells, not merely structural.\",\n      \"evidence\": \"siRNA knockdown with polysome profiling and flow cytometry across multiple cancer cell lines\",\n      \"pmids\": [\"23623922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Indirect effects of eIF3 destabilization versus direct eIF3c catalytic role not distinguished\",\n        \"Cell-type-dependent arrest patterns (G0/G1 vs. G2/M) unexplained mechanistically\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"NMR-guided dissection of the eIF3c N-terminal domain resolved how scanning fidelity is controlled: subdomain 3c0 competitively binds eIF5 versus eIF1, while 3c1 and 3c2 anchor eIF1 to the PIC, with eIF5 displacing eIF1 upon start codon recognition.\",\n      \"evidence\": \"NMR, co-immunoprecipitation, mutagenesis, and in vitro binding assays\",\n      \"pmids\": [\"28297669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamic conformational changes during scanning-to-recognition transition not captured in real time\",\n        \"Functional consequences of NTD mutations on mRNA-specific translation not tested genome-wide\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that YTHDF1 binds m6A-modified EIF3C mRNA to enhance its translation without altering mRNA levels established a post-transcriptional feedforward loop controlling translational capacity.\",\n      \"evidence\": \"m6A-seq, RIP, polysome fractionation, and YTHDF1 knockdown/overexpression in ovarian cancer cells\",\n      \"pmids\": [\"31996915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific m6A sites on EIF3C mRNA required for YTHDF1-mediated enhancement not mapped at single-nucleotide resolution\",\n        \"Whether this regulation operates in non-cancer contexts unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"eCLIP-seq identification of eIF3c binding to pyrimidine-rich 5'-UTR motifs, combined with ribosome profiling showing selective translational reduction of these targets (including Ptch1) in Eif3c-mutant embryos, resolved the long-standing question of how a general translation factor controls tissue patterning.\",\n      \"evidence\": \"eCLIP-seq and ribosome profiling in Eif3c loss-of-function mouse embryos\",\n      \"pmids\": [\"34752747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether eIF3c binds these motifs as a free subunit or within the holo-eIF3 complex not determined\",\n        \"Structural basis for pyrimidine-rich motif recognition unknown\",\n        \"Full repertoire of eIF3c-dependent transcripts in adult tissues not characterized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that circPDE5A sequesters WTAP to block m6A methylation of EIF3C mRNA, reducing EIF3C protein and inactivating MAPK signaling, placed eIF3c translational regulation within a broader epitranscriptomic circRNA network.\",\n      \"evidence\": \"RNA pulldown + mass spectrometry, MeRIP-seq, dual-luciferase reporter, and in vivo metastasis assays in prostate cancer models\",\n      \"pmids\": [\"35650605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether circPDE5A-WTAP regulation of EIF3C is tissue-specific or generalizable not tested\",\n        \"Direct link between reduced EIF3C and MAPK inactivation (specific translational targets) not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural basis for how eIF3c selectively recognizes pyrimidine-rich 5'-UTR elements, and whether this selectivity operates within the holo-eIF3 complex or requires a free eIF3c subunit, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No co-crystal or cryo-EM structure of eIF3c bound to a pyrimidine-rich RNA element\",\n        \"Whether eIF3c mRNA-selective function is modulated by post-translational modification unknown\",\n        \"Role of intrinsically disordered NTD region (residues 166–266) in mRNA selectivity not functionally tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 4, 11]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006412\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"eIF3\",\n      \"43S pre-initiation complex\"\n    ],\n    \"partners\": [\n      \"RACK1\",\n      \"EIF4G1\",\n      \"EIF1\",\n      \"EIF5\",\n      \"EIF3D\",\n      \"EIF3E\",\n      \"NF2\",\n      \"YTHDF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EIF3C encodes a core scaffold subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that is essential for pre-initiation complex (PIC) assembly, mRNA recruitment, and both global and transcript-selective translation. Its N-terminal domain anchors eIF1 (via 3c1/3c2 subdomains) and eIF5 (via 3c0) to the scanning PIC, coordinating start-codon recognition and eIF1 release, while its C-terminal PCI domain bridges eIF3 to the 40S ribosomal subunit through direct contacts with RACK1/ASC1 and non-specific RNA binding [PMID:28297669, PMID:22123745]. eIF4G docks onto eIF3 at a surface composed of eIF3c, eIF3d, and eIF3e to recruit mRNA, and eIF3 exhibits transcript-selective translational control by recognizing pyrimidine-rich 5′-UTR motifs — notably in Ptch1 — thereby coupling eIF3c to Sonic Hedgehog signaling and limb patterning in vivo [PMID:24092755, PMID:34752747, PMID:21292980]. EIF3C mRNA is itself a target of m6A-dependent translational amplification via YTHDF1 and WTAP, and EIF3C depletion reduces global protein synthesis, arrests the cell cycle, and triggers apoptosis in multiple cancer models [PMID:31996915, PMID:35650605, PMID:23623922].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"An early interaction screen linked eIF3c to the NF2 tumor suppressor merlin, raising the question of whether eIF3c has functions beyond core translation — specifically in growth-suppressive signaling.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown and cell proliferation assays in meningioma-derived cells\",\n      \"pmids\": [\"16497727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single co-IP without reciprocal validation or structural mapping of the interaction interface\",\n        \"Functional consequence of merlin–eIF3c binding on translation not directly measured\",\n        \"Not independently reproduced\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies established eIF3c's dual role in ribosome bridging and developmental signaling: its PCI domain was shown to directly contact RACK1/ASC1 on the 40S head and to bind RNA, while mouse loss-of-function alleles revealed a specific requirement for eIF3c in SHH/GLI3-dependent limb patterning.\",\n      \"evidence\": \"Yeast mutant genetics with sedimentation and RNA-binding assays (PCI domain); mouse forward genetics with in situ hybridization and Gli3 processing analysis (developmental role)\",\n      \"pmids\": [\"22123745\", \"21292980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of PCI–RACK1 interface at atomic resolution not yet determined\",\n        \"Whether the limb phenotype reflects global or transcript-selective translation was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two advances defined eIF3c's role in mRNA recruitment and global translation: eIF4G was shown to bind eIF3 through a surface shared by eIF3c/d/e, and eIF3c knockdown in cancer cells caused polysome run-off and cell cycle arrest, confirming eIF3c is rate-limiting for translation initiation in mammalian cells.\",\n      \"evidence\": \"Site-specific cross-linking and fluorescence anisotropy for eIF4G–eIF3 interaction; siRNA knockdown with polysome profiling and flow cytometry in multiple cancer lines\",\n      \"pmids\": [\"24092755\", \"23623922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the eIF4G–eIF3c/d/e interface was lacking\",\n        \"Relative contribution of eIF3c versus other subunits to the eIF4G docking site not dissected\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"NMR/crystallography resolved the tripartite architecture of the eIF3c N-terminal domain (3c0/3c1/3c2), revealing how eIF1 and eIF5 are positioned during scanning and how their coordinated release at the start codon is governed by competitive binding at the 3c0 subdomain.\",\n      \"evidence\": \"NMR and X-ray crystallography combined with yeast start-codon recognition assays and mutagenesis\",\n      \"pmids\": [\"28297669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full PIC-context cryo-EM showing all three subdomains simultaneously was not available\",\n        \"Dynamics of 3c0-mediated eIF1 release during scanning not captured in real time\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cancer biology studies showed that eIF3c depletion suppresses tumorigenicity in hepatocellular and breast carcinoma, connecting eIF3c levels to KRAS/VEGF/Hedgehog and mTOR pathway activity and establishing eIF3c as a proliferation-promoting factor in multiple tumor types.\",\n      \"evidence\": \"shRNA/siRNA knockdown with xenograft assays, GSEA pathway analysis, phospho-protein arrays\",\n      \"pmids\": [\"28231410\", \"28854163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct translational targets mediating these signaling effects were not identified\",\n        \"Pathway activation inferred from GSEA and phospho-arrays rather than direct biochemical reconstitution\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An unexpected non-canonical function was described: EIF3C overexpression increased extracellular exosome secretion and promoted tumor angiogenesis via S100A11, suggesting eIF3c influences vesicle biogenesis or cargo loading.\",\n      \"evidence\": \"EIF3C overexpression with exosome quantification (EM, NTA), HUVEC tube formation, and GW4869 inhibitor rescue\",\n      \"pmids\": [\"29568350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which a translation factor alters exosome biogenesis is unexplained\",\n        \"Whether effect is direct or secondary to translational upregulation of vesicle-pathway components is untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies addressed how EIF3C itself is regulated and how its abundance sets translational capacity: YTHDF1 was shown to bind m6A-modified EIF3C mRNA and boost its translation (not transcription), while eIF3c overexpression in engineered cells enhanced both cap- and IRES-dependent protein synthesis and c-Myc expression.\",\n      \"evidence\": \"Multi-omics (m6A-seq, ribosome profiling, proteomics) with YTHDF1 manipulation in ovarian cancer; stable overexpression in CHOK1/HEK293 with global synthesis measurement\",\n      \"pmids\": [\"31996915\", \"32061967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether eIF3c is the primary or sole translation-relevant target of YTHDF1 was not determined\",\n        \"Structural basis for m6A-mediated enhancement of EIF3C translation unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A landmark study resolved the long-standing question of transcript selectivity: eCLIP-seq and ribosome profiling in Eif3c-mutant mouse embryos demonstrated that eIF3 binds pyrimidine-rich 5′-UTR motifs and selectively promotes translation of Ptch1, mechanistically explaining the Hedgehog-pathway phenotypes seen in eIF3c mutants.\",\n      \"evidence\": \"Conditional Eif3c knockout mice, eCLIP-seq, ribosome profiling, quantitative translation analysis\",\n      \"pmids\": [\"34752747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full repertoire of eIF3c-dependent transcripts beyond Ptch1 not comprehensively validated\",\n        \"Whether the pyrimidine-rich motif is sufficient for eIF3-dependent regulation in reporter assays was not shown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An upstream epitranscriptomic circuit was delineated: circPDE5A sequesters the m6A writer WTAP, reducing m6A on EIF3C mRNA and thereby lowering EIF3C protein levels; this axis inactivates MAPK signaling and suppresses prostate cancer metastasis, establishing a circRNA–m6A–EIF3C regulatory pathway.\",\n      \"evidence\": \"RNA pulldown with mass spectrometry, MeRIP-seq, RIP, dual-luciferase reporters, in vivo functional assays\",\n      \"pmids\": [\"35650605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional m6A writers besides WTAP contribute to EIF3C methylation not addressed\",\n        \"MAPK pathway activation attributed to EIF3C but direct translational targets linking EIF3C to MAPK are unidentified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the full catalog of eIF3c-dependent selectively translated mRNAs in different tissues, the structural basis of the intrinsically disordered eIF1-binding region during scanning in a full PIC context, and whether eIF3c's effects on exosome biogenesis and non-translational pathways reflect direct functions or indirect consequences of altered translational output.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Comprehensive translatome analysis across tissues is lacking\",\n        \"Cryo-EM of full PIC with eIF3c NTD resolved in scanning versus closed conformations not yet achieved\",\n        \"Direct versus indirect role in exosome secretion remains untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 4, 9, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 14]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 4, 9, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 10, 11]}\n    ],\n    \"complexes\": [\n      \"eIF3\",\n      \"43S pre-initiation complex\"\n    ],\n    \"partners\": [\n      \"EIF1\",\n      \"EIF5\",\n      \"EIF4G1\",\n      \"RACK1\",\n      \"EIF3D\",\n      \"EIF3E\",\n      \"NF2\",\n      \"EIF3I\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}