Affinage

EIF3C

Eukaryotic translation initiation factor 3 subunit C · UniProt Q99613

Round 2 corrected
Length
913 aa
Mass
105.3 kDa
Annotated
2026-04-28
54 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 Medium

    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

    PMID:16497727

    Open questions at the time
    • 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
  2. 2011 High

    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)

    PMID:21292980 PMID:22123745

    Open questions at the time
    • Structural basis of PCI–RACK1 interface at atomic resolution not yet determined
    • Whether the limb phenotype reflects global or transcript-selective translation was unresolved
  3. 2013 High

    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

    PMID:23623922 PMID:24092755

    Open questions at the time
    • 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
  4. 2017 High

    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

    PMID:28297669

    Open questions at the time
    • 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
  5. 2017 Medium

    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

    PMID:28231410 PMID:28854163

    Open questions at the time
    • Direct translational targets mediating these signaling effects were not identified
    • Pathway activation inferred from GSEA and phospho-arrays rather than direct biochemical reconstitution
  6. 2018 Medium

    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

    PMID:29568350

    Open questions at the time
    • 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
  7. 2020 High

    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

    PMID:31996915 PMID:32061967

    Open questions at the time
    • 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
  8. 2021 High

    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

    PMID:34752747

    Open questions at the time
    • 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
  9. 2022 High

    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

    PMID:35650605

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 4 GO:0005198 structural molecule activity 3 GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 2 GO:0005840 ribosome 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
EIF1EIF3DEIF3EEIF3IEIF4G1EIF5NF2RACK1
Complex memberships
43S pre-initiation complexeIF3

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. Fluorescence anisotropy, site-specific cross-linking, eIF4G-dependent translation assay The Journal of biological chemistry High 24092755
2011 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. Yeast genetics (lethal/slow-growth mutants), in vivo sedimentation, co-immunoprecipitation, RNA-binding assays Nucleic acids research High 22123745
2017 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. NMR, X-ray crystallography, biochemical binding assays, yeast genetics (start codon recognition assays) Cell reports High 28297669
2006 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. Co-immunoprecipitation/pulldown (interaction identification), cell proliferation assays, immunohistochemistry of meningiomas Human molecular genetics Medium 16497727
2013 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. RNAi knockdown, polysome profiling, cell cycle analysis by flow cytometry, MTT proliferation assay Cancer letters Medium 23623922
2017 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. shRNA knockdown, xenograft tumor assay, GSEA pathway analysis Cancer science Medium 28231410
2017 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. siRNA knockdown, BrdU incorporation, colony formation, flow cytometry apoptosis assay, phospho-protein antibody array, western blotting Medical science monitor Medium 28854163
2018 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. EIF3C overexpression, exosome quantification (EM, NTA, PKH26 labeling), HUVEC tube formation assay, plug assay in nude mice, GW4869 inhibitor rescue Oncotarget Medium 29568350
2011 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. Mouse forward genetics, in situ hybridization, Gli3 processing western blot, haploinsufficiency analysis FASEB journal High 21292980
2021 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. Eif3c knockout mice, eCLIP-seq, ribosome profiling, quantitative translation analysis Developmental cell High 34752747
2020 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. Multi-omics (m6A-seq, ribosome profiling, proteomics), m6A-RIP, YTHDF1 knockdown/overexpression, translation reporter assays Nucleic acids research High 31996915
2022 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. RNA pulldown with mass spectrometry, RIP, MeRIP-seq (m6A-seq), ChIP, dual-luciferase reporter, in vitro/in vivo functional assays Journal of experimental & clinical cancer research High 35650605
2021 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. Gene expression profiling, siRNA/shRNA knockdown, overexpression rescue experiments, in vitro and in vivo tumor assays Cell death & disease Medium 33414445
2023 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. RNA sequencing, siRNA knockdown, wound-healing/transwell migration assay, ELISA for cytokines Journal of translational medicine Medium 37996918
2020 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. Stable overexpression in CHOK1/HEK293 cells, global protein synthesis rate measurement, recombinant reporter protein assay, western blotting for c-Myc Metabolic engineering Medium 32061967
2025 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. NMR spectroscopy (backbone/side-chain assignments, CSI analysis, CSTC analysis) bioRxivpreprint Medium bio_10.1101_2025.09.13.675972

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 946 16286006
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science (New York, N.Y.) 653 32680882
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2020 The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic acids research 587 31996915
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2013 Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome. The Journal of biological chemistry 133 24092755
2018 Overexpressed circ_0067934 acts as an oncogene to facilitate cervical cancer progression via the miR-545/EIF3C axis. Journal of cellular physiology 95 30362562
2011 The eIF3c/NIP1 PCI domain interacts with RNA and RACK1/ASC1 and promotes assembly of translation preinitiation complexes. Nucleic acids research 63 22123745
2022 circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA. Journal of experimental & clinical cancer research : CR 58 35650605
2017 Molecular Landscape of the Ribosome Pre-initiation Complex during mRNA Scanning: Structural Role for eIF3c and Its Control by eIF5. Cell reports 58 28297669
2018 EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma. Oncotarget 49 29568350
2006 Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c). Human molecular genetics 39 16497727
2017 Transcriptomic analyses of RNA-binding proteins reveal eIF3c promotes cell proliferation in hepatocellular carcinoma. Cancer science 35 28231410
2013 eIF3c: a potential therapeutic target for cancer. Cancer letters 31 23623922
2013 Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells. Journal of Zhejiang University. Science. B 27 23733421
2020 Engineered transient and stable overexpression of translation factors eIF3i and eIF3c in CHOK1 and HEK293 cells gives enhanced cell growth associated with increased c-Myc expression and increased recombinant protein synthesis. Metabolic engineering 26 32061967
2020 New Pancreatic Cancer Biomarkers eIF1, eIF2D, eIF3C and eIF6 Play a Major Role in Translational Control in Ductal Adenocarcinoma. Anticancer research 25 32487605
2017 Decreasing Eukaryotic Initiation Factor 3C (EIF3C) Suppresses Proliferation and Stimulates Apoptosis in Breast Cancer Cell Lines Through Mammalian Target of Rapamycin (mTOR) Pathway. Medical science monitor : international medical journal of experimental and clinical research 23 28854163
2021 ZNF280A promotes lung adenocarcinoma development by regulating the expression of EIF3C. Cell death & disease 22 33414445
2021 Controlling tissue patterning by translational regulation of signaling transcripts through the core translation factor eIF3c. Developmental cell 22 34752747
2023 Complement factor H attenuates TNF-α-induced inflammation by upregulating EIF3C in rheumatoid arthritis. Journal of translational medicine 19 37996918
2019 Upregulated expression of eIF3C is associated with malignant behavior in renal cell carcinoma. International journal of oncology 12 31638200
2011 The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 21292980
2022 EIF3C Promotes Lung Cancer Tumorigenesis by Regulating the APP/HSPA1A/LMNB1 Axis. Disease markers 7 36157221
2022 Targeting EIF3C to suppress the development and progression of nasopharyngeal carcinoma. Frontiers in bioengineering and biotechnology 6 36147539
2020 Knockdown EIF3C Suppresses Cell Proliferation and Increases Apoptosis in Pancreatic Cancer Cell. Dose-response : a publication of International Hormesis Society 6 32973416
2019 Knockdown of EIF3C promotes human U-2OS cells apoptosis through increased CASP3/7 and Chk1/2 by upregulating SAPK/JNK. OncoTargets and therapy 6 30863090
2025 Proteome of amino acids or IGF1-stimulated pacu muscle cells offers molecular insights and suggests FN1B and EIF3C as candidate markers of fish muscle growth. Biochemical and biophysical research communications 0 40107112