Affinage

EIF3C

Eukaryotic translation initiation factor 3 subunit C · UniProt Q99613

Length
913 aa
Mass
105.3 kDa
Annotated
2026-06-09
24 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3C (eIF3c/NIP1) is a core scaffold subunit of the eIF3 complex that drives translation initiation by organizing the assembly and function of the 43S/48S preinitiation complex (PIC) (PMID:28297669, PMID:23623922). Its C-terminal PCI domain forms an intermolecular bridge that tethers eIF3 to the 40S ribosomal head by contacting RACK1/ASC1 (and likely 18S rRNA), with PCI mutations or ASC1 loss reducing ribosome-associated eIF3 and eIF5 (PMID:22123745). Its N-terminal domain is partitioned into 3c0/3c1/3c2 subregions that coordinate start-codon fidelity: 3c0 binds eIF5 strongly and eIF1 weakly, 3c1 and 3c2 anchor eIF1 to the scanning PIC, and competing 3c0:eIF5 versus 3c0:eIF1 interactions stabilize scanning and then facilitate eIF1 release upon start-codon recognition (PMID:28297669). eIF3c additionally bridges the cap-binding machinery to the ribosome through a surface formed with eIF3d and eIF3e that engages two subdomains of eIF4G required for mRNA recruitment (PMID:24092755). Beyond its general role, eIF3 binds a pyrimidine-rich 5'-UTR motif and selectively promotes translation of specific developmental signaling transcripts including Ptch1; loss of Eif3c disrupts Shh/Gli3-mediated tissue patterning, and global knockdown causes polysome run-off, cell-cycle arrest, and apoptosis (PMID:34752747, PMID:23623922, PMID:21292980). EIF3C is itself controlled at the translational level by m6A: the reader YTHDF1 binds m6A-modified EIF3C mRNA to augment its translation, while a circPDE5A–WTAP interaction limits WTAP-dependent m6A methylation of EIF3C (PMID:31996915, PMID:35650605).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2006 Medium

    Established the first functional link of eIF3c to growth control by showing the NF2 tumor suppressor merlin acts on it, framing eIF3c as a translation node relevant to proliferation.

    Evidence Protein interaction pulldown/Co-IP with merlin plus cellular proliferation assays

    PMID:16497727

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • No mapping of the merlin-binding region on eIF3c
    • Mechanistic link to translation inferred, not demonstrated
  2. 2011 High

    Defined how eIF3c physically anchors the entire eIF3 complex to the small ribosomal subunit, answering how eIF3 docks onto the 40S head.

    Evidence Yeast in vivo ribosome fractionation, PCI-domain mutagenesis, ASC1 deletion genetics, and RNA binding assays

    PMID:22123745

    Open questions at the time
    • RNA binding by the PCI domain is nonspecific
    • Direct 18S rRNA contact inferred
    • Human ortholog interaction not directly tested here
  3. 2011 Medium

    Placed eIF3c genetically upstream of SHH/GLI3 signaling, the first in vivo evidence that eIF3c shapes a specific developmental pathway rather than only bulk translation.

    Evidence Two independent mouse loss-of-function alleles with in situ hybridization of Shh, Ptch1, and Gli3

    PMID:21292980

    Open questions at the time
    • Mechanism of pathway control inferred, not biochemically defined
    • Whether the effect is direct on specific transcripts not yet shown
  4. 2013 Medium

    Demonstrated that eIF3c is required for global translation initiation, converting the genetic and interaction data into a direct ribosomal function.

    Evidence siRNA knockdown with polysome profiling, cell-cycle analysis, and viability assays across cancer cell lines

    PMID:23623922

    Open questions at the time
    • Cell-cycle arrest phase is cell-type dependent
    • Does not separate scaffold versus regulatory contributions
  5. 2013 High

    Identified how the cap-binding machinery is bridged to eIF3, showing eIF3c (with eIF3d/e) provides the eIF4G docking surface needed for mRNA recruitment.

    Evidence Site-specific cross-linking, fluorescence anisotropy, and eIF4G-dependent translation assay

    PMID:24092755

    Open questions at the time
    • Relative contributions of eIF3c versus eIF3d/e not resolved
    • Structural detail of the contact not defined
  6. 2017 High

    Resolved the domain logic of how eIF3c governs start-codon recognition by mapping 3c0/3c1/3c2 contacts with eIF1, eIF5, and the 40S.

    Evidence NMR, mutagenesis, and in vitro PIC assembly/scanning assays

    PMID:28297669

    Open questions at the time
    • Dynamics of the 3c0 eIF5/eIF1 switch in cells not directly observed
  7. 2020 High

    Showed EIF3C is itself controlled translationally, with the m6A reader YTHDF1 boosting EIF3C protein output to raise overall translation.

    Evidence m6A-seq, ribosome profiling, RIP, and YTHDF1 knockdown/overexpression in ovarian cancer cells

    PMID:31996915

    Open questions at the time
    • Specific m6A sites on EIF3C not pinpointed
    • Generality across tissues untested
  8. 2021 High

    Established that eIF3c confers transcript selectivity, binding a 5'-UTR pyrimidine-rich motif to preferentially translate developmental transcripts including Ptch1.

    Evidence Mouse loss-of-function genetics, eCLIP-seq, and ribosome profiling of embryos

    PMID:34752747

    Open questions at the time
    • Whether eIF3c subunit alone or whole eIF3 confers motif recognition
    • Full transcript set under this control not enumerated
  9. 2022 Medium

    Extended translational regulation of EIF3C upstream, showing a circPDE5A–WTAP complex limits WTAP-dependent m6A methylation of EIF3C mRNA.

    Evidence RNA pulldown with mass spectrometry, RIP, MeRIP-seq, and in vitro/in vivo prostate cancer assays

    PMID:35650605

    Open questions at the time
    • Single-lab study
    • Direct effect on EIF3C translation versus downstream MAPK output not fully separated
  10. 2025 Medium

    Began structural characterization of the eIF1-binding region, showing eIF3c residues 166–266 are intrinsically disordered with conserved FLKK motifs at transient structural junctions.

    Evidence Solution NMR backbone assignment of the human eIF3c 166–266 fragment (preprint)

    PMID:bio_10.1101_2025.09.13.675972

    Open questions at the time
    • Single preprint with no mutagenesis or binding validation
    • Functional role of FLKK motifs untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the cancer-associated phenotypes (mTOR/JNK signaling, exosome biogenesis, inflammatory responses) mechanistically connect to eIF3c's defined translation-scaffold activity remains unresolved.
  • Pathway links rest on knockdown phospho-array correlations without direct mechanism
  • No structural model of full-length eIF3c in the 48S PIC
  • Selectivity rules for motif-containing transcripts incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 2 GO:0005198 structural molecule activity 2
Localization
GO:0005840 ribosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 2
Partners
EIF1EIF3DEIF3EEIF4G1EIF5NF2RACK1YTHDF1
Complex memberships
43S/48S preinitiation complexeIF3 complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Human eIF4G binds to eIF3 through a surface comprised of eIF3c, eIF3d, and eIF3e subunits, identified by site-specific cross-linking. Two distinct eIF3-binding subdomains within eIF4G were identified, and both are required for efficient mRNA recruitment to the ribosome and stimulation of translation, as shown by a fluorescence anisotropy assay and an eIF4G-dependent translation assay. Site-specific cross-linking, fluorescence anisotropy, eIF4G-dependent translation assay The Journal of biological chemistry High 24092755
2011 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 shows strong but unspecific RNA binding. Mutations disrupting the PCI domain reduce 40S-bound eIF3 and eIF5 in vivo, and deletion of ASC1 similarly reduces eIF3 association with ribosomes, indicating that eIF3c forms an intermolecular bridge between eIF3 and the 40S head via RACK1/ASC1 and likely 18S rRNA. In vivo ribosome association assays, site-directed mutagenesis, genetic interaction (ASC1 deletion), RNA binding assays, yeast genetics 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 contacts eIF1 through Arg-53 and Leu-96; 3c2 faces 40S protein uS15/S13 to anchor eIF1 to the scanning pre-initiation complex (PIC). The 3c0:eIF5 interaction stabilizes the scanning PIC by precluding the inhibitory 3c0:eIF1 interaction, and upon start codon recognition, eIF5 interactions involving 3c0 facilitate eIF1 release. NMR, structural analysis, mutagenesis, in vitro binding assays, ribosome scanning assays Cell reports High 28297669
2006 The NF2 tumor suppressor schwannomin (merlin) directly interacts with eIF3c (p110 subunit). Schwannomin was most effective at inhibiting cellular proliferation when eIF3c was highly expressed, suggesting that schwannomin acts through eIF3c-mediated regulation of protein translation to suppress proliferation. Protein interaction screen (pulldown/co-immunoprecipitation), cellular proliferation assay, immunohistochemistry 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 in vivo, demonstrating that eIF3c is essential for translation initiation. Knockdown also causes G0/G1 or G2/M cell cycle arrest in a cell-type-dependent manner, leading to reduced proliferation and cell death. siRNA knockdown, polysome profiling, cell cycle analysis by flow cytometry, cell viability assays Cancer letters Medium 23623922
2021 Loss-of-function of Eif3c in mice causes sensitivity to Ptch1 dosage and disrupts Shh-mediated tissue patterning. Genome-wide eCLIP-seq shows eIF3 binds a pyrimidine-rich motif in subsets of 5'-UTRs; ribosome profiling in Eif3c loss-of-function embryos shows reduced translation of transcripts containing this motif, including Ptch1, demonstrating that eIF3c selectively controls translation of specific developmental signaling transcripts through their 5'-UTR pyrimidine-rich motifs. Mouse loss-of-function genetics, eCLIP-seq, ribosome profiling, in situ hybridization Developmental cell High 34752747
2011 Two Eif3c mutations (p.Arg303X and p.Leu568_Leu586del) in mouse cause a pleiotropic phenotype (anterior polydactyly, hypopigmentation) associated with ectopic Shh and Ptch1 expression and aberrant Gli3 processing in anterior limb buds, placing eIF3c upstream of SHH/GLI3 signaling in limb patterning. Mouse genetics (two Xs alleles), in situ hybridization, genetic mapping FASEB journal Medium 21292980
2020 The m6A reader YTHDF1 binds m6A-modified EIF3C mRNA and augments EIF3C translation in an m6A-dependent manner, thereby increasing overall translational output in ovarian cancer cells. Knockdown of YTHDF1 reduces EIF3C protein but not mRNA levels. m6A-seq, ribosome profiling, m6A-IP, RNA immunoprecipitation, YTHDF1 knockdown/overexpression, multi-omics Nucleic acids research High 31996915
2022 circPDE5A interacts with the m6A writer WTAP (verified by RNA pulldown and mass spectrometry, and RIP assays), forming a circPDE5A-WTAP complex that blocks WTAP-dependent m6A methylation of EIF3C mRNA, thereby reducing EIF3C translation. Loss of circPDE5A increases EIF3C expression and activates the MAPK pathway, promoting prostate cancer metastasis. RNA pulldown with mass spectrometry, RNA immunoprecipitation, MeRIP-seq, functional in vitro and in vivo assays Journal of experimental & clinical cancer research Medium 35650605
2017 EIF3C knockdown in breast cancer cells activates the mTOR signaling pathway and leads to reduced proliferation and increased apoptosis, with altered phosphorylation of mTOR pathway components detected by antibody array and western blot. siRNA knockdown, antibody phosphoprotein array, western blotting, flow cytometry, colony formation assay Medical science monitor Low 28854163
2019 EIF3C knockdown in osteosarcoma U-2OS cells leads to upregulation of CASP3/7, Chk1/2, and SAPK/JNK, indicating that eIF3c knockdown promotes apoptosis through the SAPK/JNK pathway. shRNA knockdown, PathScan antibody array, flow cytometry, MTT assay OncoTargets and therapy Low 30863090
2018 EIF3C overexpression in HCC cells increases secretion of extracellular exosomes (confirmed by fluorescent labeling, electron microscopy, nanoparticle tracking, and exosome markers) and activates S100A11 expression, promoting tumor angiogenesis via exosome-mediated tube formation; exosome inhibitor GW4869 reverses these effects. EIF3C overexpression, PKH26 exosome labeling, electron microscopy, nanoparticle tracking analysis, tube formation assay, in vivo plug assay, exosome inhibitor treatment Oncotarget Medium 29568350
2023 RNA-seq analysis identified EIF3C as a target upregulated by CFH in RA monocytes and FLS; EIF3C knockdown under CFH+TNF-α stimulation promoted FLS migration and enhanced IL-6, IL-8, and MMP-3 expression, indicating that CFH-induced EIF3C upregulation mediates anti-inflammatory and anti-migratory effects in RA synoviocytes. RNA sequencing, siRNA knockdown, wound healing assay, transwell assay, ELISA Journal of translational medicine Low 37996918
2025 NMR backbone assignments of human eIF3c residues 166–266 (immediately N-terminal to the PINT/PCI domain) show this region is intrinsically disordered in solution, with short segments of modest α-helical or β-strand propensity. Three conserved FLKK motifs are located at junctions of transient structural elements, with Motif 3 in the subsegment with slightly greater structural propensity. This fragment encompasses the reported eIF1-binding site. Solution NMR (1H-15N HSQC, chemical shift index, temperature coefficients) bioRxivpreprint Medium bio_10.1101_2025.09.13.675972

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic acids research 592 31996915
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 134 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 60 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 26 32487605
2021 Controlling tissue patterning by translational regulation of signaling transcripts through the core translation factor eIF3c. Developmental cell 23 34752747
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
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

Missed literature

Know a paper Affinage missed for EIF3C? Flag it for the maintainers and the community.

No submissions yet.