Affinage

EIF3G

Eukaryotic translation initiation factor 3 subunit G · UniProt O75821

Length
320 aa
Mass
35.6 kDa
Annotated
2026-06-09
16 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3G is a core subunit of the eIF3 translation initiation complex that is essential for cap-dependent protein synthesis and contributes to transcript-selective and non-canonical translation through its RNA recognition motif (RRM) (PMID:20679478, PMID:10887144). Within the 40S preinitiation complex it positions near the mRNA entry channel, interacting with ribosomal proteins Rps3 and Rps20, and its RRM is required for post-termination scanning and reinitiation, promoting processive scanning through structured 5' regions in yeast (PMID:20679478). The RRM confers sequence-specific RNA binding, with a preference for GUCG-centered motifs in 5'-terminal coding regions that drive transcript-specific translational induction of heat-stress-responsive mRNAs in concert with eIF3i (PMID:41556339). EIF3G also enables specialized and non-canonical translation modes: it binds SLIP1 through a defined SLIP1-binding motif, linking histone mRNA machinery to initiation factors (PMID:23804756), and forms a direct bridge to the EJC component eIF4A3 to license internal ribosome entry and translation of circular RNAs (PMID:37811880). Its RRM is co-opted by SARS-CoV-2 Nsp1, where a surface above the mRNA-binding channel is sufficient, together with 40S subunits, to endonucleolytically cleave host mRNAs (PMID:37821106). During apoptosis, caspase cleavage at SLRD220G releases an N-terminal EIF3G fragment that translocates to the nucleus, activates caspase-3, and exhibits DNase activity, coupling translational regulation to cell death (PMID:24080033).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 Medium

    Established that EIF3G is functionally required for translation, not merely a passive complex subunit, by showing its depletion abolishes cell-free protein synthesis.

    Evidence Yeast two-hybrid, in vitro binding, co-IP, and immunodepletion of reticulocyte translation system identifying cytoskeletal protein 4.1R as a direct partner

    PMID:10887144

    Open questions at the time
    • Functional consequence of the 4.1R interaction for translation not defined
    • Single-lab interaction mapping without structural validation
  2. 2006 Medium

    Linked EIF3G to apoptotic translational shutdown by showing AIF binds its N-terminus, inhibits translation, and triggers caspase-7-dependent cleavage.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, confocal microscopy, and in vitro translation inhibition assay

    PMID:17094969

    Open questions at the time
    • Physiological context of AIF–eIF3G regulation in vivo not established
    • Fate and function of cleaved eIF3G not addressed here
  3. 2010 High

    Defined the RRM's role in scanning and reinitiation and placed eIF3g near the mRNA entry channel through contacts with Rps3 and Rps20, providing a structural rationale for its function in start-codon traversal.

    Evidence In vivo mutagenesis, GCN4-lacZ reporters, ribosome sedimentation, and co-IP in S. cerevisiae

    PMID:20679478

    Open questions at the time
    • Direct RNA target of the RRM during scanning not yet identified
    • Generalizability beyond GCN4 reinitiation unresolved at this stage
  4. 2010 Medium

    Connected EIF3G to mRNA surveillance and cytoskeletal localization by identifying PELO as a direct partner localizing to actin filaments.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, and BiFC with domain mapping

    PMID:20406461

    Open questions at the time
    • Functional output of the PELO–eIF3G complex not determined
    • Significance of actin-filament localization unclear
  5. 2013 High

    Identified a discrete SLIP1-binding motif in eIF3g, providing a molecular route to couple histone mRNA machinery to translation initiation.

    Evidence Crystal structures of SLIP1 with an SBM peptide plus GST pull-down

    PMID:23804756

    Open questions at the time
    • Direct structure of the eIF3g SBM bound to SLIP1 not solved (peptide from related protein used)
    • Functional impact on histone mRNA translation not measured here
  6. 2013 Medium

    Revealed a moonlighting pro-apoptotic activity: caspase cleavage at SLRD220G generates a nuclear N-terminal fragment with DNase activity that activates caspase-3.

    Evidence Cleavage-site mapping by mutagenesis, nuclear translocation assays, and DNase activity assays in T24 cells

    PMID:24080033

    Open questions at the time
    • Mechanism of DNase activity by an initiation factor fragment unexplained
    • Single-lab finding without reciprocal confirmation
  7. 2016 Low

    Reported a nuclear interactome of eIF3g in breast cancer cells, raising the possibility of nuclear roles beyond cytoplasmic translation.

    Evidence Nuclear co-IP, mass spectrometry, cross-linking, GST pull-down, and confocal co-localization

    PMID:26935993

    Open questions at the time
    • Descriptive interactome with no functional consequence established
    • Single-lab, low-confidence observations not independently validated
  8. 2023 High

    Showed EIF3G bridges the EJC to eIF3, enabling internal ribosome entry and translation of circular RNAs.

    Evidence Reciprocal co-IP, in vitro circRNA translation, polysomal fractionation, and transcriptome-wide ribosome association

    PMID:37811880

    Open questions at the time
    • Structural basis of the eIF4A3–eIF3g bridge not resolved
    • Scope of circRNAs dependent on this interaction not fully mapped
  9. 2023 High

    Defined the EIF3G RRM as the catalytic determinant co-opted by SARS-CoV-2 Nsp1 for host mRNA cleavage, with a minimal 40S+RRM system sufficient for cleavage.

    Evidence In vitro reconstitution with minimal components and mutational mapping of a surface above the mRNA-binding channel

    PMID:37821106

    Open questions at the time
    • Whether the RRM surface is intrinsically nucleolytic or requires Nsp1 catalysis unresolved
    • Endogenous (non-viral) function of this RRM surface not addressed
  10. 2026 High

    Established that eIF3g directly reads GUCG-centered motifs in 5'-coding regions to drive transcript-specific translational induction under heat stress, defining a sequence-specific mRNA selection function.

    Evidence SELEX, biolayer interferometry, ribosome profiling, reporter assays, and mutagenesis in yeast

    PMID:41556339

    Open questions at the time
    • Whether GUCG-motif recognition operates in mammalian cells not tested
    • Mechanism coupling motif binding to enhanced initiation not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same RRM domain reconciles sequence-specific mRNA selection, scanning/reinitiation, circRNA IRES function, and viral-coopted endonucleolytic cleavage within the intact 40S–eIF3 complex remains unresolved.
  • No unified structural model of the eIF3g RRM engaging different RNA classes
  • Relationship between yeast scanning role and mammalian motif-recognition role unclear
  • Endogenous physiological substrates of the RRM cleavage surface unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 4 GO:0003723 RNA binding 3 GO:0060090 molecular adaptor activity 2 GO:0140097 catalytic activity, acting on DNA 1 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005840 ribosome 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953854 Metabolism of RNA 2
Complex memberships
eIF3

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 The RNA recognition motif (RRM) of yeast eIF3g/Tif35 is required for resumption of scanning by post-termination 40S ribosomes after uORF1 in GCN4 mRNA, and a triple-Ala substitution of conserved RRM residues (g/tif35-KLF) impairs reinitiation at GCN4, reduces processivity of scanning through stable mRNA secondary structures, and eIF3g specifically interacts with ribosomal proteins Rps3 and Rps20 near the mRNA entry channel. In vivo mutagenesis, growth assays, GCN4-lacZ reporter assays, ribosome sedimentation, and co-immunoprecipitation with ribosomal proteins in S. cerevisiae Molecular and cellular biology High 20679478
2013 eIF3g contains a SLIP1-binding motif (SBM) that allows direct physical interaction with the MIF4G-like protein SLIP1, which bridges SLBP with translation initiation factors; the interaction was confirmed by pull-down assay and a 3.25 Å crystal structure of SLIP1 bound to an SBM-containing peptide from a related protein (DBP5). Crystal structure determination (2.5 Å and 3.25 Å), GST pull-down assay Nucleic acids research High 23804756
2023 eIF3g directly interacts with eIF4A3 (a core EJC component), and this eIF4A3–eIF3g interaction acts as a molecular linker between the EJC and the eIF3 complex to facilitate internal ribosomal entry and translation of circular RNAs; disruption of this interaction abolishes eIF4A3-driven internal translation from in vitro-synthesized circRNA. Co-immunoprecipitation, in vitro circRNA translation assay, polysomal fractionation, transcriptome-wide ribosome association analysis Nucleic acids research High 37811880
2006 Apoptosis-inducing factor (AIF) directly interacts with the N-terminus of eIF3g (via AIF's C-terminal region), inhibits protein synthesis in vitro, and this inhibition is competitively blocked by excess eIF3g; AIF overexpression also activates caspase-7 leading to cleavage of eIF3g. Yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, confocal microscopy, in vitro TNT transcription-translation inhibition assay, cell-based overexpression FEBS letters Medium 17094969
2000 Cytoskeletal protein 4.1R directly binds eIF3g (eIF3-p44) via its C-terminal domain (residues 525–622) interacting with eIF3g residues 54–321; depletion of eIF3g from reticulocyte lysates (by antibody or GST/4.1R fusion) severely impairs cell-free protein synthesis, demonstrating that eIF3g is essential for translation. Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, immunodepletion of cell-free translation system Blood Medium 10887144
2023 In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage demonstrated that the RRM domain of eIF3g is essential for cleavage: a minimal system of 40S subunits plus eIF3g's RRM domain was sufficient for CrPV IRES mRNA cleavage; mutational analysis identified a surface above the mRNA-binding channel on eIF3g's RRM domain with residues critical for cleavage across all tested mRNA types. In vitro reconstitution, mutational analysis, minimal-component cleavage assay with 40S subunits and isolated eIF3g RRM domain Genes & development High 37821106
2013 During apoptosis induced by cisplatin, caspase activity cleaves eIF3g at SLRD(220)G; the resulting N-terminal fragment translocates to the nucleus, activates caspase-3, and exhibits strong DNase activity. Caspase cleavage site mapping by mutagenesis, subcellular fractionation/nuclear translocation assay, DNase activity assay in T24 cells FEBS letters Medium 24080033
2010 PELO (Pelota) directly interacts with eIF3g; the interaction domain was mapped to PELO residues 268–385; protein complexes formed by PELO and eIF3g localize to actin cytoskeletal filaments as shown by bimolecular fluorescence complementation. Yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) BMC cell biology Medium 20406461
2016 eIF3g is present in the nucleus of breast cancer cells and interacts there with hnRNP U/SAF-A, ZNF823, and β-actin, as identified by nuclear co-immunoprecipitation, mass spectrometry, cross-linking, GST pull-down, and confocal co-localization. Nuclear co-immunoprecipitation, mass spectrometry, GST pull-down, confocal microscopy Molecular medicine reports Low 26935993
2026 eIF3g (and its binding partner eIF3i) mediates transcript-specific translational induction under mild heat stress in yeast by directly binding GUCG-centered motifs (GUCG boxes) located in the 5'-terminal coding regions of heat-stress-responsive mRNAs; SELEX identified the GUCG motif as the preferred eIF3g-binding sequence, biolayer interferometry confirmed direct binding, and disruption of the motif impairs both eIF3g binding and translational induction in reporter assays. SELEX, ribosome profiling, reporter assays, mutational analysis, biolayer interferometry Nucleic acids research High 41556339
2025 Loss-of-function mutations in eIF3g (and eIF3i) in S. cerevisiae cause a similar reduction in translation of GFP reporters regardless of 5' UTR length (short vs. long unstructured UTRs), consistent with a role in ribosome recruitment or start-codon recognition rather than rate-limiting helicase-driven scanning; mutations in eIF3g did not specifically sensitize translation to 5' UTR secondary structures compared to helicase mutants. GFP reporter assays with variable-length 5' UTRs in S. cerevisiae, loss-of-function mutations, comparison with helicase mutants (eIF4A, Ded1) bioRxivpreprint Low bio_10.1101_2024.12.30.630811

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The RNA recognition motif of eukaryotic translation initiation factor 3g (eIF3g) is required for resumption of scanning of posttermination ribosomes for reinitiation on GCN4 and together with eIF3i stimulates linear scanning. Molecular and cellular biology 93 20679478
2013 Structural and biochemical studies of SLIP1-SLBP identify DBP5 and eIF3g as SLIP1-binding proteins. Nucleic acids research 32 23804756
2023 An interaction between eIF4A3 and eIF3g drives the internal initiation of translation. Nucleic acids research 31 37811880
2006 Apoptosis-inducing factor (AIF) inhibits protein synthesis by interacting with the eukaryotic translation initiation factor 3 subunit p44 (eIF3g). FEBS letters 28 17094969
2000 Protein 4.1R binding to eIF3-p44 suggests an interaction between the cytoskeletal network and the translation apparatus. Blood 28 10887144
2010 Pelota interacts with HAX1, EIF3G and SRPX and the resulting protein complexes are associated with the actin cytoskeleton. BMC cell biology 24 20406461
2015 EIF3G is associated with narcolepsy across ethnicities. European journal of human genetics : EJHG 21 25669430
2023 In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g. Genes & development 19 37821106
2021 Long non-coding RNA LINC02446 suppresses the proliferation and metastasis of bladder cancer cells by binding with EIF3G and regulating the mTOR signalling pathway. Cancer gene therapy 17 33526846
2016 Nuclear distribution of eIF3g and its interacting nuclear proteins in breast cancer cells. Molecular medicine reports 12 26935993
2013 Caspase-mediated cleavage and DNase activity of the translation initiation factor 3, subunit G (eIF3g). FEBS letters 10 24080033
2018 Eukaryotic translation initiation factor 3 subunit G (EIF3G) resensitized HCT116/5-Fu to 5-fluorouracil (5-Fu) via inhibition of MRP and MDR1. OncoTargets and therapy 4 30214237
2023 In vitro reconstitution of SARS CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g. bioRxiv : the preprint server for biology 2 37292671
2026 eIF3g binding to GUCG boxes located in mRNA coding regions enhances translation of mild heat shock response genes in the yeast Saccharomyces cerevisiae. Nucleic acids research 0 41556339
2011 [Construction and application of inducible artificial microRNA expression vector targeting eIF3g gene]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 21315039
2007 [Expression of (His)(6)-eIF3s4 fusion protein in human breast cancer cell Bcap37]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 17618584

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