Affinage

EIF3G

Eukaryotic translation initiation factor 3 subunit G · UniProt O75821

Round 2 corrected
Length
320 aa
Mass
35.6 kDa
Annotated
2026-04-28
46 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3G is a subunit of the eukaryotic translation initiation factor 3 (eIF3) complex whose RNA recognition motif (RRM) domain mediates sequence-specific RNA binding to GUCG box motifs and is essential for processive mRNA scanning, reinitiation after upstream open reading frames, and stress-responsive translational regulation (PMID:20679478, PMID:41556339). EIF3G functions as a molecular scaffold at the mRNA entry channel through direct interactions with ribosomal proteins Rps3 and Rps20, and bridges specialized translation pathways by binding SLIP1 for histone mRNA translation and eIF4A3 for EJC-dependent circular RNA internal initiation (PMID:20679478, PMID:23804756, PMID:37811880). During apoptosis, caspase cleavage at SLRD(220)G generates an N-terminal fragment that translocates to the nucleus and exhibits DNase activity, contributing to apoptotic DNA degradation (PMID:24080033). The RRM domain is co-opted by SARS-CoV-2 Nsp1, where it constitutes the minimal eIF3 component required for endonucleolytic cleavage of host mRNAs on the 40S subunit (PMID:37821106).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 Medium

    Establishing that eIF3g is essential for translation initiation, not merely a peripheral eIF3 subunit, was addressed by showing that immunodepletion of eIF3g from reticulocyte lysates abolishes protein synthesis.

    Evidence Antibody and GST-fusion protein depletion of eIF3g from rabbit reticulocyte cell-free translation system; confirmed by Y2H and Co-IP with protein 4.1R

    PMID:10887144

    Open questions at the time
    • Functional relevance of the 4.1R–eIF3g interaction in intact erythroid cells remains unresolved
    • Mechanism by which eIF3g depletion blocks initiation not distinguished from loss of whole eIF3 complex
  2. 2006 Medium

    The question of whether eIF3g connects translation and apoptosis was answered by demonstrating that AIF binds eIF3g and caspase-7 cleaves it, inhibiting protein synthesis during cell death.

    Evidence Y2H, GST pull-down, Co-IP, in vitro translation inhibition assay with AIF overexpression in HeLa cells

    PMID:17094969

    Open questions at the time
    • Physiological stoichiometry of AIF–eIF3g interaction during apoptosis not determined
    • Single-lab finding without independent replication
  3. 2010 High

    Whether eIF3g's RRM domain has a direct mechanistic role in scanning and reinitiation was resolved by showing that RRM mutations impair post-termination scanning on GCN4 mRNA and that eIF3g contacts ribosomal proteins Rps3/Rps20 at the mRNA entry channel.

    Evidence Alanine-scanning mutagenesis of yeast Tif35 RRM, GCN4-lacZ reporter assays, polysome profiling, Co-IP in S. cerevisiae

    PMID:20679478

    Open questions at the time
    • Structural basis for eIF3g–Rps3/Rps20 interaction not resolved at atomic level
    • Whether the RRM directly contacts mRNA during scanning was not shown
  4. 2010 Medium

    Identification of PELO (Pelota) as a direct binding partner placed eIF3g at the interface of translation quality control and cytoskeletal localization.

    Evidence Y2H, GST pull-down, Co-IP, BiFC showing PELO–eIF3g complexes on actin filaments

    PMID:20406461

    Open questions at the time
    • Functional consequence of PELO–eIF3g interaction for no-go decay or ribosome rescue not tested
    • Cytoskeletal localization significance unexplored
  5. 2013 High

    How eIF3g connects to replication-dependent histone mRNA translation was clarified by identifying a SLIP1-binding motif (SBM) in eIF3g, providing a structural framework for the SLBP–SLIP1–eIF3 bridging pathway.

    Evidence Crystal structures (2.5 Å and 3.25 Å) of SLIP1 plus GST pull-down confirming eIF3g SBM interaction

    PMID:23804756

    Open questions at the time
    • No structure of the direct eIF3g SBM–SLIP1 complex
    • In vivo contribution to histone mRNA translation not directly measured
  6. 2013 Medium

    The precise caspase cleavage site in eIF3g and the fate of the resulting fragment were defined: cleavage at SLRD(220)G produces an N-terminal fragment that enters the nucleus and possesses DNase activity, establishing a non-canonical apoptotic effector function.

    Evidence Site-directed mutagenesis, subcellular fractionation, DNase and caspase-3 activation assays after cisplatin treatment

    PMID:24080033

    Open questions at the time
    • DNase activity of the fragment has not been reconstituted with purified protein
    • Whether nuclear eIF3g fragment contributes to apoptotic DNA laddering in vivo is untested
  7. 2023 Medium

    The mechanism by which exon junction complexes drive circular RNA translation was elucidated by showing that eIF4A3 directly binds eIF3g, forming the molecular bridge between the EJC and eIF3 that enables internal initiation on circRNAs including endogenous circβ-catenin.

    Evidence Co-IP, in vitro circRNA translation, polysome profiling, RIP-seq in human cells

    PMID:37811880

    Open questions at the time
    • Structural details of the eIF4A3–eIF3g interface are unknown
    • Whether this bridge functions on linear mRNAs with EJCs remains untested
  8. 2023 High

    The minimal host machinery hijacked by SARS-CoV-2 Nsp1 for endonucleolytic mRNA cleavage was defined: the eIF3g RRM domain plus the 40S subunit suffices, with a positively charged RRM surface essential for cleavage 18 nt downstream of the mRNA entrance.

    Evidence In vitro reconstitution with purified 40S, eIF3g RRM, and Nsp1; mutational analysis; toe-printing to map cleavage site

    PMID:37821106

    Open questions at the time
    • Whether other eIF3 subunits modulate cleavage efficiency in vivo is unresolved
    • Structural basis for the eIF3g RRM–Nsp1 functional interaction not yet determined at atomic resolution
  9. 2026 High

    The RNA sequence specificity of eIF3g was defined by SELEX identification of the GUCG box motif, and its physiological relevance was demonstrated by showing that GUCG elements in 5′ coding regions drive eIF3g/eIF3i-dependent translational induction under heat stress.

    Evidence SELEX, ribosome profiling of eIF3i mutants, biolayer interferometry binding assays, reporter mutagenesis in S. cerevisiae

    PMID:41556339

    Open questions at the time
    • Whether GUCG-dependent regulation occurs in mammalian cells is unknown
    • Structural basis for GUCG recognition by the eIF3g RRM not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of eIF3g's RRM bound to its GUCG RNA target, the in vivo significance of the nuclear DNase fragment during apoptosis, and whether eIF3g's scaffolding and RNA-binding functions are independently regulated under different cellular stresses.
  • No high-resolution structure of eIF3g RRM–GUCG RNA complex
  • Relative contribution of eIF3g's scanning-stimulatory vs. sequence-specific RNA-binding functions to gene-specific translational control is unclear
  • Nuclear functions of eIF3g beyond the apoptotic fragment remain poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0005198 structural molecule activity 3 GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005840 ribosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1643685 Disease 1
Partners
AIFEIF3IEIF4A3EPB41PELORPS20RPS3SLIP1
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 for reinitiation on GCN4 mRNA downstream of uORF1. A triple-Ala substitution of conserved RRM residues (g/tif35-KLF) reduces processivity of scanning through stable secondary structures and impairs GCN4 induction. eIF3g specifically interacts with ribosomal proteins Rps3 and Rps20 located near the mRNA entry channel. Yeast genetics (alanine-scanning mutagenesis), in vivo translation assays, polysome profiling, GCN4-lacZ reporter assays, co-immunoprecipitation Molecular and cellular biology High 20679478
2013 eIF3g contains a SLIP1-binding motif (SBM) that mediates direct interaction with SLIP1, a MIF4G-like protein that bridges SLBP to translation initiation factors. The interaction was confirmed by pull-down assays and the crystal structure of SLIP1 bound to the DBP5 SBM (3.25 Å) provided structural context for SBM recognition. Crystal structure (2.5 Å and 3.25 Å), GST pull-down assays Nucleic acids research High 23804756
2006 Apoptosis-inducing factor (AIF) directly interacts with eIF3g (p44) via its C-terminal region binding the eIF3g N-terminus, and this interaction inhibits protein synthesis in vitro. Mature AIF overexpression activates caspase-7, which cleaves eIF3g, amplifying translational inhibition during apoptosis. Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, confocal microscopy, in vitro TNT transcription-translation assay, competitive inhibition assay FEBS letters Medium 17094969
2000 Erythroid protein 4.1R directly associates with eIF3g (eIF3-p44) via its C-terminal domain (residues 525–622) binding to eIF3g residues 54–321. Depletion of eIF3g from rabbit reticulocyte lysates by antibody or GST/4.1R fusion protein abolishes cell-free protein synthesis, demonstrating that eIF3g is essential for translation initiation. Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, antibody/fusion-protein depletion of cell-free translation system Blood Medium 10887144
2013 During apoptosis induced by cisplatin, caspases cleave eIF3g at the site SLRD(220)G. The cleaved N-terminal fragment translocates to the nucleus, activates caspase-3, and exhibits DNase activity, revealing a role for eIF3g in DNA degradation during apoptosis. Site-directed mutagenesis to identify cleavage site, subcellular fractionation, caspase activity assay, DNase activity assay, western blotting FEBS letters Medium 24080033
2010 PELO (Pelota) directly interacts with eIF3g; the interaction domain maps to PELO residues 268–385 (C-terminal/acidic tail). PELO–eIF3g protein complexes localize to actin cytoskeletal filaments as shown by bimolecular fluorescence complementation (BiFC). Yeast two-hybrid, GST pull-down, co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) BMC cell biology Medium 20406461
2023 eIF4A3 (a core EJC component) directly interacts with eIF3g, forming a molecular linker between the EJC and the eIF3 complex that facilitates internal ribosome entry. This interaction is required for eIF4A3-driven translation of circular RNAs, including production of full-length β-catenin from endogenous circRNAs. Co-immunoprecipitation, in vitro circRNA translation assay, polysome profiling, transcriptome-wide ribosome association analysis (RIP-seq/polysome-seq) Nucleic acids research Medium 37811880
2023 In vitro reconstitution of SARS-CoV-2 Nsp1-induced endonucleolytic mRNA cleavage demonstrates that eIF3g's RRM domain is a minimal and essential component: 40S subunits plus eIF3g's RRM domain alone support cleavage of CrPV IRES mRNA. Mutational analysis identified a positively charged surface on eIF3g's RRM domain above the mRNA-binding channel that is required for cleavage on all tested mRNAs, and the cleavage site maps 18 nt downstream of the mRNA entrance in the coding region. In vitro reconstitution with purified components, mutational analysis, toe-printing/mapping of cleavage site Genes & development High 37821106
2016 eIF3g is present in the nucleus of breast cancer cells and interacts there with hnRNP U/SAF-A, ZNF823 (HSZFP36), and β-actin, as identified by nuclear co-immunoprecipitation followed by mass spectrometry, cross-linking, and GST pull-down, suggesting nuclear functions beyond translation initiation. Nuclear co-immunoprecipitation, mass spectrometry, cross-linking, GST pull-down, confocal co-localization Molecular medicine reports Low 26935993
2026 eIF3g, together with its binding partner eIF3i, binds a specific GUCG-centered RNA motif (GUCG box) identified by SELEX. GUCG boxes in the 5′-terminal coding regions of mRNAs drive elevated ribosome occupancy and translational induction under mild heat stress in yeast, as shown by ribosome profiling of eIF3i mutants and reporter assays. Mutational disruption of the GUCG motif impairs eIF3g binding (measured by biolayer interferometry) and abolishes translational induction. SELEX, ribosome profiling, reporter assays, mutational analysis, biolayer interferometry Nucleic acids research High 41556339
2025 Loss-of-function mutations in eIF3g (along with eIF3i, eIF4A, Ded1, eIF4G, and eIF4B) produce a similar modest decrease in translation of GFP reporters with short and long unstructured 5′ UTRs in yeast, consistent with eIF3g's role in stimulating mRNA scanning but indicating that scanning per se is driven by one-dimensional diffusion rather than helicase-powered translocation. GFP reporter assays in Saccharomyces cerevisiae with loss-of-function mutations bioRxivpreprint Low bio_10.1101_2024.12.30.630811

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
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
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
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
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
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
2018 mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 617 30232453
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
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 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2015 eIF3 targets cell-proliferation messenger RNAs for translational activation or repression. Nature 340 25849773
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
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
2023 An interaction between eIF4A3 and eIF3g drives the internal initiation of translation. Nucleic acids research 25 37811880
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 20 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 17 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