Affinage

EIF4G3

Eukaryotic translation initiation factor 4 gamma 3 · UniProt O43432

Length
1585 aa
Mass
176.7 kDa
Annotated
2026-06-09
22 papers in source corpus 18 papers cited in narrative 18 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

EIF4G3 (eIF4GII) is a scaffold subunit of the eIF4F cap-binding complex that supports cap-dependent translation initiation through selective, regulated recruitment to capped mRNA, functioning non-redundantly with its paralog eIF4GI (PMID:15143184, PMID:22514323). During cell differentiation it is preferentially recruited to the m7G cap, coincident with sustained eIF4E phosphorylation and 4E-BP1 release, indicating context-specific deployment of EIF4G3 versus eIF4GI (PMID:15143184). Its participation in the cap complex is gated by phosphorylation: CaMKI phosphorylates EIF4G3 at Ser1156 in response to neuronal activity to selectively promote its assembly into eIF4F and enhance cap-dependent translation driving dendritic spine formation (PMID:22514323), and it undergoes Cdk1-dependent N-terminal phosphorylation during mitosis when translation factors concentrate at the spindle, microtubule organizing centers, and midbody (PMID:24091728). In male meiosis EIF4G3 is required to translate HSPA2 mRNA, and its loss abolishes HSPA2 protein while sparing transcript, collapsing CDK1 kinase activity and arresting spermatocytes at the G2/MI transition (PMID:20430745); EIF4G3 also localizes to the spermatocyte nucleus and is enriched in the transcriptionally silent XY body (PMID:29161344). As a translation-initiation hub, EIF4G3 is a target of picornaviral 2A/Lb proteases, which cleave it at a site distinct from eIF4GI (PLLNV699*GSR), and cleavage of both isoforms is required for complete host translational shutoff during infection (PMID:9736694, PMID:12663812). EIF4G3 abundance is controlled both transcriptionally by DEAF1 and post-transcriptionally by miR-520c-3p, the latter limiting global translation and proliferation (PMID:22923498, PMID:24497838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Established that EIF4G3, distinct from eIF4GI, must be proteolyzed for complete host translation shutoff, identifying it as a functionally relevant target during picornaviral infection rather than a redundant paralog.

    Evidence Western blot of eIF4GII cleavage kinetics in poliovirus-infected HeLa cells correlated with protein synthesis rates

    PMID:9736694

    Open questions at the time
    • Did not map the cleavage site or the responsible protease
    • Did not determine whether the cleavage fragments retain partial function
  2. 1999 High

    Showed that EIF4G3 cleavage is the rate-limiting step in rhinovirus-induced shutoff, refining the kinetic hierarchy by which the two eIF4G isoforms are inactivated.

    Evidence Western blot of eIF4GI/eIF4GII cleavage kinetics in HRV-14-infected HeLa cells with metabolic labeling

    PMID:10074204

    Open questions at the time
    • Mechanism explaining slower eIF4GII cleavage not defined
  3. 2001 Medium

    Determined that EIF4G3 directly binds the FMDV IRES and that the protease-generated C-terminal fragment retains IRES binding, defining how the cleaved factor can still support viral cap-independent translation.

    Evidence UV crosslinking, competition assays, and in vitro Lb protease cleavage followed by IRES binding

    PMID:11565745

    Open questions at the time
    • Single lab
    • RNA determinants shared with eIF4GI, so isoform-specific contribution unresolved
  4. 2002 Medium

    Distinguished EIF4G3 protease susceptibility profiles by showing it is not cleaved by HIV-1 protease while eIF4GI is, and that rhinovirus 2A cleaves it directly rather than via a cellular protease.

    Evidence In vitro cleavage assays with recombinant HIV-1 protease and a thermosensitive HRV2 2A mutant

    PMID:12054764 PMID:12123803

    Open questions at the time
    • In vitro systems only
    • Single lab per result
  5. 2003 High

    Mapped the rhinovirus 2A cleavage site in EIF4G3 to PLLNV699*GSR, seven residues C-terminal to the eIF4GI site, proving the isoforms are processed at non-identical positions.

    Evidence In vitro cleavage with recombinant HRV2 2Apro and N-terminal sequencing of products

    PMID:12663812

    Open questions at the time
    • Functional consequence of the distinct cut site for translation not addressed here
  6. 2004 Medium

    Revealed EIF4G3-specific, non-redundant translational roles by showing selective recruitment to capped mRNA at the onset of differentiation, linking it to eIF4E phosphorylation and cytokine signaling.

    Evidence m7GTP-Sepharose cap-affinity pulldown from differentiating erythroid/megakaryocytic cells with phosphorylation analysis

    PMID:15143184

    Open questions at the time
    • mRNA targets selectively translated via EIF4G3 not identified
    • Single lab
  7. 2006 Medium

    Functionally separated EIF4G3 from eIF4GI by showing it is preferentially required for reinitiation on pre-existing mRNAs and for Hsp70 mRNA translation, defining distinct mRNA-class dependencies.

    Evidence Differential 2Apro-mediated cleavage of eIF4GI vs eIF4GII with luciferase reporters and metabolic labeling

    PMID:16959778

    Open questions at the time
    • Molecular basis for mRNA selectivity unresolved
    • Single lab
  8. 2009 Medium

    Quantified the cellular requirement for EIF4G3 in bulk translation by RNAi and confirmed direct, specific 2A cleavage in living infected cells, bounding its individual contribution and virus-dependence.

    Evidence siRNA depletion with metabolic labeling, and FRET cleavage biosensors during enterovirus infection

    PMID:19655339 PMID:19769989

    Open questions at the time
    • Partial functional redundancy with eIF4GI limits interpretation of single knockdown
    • Single lab per study
  9. 2010 High

    Defined an essential in vivo function: EIF4G3 is specifically required to translate HSPA2 in spermatocytes, linking its loss to failed CDK1 activation and meiotic arrest.

    Evidence ENU repro8 mutant mice with western blot for HSPA2/CDK1 activity and RT-PCR confirming transcript presence

    PMID:20430745

    Open questions at the time
    • How EIF4G3 selectively engages Hspa2 mRNA not defined
    • Other meiotic mRNA targets not identified
  10. 2012 High

    Identified phosphoregulation of EIF4G3 by CaMKI at Ser1156 as an activity-dependent switch promoting its selective entry into eIF4F to drive spine formation, establishing a signaling-to-translation mechanism unique to this isoform.

    Evidence In vitro kinase assays, S1156A phosphomutant, cap-affinity pulldown, RNAi, and spine-density imaging in neurons

    PMID:22514323

    Open questions at the time
    • Specific mRNAs translated downstream not enumerated
    • Structural basis of phospho-dependent recruitment unknown
  11. 2012 Medium

    Showed EIF4G3 expression and isoform diversity are actively controlled — transcriptionally by DEAF1 and via alternative promoters/splicing/CUG initiation — with the EIF4G3 N-terminus contributing distinctly to initiation-factor assembly.

    Evidence Deaf1 KO/siRNA with polysome profiling; 5'RACE, RT-PCR and rescue of double-knockdown cells with defined isoforms

    PMID:22909319 PMID:22923498

    Open questions at the time
    • Functional role of N-terminal extension mechanistically undefined
    • Single lab per study
  12. 2013 Medium

    Connected EIF4G3 to the cell cycle by identifying Cdk1-dependent N-terminal phosphorylation in mitosis and its localization to spindle, MTOC, and midbody, implying spatially regulated translation during division.

    Evidence Confocal microscopy and mobility-shift phosphorylation analysis in synchronized HeLa cells with Cdk1 inhibitor

    PMID:24091728

    Open questions at the time
    • Functional consequence of mitotic phosphorylation not tested
    • Single lab
  13. 2014 Medium

    Demonstrated post-transcriptional control of EIF4G3 by miR-520c-3p, linking its abundance to global translation, proliferation, and senescence in cancer cells.

    Evidence miRNA overexpression, siRNA knockdown, colony-formation and xenograft assays

    PMID:24497838

    Open questions at the time
    • Direct luciferase target validation only implied
    • Single lab
  14. 2018 Medium

    Localized EIF4G3 to the spermatocyte nucleus and the transcriptionally silent XY body, raising the possibility of pre-positioning translation complexes ahead of meiotic divisions.

    Evidence Immunofluorescence confocal microscopy and fractionation during spermatogenesis with XY body markers

    PMID:29161344

    Open questions at the time
    • Functional role at the XY body inferred but not tested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The transcriptome-wide set of mRNAs selectively dependent on EIF4G3 versus eIF4GI, and the structural basis by which phosphorylation and isoform N-termini gate its entry into eIF4F, remain undefined.
  • No genome-wide EIF4G3-specific translatome
  • No structural model of phospho-regulated eIF4F assembly
  • Mechanism of mRNA selectivity (Hspa2, reinitiation substrates) unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1474165 Reproduction 2 R-HSA-1643685 Disease 2
Partners
EIF4EHSPA2
Complex memberships
eIF4F

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Proteolysis of eIF4GII (EIF4G3) by poliovirus-induced mechanisms is required for complete shutoff of host cell protein synthesis after poliovirus infection; cleavage of eIF4GI alone is insufficient, and full shutoff coincides with cleavage of both eIF4GI and eIF4GII. Western blot analysis of eIF4GII cleavage kinetics in poliovirus-infected HeLa cells, with and without virus replication inhibitors; correlation with host protein synthesis rates Proceedings of the National Academy of Sciences of the United States of America High 9736694
1999 Cleavage of eIF4GII (EIF4G3) by human rhinovirus 14 (HRV-14) 2A protease is the rate-limiting step in the shutoff of host cell protein synthesis after rhinovirus infection, with eIF4GII cleavage lagging behind eIF4GI cleavage. Western blot analysis of eIF4GI and eIF4GII cleavage kinetics in HRV-14-infected HeLa cells correlated with metabolic labeling of protein synthesis Journal of virology High 10074204
2001 eIF4GII (EIF4G3) directly interacts with the FMDV IRES; the C-terminal fragment of eIF4GII generated by Lb protease cleavage retains IRES-binding activity. The RNA determinants for eIF4GII–IRES interaction are shared with eIF4GI. UV crosslinking and competition assays; in vitro cleavage with FMDV Lb protease followed by IRES binding assays RNA (New York, N.Y.) Medium 11565745
2002 eIF4GII (EIF4G3) is NOT a substrate for HIV-1 protease in vitro, in contrast to eIF4GI which is cleaved at multiple sites by HIV-1 protease. In vitro cleavage assay using cell extracts and rabbit reticulocyte lysate system with recombinant HIV-1 protease; western blot detection Journal of molecular biology Medium 12054764
2002 Human rhinovirus 2 2A protease directly cleaves both eIF4GI and eIF4GII (not via activation of a cellular protease), as demonstrated using a thermosensitive 2A protease mutant. Temperature-shift experiments with thermosensitive HRV2 2A protease mutant in cytoplasmic HeLa cell extracts; western blot of cleavage products FEBS letters Medium 12123803
2003 The cleavage site of human rhinovirus 2 2A protease in eIF4GII (EIF4G3) is PLLNV(699)*GSR, located seven amino acids C-terminal to the corresponding cleavage site in eIF4GI (LSTR681*GPP), demonstrating the two isoforms have distinct cleavage sites. In vitro cleavage assay with recombinant HRV2 2Apro; N-terminal sequencing of cleavage products Journal of virology High 12663812
2004 eIF4GII (EIF4G3), but not eIF4GI, is selectively recruited to capped mRNA at the onset of cell differentiation (erythropoiesis/thrombopoiesis), coincident with strong and long-lasting eIF4E phosphorylation and release of 4E-BP1 from the cap structure. Cytokines such as thrombopoietin differentially regulate eIF4GI vs. eIF4GII activities. m7GTP-Sepharose cap-affinity pulldown from differentiating cells; western blot; phosphorylation analysis Molecular and cellular biology Medium 15143184
2006 eIF4GII (EIF4G3) integrity is required for reinitiation of translation of pre-existing mRNAs after polysome run-off; de novo translation of newly synthesized mRNAs is more dependent on eIF4GI. Translation of Hsp70 mRNA is more susceptible to eIF4GII hydrolysis than to eIF4GI hydrolysis. Electroporation of IRES-driven poliovirus 2Apro mRNA in HeLa and BHK-21 cells causing differential cleavage of eIF4GI vs. eIF4GII; luciferase reporter assays; metabolic labeling The Journal of biological chemistry Medium 16959778
2009 FRET-based biosensors confirmed that EV 2A protease directly and specifically cleaves eIF4GII (EIF4G3) in intact infected cells, independent of other viral proteases, activated caspases, or general translation inhibition. FRET biosensors with GFP2-cleavage motif-DsRed2 fusion constructs expressed in cells; quantitative fluorescence imaging during EV infection Biotechnology and bioengineering Medium 19655339
2009 Depletion of eIF4GI or eIF4GII individually only moderately inhibits cellular protein synthesis, whereas depletion of both has a slightly higher effect. VSV mRNA translation does not require eIF4GI/II, while vaccinia virus mRNA translation is substantially reduced by eIF4G depletion. siRNA depletion of eIF4GI and/or eIF4GII in HeLa cells; metabolic labeling; western blot Journal of molecular biology Medium 19769989
2010 EIF4G3 is required for translation of HSPA2 protein in mouse spermatocytes; loss-of-function (repro8 ENU mutation in Eif4g3) causes absence of HSPA2 protein despite presence of Hspa2 transcript, dramatically reduced CDK1 (CDC2A) kinase activity, and arrest at the G2/MI meiotic transition causing male infertility. ENU mutagenesis screen; genetic mapping; Sanger sequencing of Eif4g3 mutation; western blot for HSPA2 and CDK1 activity assay in mutant spermatocytes; RT-PCR confirming transcript presence Development (Cambridge, England) High 20430745
2012 DEAF1 transcriptionally regulates Eif4g3 expression in lymph node stromal cells; reduced DEAF1 function decreases eIF4GII levels and results in diminished polysomal translation of multiple genes including Anpep (aminopeptidase N). Deaf1 knockout mice and siRNA silencing; qRT-PCR; polysome profiling; western blot Journal of molecular cell biology Medium 22923498
2012 CaMKI phosphorylates eIF4GII (EIF4G3) at Ser1156 in response to neuronal activity, promoting selective recruitment of eIF4GII (but not eIF4GI) to the eIF4F cap-binding complex, thereby enhancing cap-dependent translation. This mechanism regulates dendritic spine formation without affecting dendritic arborization. In vitro CaMKI phosphorylation assays; m7GTP-Sepharose pulldown from neurons treated with bicuculline/gabazine; S1156A phosphomutant; CaMKK inhibitor STO-609; RNAi knockdown of CaMKI isoforms and eIF4GII; bicistronic luciferase reporter; confocal imaging of spine density The Journal of neuroscience : the official journal of the Society for Neuroscience High 22514323
2012 Multiple isoforms of eIF4GII (EIF4G3) are generated via alternative promoters, alternative splicing, and a non-canonical CUG initiation codon that extends the N-terminus. Novel eIF4GII isoforms rescue translation in eIF4GI/eIF4GII double-knockdown cells as effectively as eIF4GIf/e isoforms, suggesting the eIF4GII N-terminus plays a distinct role in initiation factor assembly. 5' RACE, RT-PCR, reporter assays, RNAi knockdown of eIF4GI and eIF4GII followed by rescue with isoform expression constructs; metabolic labeling The Biochemical journal Medium 22909319
2013 eIF4GII (EIF4G3) undergoes novel Cdk1-dependent N-terminal phosphorylation in nocodazole-arrested cells. Translation initiation factors including eIF4GII are enriched at microtubule organizing centers, mitotic spindle, and midbody during cytokinesis. Confocal microscopy; phosphorylation analysis by mobility shift; synchronized HeLa cells using thymidine block or Cdk1 inhibitor RO3306; metabolic labeling Cell cycle (Georgetown, Tex.) Medium 24091728
2014 miR-520c-3p directly targets eIF4GII (EIF4G3) mRNA to negatively regulate eIF4GII protein synthesis; downregulation of eIF4GII by siRNA decreases global translation, cell proliferation, and colony formation ability, and induces cellular senescence in HeLa and DLBCL cells. miRNA overexpression, western blot, siRNA knockdown of eIF4GII, colony formation assays, xenograft mouse model, luciferase reporter (implied by direct targeting claim) PLoS genetics Medium 24497838
2018 EIF4G3 localizes to the nucleus of mouse spermatocytes and is highly enriched in the XY body (the transcriptionally inactive sex chromosome domain); many translation-related proteins also localize to the XY body, suggesting a role in mRNA metabolism or poising of translation complexes before meiotic divisions. Immunofluorescence confocal microscopy and fractionation during spermatogenesis; co-localization with XY body markers Biology of reproduction Medium 29161344
2001 Both eIF4GI and eIF4GII are cleaved in Jurkat T cells treated with proteasome inhibitors (MG132, lactacystin) or immunosuppressants (FTY720, cyclosporin A) via caspase-8-independent mechanisms. Novel eIF4GI cleavage fragments generated lack the ability to interact with eIF4E. Western blot with specific anti-peptide antisera against eIF4GI and eIF4GII in wild-type and caspase-8-deficient Jurkat cells; caspase activity assays FEBS letters Medium 11513883

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Proteolysis of human eukaryotic translation initiation factor eIF4GII, but not eIF4GI, coincides with the shutoff of host protein synthesis after poliovirus infection. Proceedings of the National Academy of Sciences of the United States of America 287 9736694
2001 IRES interaction with translation initiation factors: functional characterization of novel RNA contacts with eIF3, eIF4B, and eIF4GII. RNA (New York, N.Y.) 103 11565745
1999 Eukaryotic initiation factor 4GII (eIF4GII), but not eIF4GI, cleavage correlates with inhibition of host cell protein synthesis after human rhinovirus infection. Journal of virology 102 10074204
2022 Circular RNA EIF4G3 suppresses gastric cancer progression through inhibition of β-catenin by promoting δ-catenin ubiquitin degradation and upregulating SIK1. Molecular cancer 65 35780119
2010 Mutation of Eif4g3, encoding a eukaryotic translation initiation factor, causes male infertility and meiotic arrest of mouse spermatocytes. Development (Cambridge, England) 64 20430745
2002 In vitro cleavage of eIF4GI but not eIF4GII by HIV-1 protease and its effects on translation in the rabbit reticulocyte lysate system. Journal of molecular biology 64 12054764
2013 Phosphorylation of eIF4GII and 4E-BP1 in response to nocodazole treatment: a reappraisal of translation initiation during mitosis. Cell cycle (Georgetown, Tex.) 45 24091728
2006 Differential cleavage of eIF4GI and eIF4GII in mammalian cells. Effects on translation. The Journal of biological chemistry 39 16959778
2014 Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development. PLoS genetics 36 24497838
2004 Selective modification of eukaryotic initiation factor 4F (eIF4F) at the onset of cell differentiation: recruitment of eIF4GII and long-lasting phosphorylation of eIF4E. Molecular and cellular biology 36 15143184
2012 Reduced DEAF1 function during type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. Journal of molecular cell biology 35 22923498
2009 Translation of mRNAs from vesicular stomatitis virus and vaccinia virus is differentially blocked in cells with depletion of eIF4GI and/or eIF4GII. Journal of molecular biology 27 19769989
2003 Human rhinovirus 2A proteinase cleavage sites in eukaryotic initiation factors (eIF) 4GI and eIF4GII are different. Journal of virology 25 12663812
2018 Nuclear localization of EIF4G3 suggests a role for the XY body in translational regulation during spermatogenesis in mice. Biology of reproduction 24 29161344
2012 Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 22514323
2012 Multiple isoforms of the translation initiation factor eIF4GII are generated via use of alternative promoters, splice sites and a non-canonical initiation codon. The Biochemical journal 16 22909319
2002 A thermosensitive mutant of HRV2 2A proteinase: evidence for direct cleavage of eIF4GI and eIF4GII. FEBS letters 15 12123803
2009 Visualizing and quantifying the differential cleavages of the eukaryotic translation initiation factors eIF4GI and eIF4GII in the enterovirus-infected cell. Biotechnology and bioengineering 14 19655339
2021 Chidamide and Radiotherapy Synergistically Induce Cell Apoptosis and Suppress Tumor Growth and Cancer Stemness by Regulating the MiR-375-EIF4G3 Axis in Lung Squamous Cell Carcinomas. Journal of oncology 13 34194495
2019 Circ-EIF4G3 promotes the development of gastric cancer by sponging miR-335. Pathology, research and practice 12 31257089
2001 Proteasome inhibitors and immunosuppressive drugs promote the cleavage of eIF4GI and eIF4GII by caspase-8-independent mechanisms in Jurkat T cell lines. FEBS letters 9 11513883
2026 The related EIF4G3 and EIF4G4 initiation factors from Leishmania: dissimilar modes of action during translation revealed by a comparative proteomic approach. Parasites & vectors 0 41776682

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