EEF1G

EEF1G (eEF1Bγ) is a subunit of the eukaryotic elongation factor 1 complex that participates in translation elongation as part of a TCTP-coordinated translational machinery alongside eEF1A2, eEF1B, eEF1D, and valyl-tRNA synthetase (PMID:30381327). Beyond its canonical elongation role, EEF1G couples cellular redox state to elongation: it senses oxidized glutathione under oxidative stress and slows elongation, reducing ribosome collisions at selenocysteine codons and enhancing production of the detoxifying selenoproteins GPX1 and GPX4 (PMID:41279241). EEF1G is recurrently appropriated or opposed at the host–pathogen interface — it is required for HIV-1 reverse transcription complex stability, co-immunoprecipitating with the p51 reverse transcriptase subunit and integrase (PMID:22628567); supports strain-specific translation of influenza A virus PB2/PA proteins (PMID:30008712); and conversely acts as a restriction factor against porcine deltacoronavirus by directly binding the Nsp12 RdRp and competing for viral genomic RNA (PMID:41157639). In the cytosol, EEF1G partners with hCdc73 in a complex that negatively regulates p53 mRNA stability (PMID:37350228). EEF1G expression is itself controlled post-transcriptionally, its m6A-modified mRNA being translationally upregulated by the reader YTHDF1 in lung adenocarcinoma [PMID:bio_10.1101_2024.09.13.612607].

1. 2012 High

   Established that beyond translation, eEF1G is physically and functionally co-opted by a virus, defining it as a host cofactor required for HIV-1 reverse transcription complex stability.

   Evidence Reciprocal Co-IP with reverse transcriptase p51 and integrase, endogenous RT assays, siRNA knockdown, and confocal co-localization in infected cells

   PMID:22628567

   Open questions at the time

   • Does not define the structural basis or binding interface of eEF1G–RTC association
   • Does not establish whether elongation-factor activity is required for the RTC role
2. 2013 Low

   Placed eEF1G within a TRAP1-associated translational apparatus linked to global protein synthesis in cancer, hinting at regulatory coupling to the elongation machinery.

   Evidence Co-IP of TRAP1 with ribosomal fractions and translation factors in colon carcinoma cells, plus tumor correlation analysis

   PMID:24113185

   Open questions at the time

   • Single Co-IP without functional validation of eEF1G's specific role
   • Association does not establish direct binding to TRAP1
3. 2015 Low

   Identified eEF1G as a target of regulatory ubiquitination during oncogene-induced senescence, implying post-translational control of the translation machinery.

   Evidence Ubiquitinome LC-MS/MS profiling of RAS-induced senescent primary human fibroblasts

   PMID:25785348

   Open questions at the time

   • Functional consequence of the ubiquitination on eEF1G activity unknown
   • Responsible E3 ligase not identified
4. 2017 Medium

   Mapped a discrete viral protein interaction to the eEF1G C-terminus, narrowing the structural region engaged by a pathogen.

   Evidence Split-ubiquitin yeast two-hybrid with FMDV cDNA library and confirmatory Co-IP in HEK293T cells

   PMID:28942178

   Open questions at the time

   • No functional consequence of the FMDV 2B interaction tested
   • Binding assays only, no reconstitution
5. 2018 High

   Showed eEF1G acts post-transcriptionally at the translation step for select viral proteins, establishing strain-specific functional dependency rather than a generic role.

   Evidence CRISPR/Cas9 eEF1G knockout cells with viral titration, protein expression, and mRNA/vRNA/cRNA quantification across IAV strains

   PMID:30008712

   Open questions at the time

   • Molecular basis for PB2/PA strain specificity unresolved
   • Whether eEF1G directly engages viral mRNA not shown
6. 2018 Low

   Defined eEF1G as a component of a TCTP-coordinated eEF1 translational complex in tumor cells, anchoring its canonical elongation context.

   Evidence Sequential affinity purification with data-independent MS (AP-DIA/SWATH) in NF1-deficient malignant tumor cells

   PMID:30381327

   Open questions at the time

   • Single AP-MS without functional validation of eEF1G in the complex
   • Direct vs. indirect TCTP association not distinguished
7. 2023 Medium

   Revealed a moonlighting cytosolic role: eEF1G in complex with hCdc73 negatively regulates p53 mRNA stability, with stress-induced differential sequestration relieving this control.

   Evidence Stress-granule imaging and selective protein/mRNA sequestration analysis under arsenic stress, building on a prior eEF1G–hCdc73 interaction

   PMID:37350228

   Open questions at the time

   • Mechanism by which the complex destabilizes p53 mRNA not defined
   • Direct RNA binding by eEF1G not demonstrated
8. 2024 Medium

   Established that eEF1G's own expression is under m6A control, with YTHDF1 accelerating its translation to drive a tumor-promoting program.

   Evidence MeRIP-seq, RIP-qPCR, Co-IP/Co-IF, and rescue/knockdown in LUAD cell lines and xenografts (preprint)

   PMID:bio_10.1101_2024.09.13.612607

   Open questions at the time

   • Specific m6A sites on EEF1G mRNA not pinpointed
   • Downstream effectors of EEF1G in LUAD not defined
9. 2025 Medium

   Defined a redox-sensing function: eEF1G detects oxidized glutathione to slow elongation and boost selenoprotein output, linking translation speed to oxidative homeostasis.

   Evidence Genome-wide CRISPR knockout screens with GPX1/GPX4 selenoprotein reporters, elongation-rate and ribosome-collision assays (preprint)

   PMID:41279241

   Open questions at the time

   • Molecular mechanism of oxidized-glutathione sensing by eEF1G not structurally resolved
   • Not yet peer-reviewed
10. 2025 High

    Demonstrated eEF1G acts as an antiviral restriction factor that directly competes with a viral polymerase for genomic RNA.

    Evidence IP-MS, Co-IP, pull-down, RNA-IP, strand-specific RT-qPCR, and knockdown/overexpression with viral titration for PDCoV Nsp12

    PMID:41157639

    Open questions at the time

    • Why overexpression fails to further restrict replication unexplained
    • RNA-binding determinants on eEF1G not mapped

• How eEF1G integrates its canonical elongation function with its redox-sensing, RNA-binding, and host–pathogen roles at the molecular and structural level remains unresolved.
• No structural model linking elongation activity to moonlighting functions
• Direct RNA-binding interface uncharacterized
• Regulatory post-translational modifications not functionally dissected