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Showing EIF4E2 — 4EHP is a alias.

EIF4E2

Eukaryotic translation initiation factor 4E type 2 · UniProt O60573

Length
245 aa
Mass
28.4 kDa
Annotated
2026-06-09
43 papers in source corpus 31 papers cited in narrative 32 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

EIF4E2 (4EHP) is a cytoplasmic cap-binding protein that functions as a sequence- and context-specific translational repressor, acting as a functional antagonist of the canonical initiation factor eIF4E (PMID:9582349, PMID:17369309). It recognizes the m7G cap through a mechanism shared with eIF4E but binds cap analogs with ~30–100-fold lower affinity and, critically, cannot bind eIF4G, so it cannot stimulate translation (PMID:9582349, PMID:17369309). Repression is achieved by recruitment to specific mRNAs through adapter proteins that tether the 5' cap to the 3'UTR or to silencing machinery: Drosophila Bicoid and mammalian Prep1 link 4EHP-bound caps to 3'UTR elements in a closed-loop mechanism (PMID:15882623, PMID:19365557), while the obligate partners GIGYF1/2 — whose binding is structurally selective for 4EHP over eIF4E and is required for repressive activity — couple it to a broad repression network (PMID:22751931, PMID:28698298). 4EHP-GIGYF1/2 complexes integrate multiple regulatory outputs, including miRNA-induced silencing via 4E-T, TNRC6A, and the CCR4-NOT/DDX6 machinery (PMID:28487484, PMID:28755203, PMID:31439631), tristetraprolin-directed decay of ARE-containing mRNAs (PMID:26763119, PMID:31439631), and ribosome-stalling-coupled co-translational mRNA decay and ribosome-associated quality control through ZNF598 and DDX6 (PMID:32726578, PMID:33053355). Cap-binding activity is tuned by post-translational modification, with ISGylation enhancing cap affinity (PMID:17289916) and non-degradative ubiquitination by ARIH1 triggering translation arrest under genotoxic stress (PMID:25624349). Physiologically, 4EHP drives hypoxia-specific, mTORC1-independent translation of select mRNAs required for cancer cell survival, migration, and tumor formation (PMID:24408918, PMID:28991229), represses antiviral genes Ifnb1 (via miR-34a) and Cgas (via miR-23a) to restrain innate immunity (PMID:33581076, PMID:39560640), and controls translation of specific neuronal mRNAs underlying synaptic plasticity, social behavior, and working memory in mice (PMID:33225984, PMID:36650535).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1998 High

    Established the founding paradox: a second cap-binding protein exists that, unlike eIF4E, cannot engage eIF4G and therefore cannot promote translation, implying a repressive rather than activating role.

    Evidence In vitro cap-binding assay, homology modeling and site-directed mutagenesis of recombinant 4EHP

    PMID:9582349

    Open questions at the time
    • No cellular mRNA targets identified
    • Mechanism of recruitment to specific transcripts unknown
  2. 2005 High

    Defined the first concrete repression mechanism — cap-dependent translational inhibition via 5'-3' tethering — showing 4EHP is recruited to a specific mRNA by a sequence-specific 3'UTR-binding adapter.

    Evidence Genetic and biochemical assays in Drosophila embryos with Bicoid and cad mRNA, cap-binding and interaction assays

    PMID:15882623

    Open questions at the time
    • Generality to mammalian systems unproven at the time
    • Did not identify other adapter proteins
  3. 2007 High

    Quantified why 4EHP does not block general translation, showing its much lower cap affinity restricts competition with eIF4E to contexts where it is locally concentrated by adapters.

    Evidence Fluorescence titration and stopped-flow kinetics on m7GpppG and m7GTP

    PMID:17369309

    Open questions at the time
    • Did not address how affinity is boosted on target mRNAs in cells
  4. 2007 Medium

    Identified ISGylation as a regulatory switch that raises 4EHP cap-binding activity, linking its repressive function to interferon, genotoxic stress, and infection.

    Evidence ISGylation assay with cap-binding readout comparing modified vs unmodified 4EHP

    PMID:17289916

    Open questions at the time
    • Modified residues not mapped at the time
    • Downstream translational consequences not defined
  5. 2003 Medium

    Implicated ARIH1/HHARI-family ubiquitin ligase machinery in 4EHP regulation, initially interpreted as degradative ubiquitination.

    Evidence Co-IP and overexpression ubiquitylation assay in mammalian cells

    PMID:14623119

    Open questions at the time
    • Degradative interpretation later revised
    • No physiological trigger identified
  6. 2012 High

    Identified GIGYF2 as a direct, mutually stabilizing 4EHP partner whose complex is physiologically essential, shifting the field from isolated adapters to a core repressor module.

    Evidence Reciprocal co-IP, mass spectrometry, mouse genetic disruption with translational and developmental readouts

    PMID:22751931

    Open questions at the time
    • Structural basis of selectivity not yet known
    • Spectrum of regulated mRNAs undefined
  7. 2017 High

    Provided the structural basis for why GIGYF1/2 bind 4EHP but not eIF4E and proved that GIGYF1/2 engagement is required for 4EHP repressive activity.

    Evidence X-ray crystallography of GIGYF1/2-4EHP, structure-guided mutagenesis, complementation in knockout cells

    PMID:28698298

    Open questions at the time
    • Did not define how the complex is delivered to specific transcripts
  8. 2016 High

    Connected the 4EHP-GIGYF2 module to ARE-mediated mRNA fate by showing it acts as a cofactor for tristetraprolin in repression and decay of ARE-containing transcripts.

    Evidence Co-IP, in vitro pull-down, mutagenesis of TTP tetraproline motifs, reporter assays, 4EHP-knockout MEFs

    PMID:26763119

    Open questions at the time
    • Relative contribution of repression vs decay not resolved
  9. 2017 High

    Placed 4EHP within the miRNA silencing pathway, showing 4E-T and TNRC6A recruit it to miRNA targets and that 4E-T binding raises its cap affinity, enabling a closed-loop block of initiation.

    Evidence Co-IP, cap-binding and tethering/miRNA reporter assays, knockdown with endogenous target analysis

    PMID:28487484 PMID:28755203

    Open questions at the time
    • Quantitative contribution of 4EHP to global miRNA silencing unclear
  10. 2018 Medium

    Dissected GIGYF2 as having both 4EHP-dependent (translational) and 4EHP-independent (CCR4-NOT/deadenylation) repressive arms, defining 4EHP as one of several GIGYF2 effector routes.

    Evidence Tethering reporter assays, domain mutagenesis, co-IP, RNA-binding and endogenous target analysis

    PMID:29554310

    Open questions at the time
    • Coordination between the two arms in vivo not resolved
  11. 2018 High

    Identified specific endogenous targets and a signaling output, showing 4EHP/miRISC represses Dusp6 via miR-145 to modulate ERK signaling, cell growth, and apoptosis.

    Evidence Ribosome profiling, reporter assay, ERK phosphorylation western blot, knockout/knockdown phenotypes

    PMID:29412140

    Open questions at the time
    • Breadth of the 4EHP-controlled translatome only partially mapped
  12. 2019 High

    Resolved the molecular architecture linking 4EHP-GIGYF to mRNA decay, showing GIGYF recruits DDX6/Me31B, HPat, and CCR4-NOT and that complex assembly is required for TTP-mediated repression.

    Evidence Co-IP, tethering and decay assays, motif mutagenesis, and a 2.4 Å GIGYF-DDX6 crystal structure with structure-guided mutants

    PMID:31114929 PMID:31439631

    Open questions at the time
    • In vivo stoichiometry and dynamics of the assembled complex unknown
  13. 2015 Medium

    Reframed ARIH1 ubiquitination of 4EHP as non-degradative, showing it drives 4EHP cap association and translation arrest as a genotoxic stress response.

    Evidence RNAi screen, co-IP, ubiquitination and cap-binding assays, polysome profiling, epistasis rescue

    PMID:25624349

    Open questions at the time
    • Ubiquitin chain topology and recognition partner not fully defined
  14. 2020 High

    Established 4EHP-GIGYF1/2 as the effector that couples ribosome stalling to translational shutoff and co-translational mRNA decay, integrating it into ribosome-associated quality control.

    Evidence Genome-wide CRISPR screens, ribosome profiling, mRNA stability assays, co-IP, knockout cells with ZNF598/DDX6 dependence

    PMID:32726578 PMID:33053355

    Open questions at the time
    • Signal that triggers GIGYF recruitment to stalled ribosomes incompletely defined
  15. 2014 High

    Revealed a distinct activating role under hypoxia, where 4EHP drives mTORC1-independent cap-dependent translation of a subset of mRNAs required for cancer cell survival and tumor formation.

    Evidence siRNA knockdown, hypoxic polysome profiling, spheroid and xenograft assays; with cadherin-22 identified as a hypoxic target driving migration/invasion

    PMID:24408918 PMID:28991229

    Open questions at the time
    • Molecular switch converting 4EHP from repressor to hypoxic activator not defined
  16. 2020 High

    Demonstrated an in vivo neuronal role, showing 4EHP loss in forebrain excitatory neurons exaggerates mGluR-LTD and impairs social behavior without altering global translation.

    Evidence Conditional knockout mice, electrophysiology, behavioral assays, polysome profiling

    PMID:33225984

    Open questions at the time
    • Specific neuronal mRNA targets not identified
  17. 2021 High

    Established 4EHP as an antiviral immune regulator, repressing Ifnb1 translation via a virus-induced miR-34a negative feedback loop in vivo.

    Evidence 4EHP knockout mice, reporter assays, polysome profiling, viral infection and cytokine measurement

    PMID:33581076

    Open questions at the time
    • Cell types responsible for the in vivo phenotype not fully resolved
  18. 2022 Medium

    Extended 4EHP control to non-cap-binding functions, showing it interacts with GSK3β to sustain proline-directed phosphorylation of p53 and resist hypoxic senescence.

    Evidence Co-IP, kinase activity and peptide inhibition assays, senescence and in vivo liver assays, S-nitrosylation analysis

    PMID:35568694

    Open questions at the time
    • How a cap-binding protein scaffolds a kinase pathway mechanistically unclear
    • Single-lab finding
  19. 2022 Medium

    Identified METTL16 as a cytoplasmic regulator that, independent of its methyltransferase activity, blocks 4EHP cap recruitment to favor eIF4E-driven selective translation.

    Evidence Co-IP, cap-binding and translation reporter assays, depletion/overexpression with polysome analysis

    PMID:36840945

    Open questions at the time
    • Which mRNAs are switched between 4EHP and eIF4E not defined
    • Single-lab finding
  20. 2022 Medium

    Showed viral subversion of the complex, with SARS-CoV-2 NSP2 binding 4EHP and GIGYF2 to impair GIGYF2-mediated repression.

    Evidence In vitro interaction and reporter-based repression assays

    PMID:35756894

    Open questions at the time
    • Consequences for host translation during infection not mapped
    • Single-lab finding
  21. 2024 High

    Defined a second antiviral axis, with 4EHP repressing Cgas via miR-23a to restrain DNA-virus sensing both in vitro and in vivo.

    Evidence 4EHP knockout cells and mice, HSV-1 and Vaccinia infection, miR-23a/Cgas reporter assays, cytokine measurement

    PMID:39560640

    Open questions at the time
    • Whether the miR-23a/Cgas axis operates in all relevant cell types unclear
  22. 2025 Medium

    Mapped 4EHP ISGylation to K134/K222 by HERC5 and linked it to enhanced GSK3β engagement and cytoprotection against ischemic stress, refining the earlier ISGylation observation.

    Evidence NITAC site-specific ISGylation tool, kinase activity assay, OGD/R stress assay, mass spectrometry

    PMID:41022323

    Open questions at the time
    • Interplay between ISGylation and cap-binding vs GSK3β arms not reconciled
    • Single-lab finding
  23. 2025 Medium

    Connected 4EHP to ATF4 stress signaling, showing in Drosophila that it binds NELF-E mRNA and supports expression of 40S/eIF3 components and ATF4 targets.

    Evidence TRIBE screen, quantitative proteomics, genetic epistasis in Drosophila fat body

    PMID:41436469

    Open questions at the time
    • Conservation of the ATF4/NELF-E network in mammals untested
    • Direct vs indirect effects on ribosomal subunit expression unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unclear what molecular switch converts 4EHP between its dominant repressor mode and its hypoxic translational-activator mode, and how its diverse adapter, modification, and kinase-scaffolding functions are coordinated on individual transcripts in vivo.
  • No unifying model reconciling repressor and activator activities
  • Determinants of target mRNA selection across pathways not defined
  • Structural basis of the GSK3β scaffolding function 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 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-112316 Neuronal System 2 R-HSA-168256 Immune System 2
Partners
4E-TARIH1DDX6GIGYF1GIGYF2GSK3BTNRC6AZNF598
Complex memberships
4EHP-GIGYF-DDX6 (Me31B) complex4EHP-GIGYF2 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 4EHP (EIF4E2) was cloned and characterized as a novel cap-binding protein with 30% identity to eIF4E. It binds specifically to capped RNA in an ATP- and divalent ion-independent manner. Homology modeling and site-directed mutagenesis strongly suggest it shares with eIF4E a common mechanism for cap binding, but unlike eIF4E, 4EHP does not interact with eIF4G and therefore cannot stimulate translation. Biochemical cap-binding assay, homology modeling, site-directed mutagenesis The Journal of biological chemistry High 9582349
2005 Drosophila 4EHP (d4EHP) specifically interacts with Bicoid (Bcd) protein to suppress caudal (cad) mRNA translation. d4EHP binds the 5' cap structure while Bcd simultaneously binds the Bicoid binding region (BBR) in the cad 3'UTR, effectively tethering the 5' and 3' ends of cad mRNA to render it translationally inactive. This defines a new paradigm for cap-dependent translational inhibition not mediated by canonical eIF4E. Genetic and biochemical assays in Drosophila embryos, cap-binding assays, interaction assays Cell High 15882623
2007 4EHP binds cap analogs m7GpppG and m7GTP with 30- and 100-fold lower affinity than eIF4E, respectively, as measured by fluorescence titration and stopped-flow measurements. This low binding affinity explains why 4EHP cannot compete with eIF4E for the cap of most mRNAs and thus does not inhibit general translation. Fluorescence titration, stopped-flow kinetic measurements RNA (New York, N.Y.) High 17369309
2007 4EHP is modified by ISG15 (ISGylation), and ISGylated 4EHP has significantly higher cap structure-binding activity than unmodified 4EHP. ISGylation of 4EHP is activated by interferon, genotoxic stress, and pathogen infection. ISGylation assay, cap-binding activity assay comparing modified vs. unmodified 4EHP Genes & development Medium 17289916
2003 HHARI (human homologue of ariadne) interacts with 4EHP via its N-terminal RING1 finger. Overexpression of 4EHP and HHARI in mammalian cells leads to polyubiquitylation of 4EHP, suggesting HHARI promotes ubiquitin-mediated degradation of 4EHP. HHARI, 4EHP, and UbcH7 do not form a stable heterotrimeric complex as 4EHP cannot immunoprecipitate UbcH7 even in the presence of HHARI. Co-immunoprecipitation, overexpression-based ubiquitylation assay in mammalian cells FEBS letters Medium 14623119
2004 4E-BP1 binds to 4EHP via the same interface used for eIF4E binding; eIF4E-binding mutants of 4E-BP1 (Y54A and L59A) fail to form complexes with 4EHP, and the W95A mutant of 4EHP inhibits its binding to 4E-BP1. Overexpression of 4EHP triggers a negative feedback loop inhibiting upstream signaling to 4E-BP1 and S6K1, dependent on the 4E-BP1 binding interaction. Co-immunoprecipitation, site-directed mutagenesis, overexpression with signaling readouts FEBS letters Medium 15094042
2009 Mammalian 4EHP co-localizes and interacts with the homeodomain transcription factor Prep1 in the cytosol of mouse oocytes. Prep1 contains a functional 4EHP-binding motif (identified by mutagenesis). Prep1 inhibits (>95%) in vitro translation of a luciferase reporter fused to the Hoxb4 3'UTR in the presence of 4EHP, and Prep1 binds the Hoxb4 3'UTR directly (EMSA), suggesting a 5'-3' mRNA tethering mechanism. Confocal microscopy, co-immunoprecipitation, pull-down, site-directed mutagenesis of binding motif, in vitro translation assay, RNA EMSA PloS one Medium 19365557
2012 Mammalian 4EHP forms a complex with GIGYF2 and ZNF598. GIGYF2 directly interacts with 4EHP, and this interaction is required for stabilization of both proteins. Disruption of the m4EHP-GIGYF2 complex leads to increased translation and perinatal lethality in mice, establishing the complex as a physiologically essential translational repressor. Co-immunoprecipitation, mass spectrometry, mouse knockout/genetic disruption with translational and developmental phenotype readouts Molecular and cellular biology High 22751931
2015 Upon DNA damage, ARIH1 E3 ubiquitin ligase associates with 4EHP and promotes its non-degradative ubiquitination. This leads to enrichment of ARIH1 in perinuclear ribosome-containing regions and 4EHP association with the mRNA 5' cap, triggering mRNA translation arrest in an ARIH1-dependent manner. Restoration of translation arrest in ARIH1-depleted cells via an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. RNAi screen, co-immunoprecipitation, ubiquitination assay, cap-binding assay, polysome profiling, epistasis rescue experiment Molecular and cellular biology Medium 25624349
2016 The 4EHP-GYF2 (GIGYF2) complex acts as a cofactor of tristetraprolin (TTP) for translational repression and mRNA decay of AU-rich element (ARE)-containing mRNAs. TTP directly interacts with GIGYF2 via conserved tetraproline motifs. Mutant TTP with diminished 4EHP-GYF2 binding is impaired in repressing ARE-mRNAs, and 4EHP knockout MEFs show increased induction and slower turnover of TTP-target mRNAs. Co-immunoprecipitation, in vitro pull-down, mutational analysis, luciferase reporter assay, 4EHP knockout MEFs RNA (New York, N.Y.) High 26763119
2017 Crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP reveal the molecular basis for selective binding of GIGYF1/2 to 4EHP but not eIF4E. Structure-guided mutants in complementation assays in GIGYF1/2-null cells demonstrate that 4EHP requires interactions with GIGYF1/2 for repressive activity on target mRNAs. X-ray crystallography, structure-based mutagenesis, complementation assay in knockout cell line Genes & development High 28698298
2017 4EHP is an integral component of the miRNA-mediated silencing machinery. 4EHP cap-binding activity contributes to translational silencing by miRNAs through the CCR4-NOT complex. 4EHP competes with eIF4E for binding to 4E-T, and this interaction increases 4EHP's affinity for the cap. A closed-loop mRNA conformation via the 4E-T/4EHP interaction is proposed to block translational initiation of miRNA targets. Co-immunoprecipitation, cap-binding assay, reporter assay (tethering and miRNA-mediated silencing), loss-of-function experiments Proceedings of the National Academy of Sciences of the United States of America High 28487484
2017 TNRC6A (a GW182 family protein) interacts with 4EHP/EIF4E2 to inhibit translation of miRNA target mRNAs. Downregulation of 4EHP/EIF4E2 relieved miRNA repression of reporter constructs and increased protein levels of endogenous miRNA targets (IMP1, PTEN, PDCD4). miRNA enhances 4EHP association with target mRNA. Co-immunoprecipitation, reporter assay, siRNA knockdown, endogenous protein level analysis Protein & cell Medium 28755203
2018 4EHP translationally represses Dusp6 mRNA (encoding ERK phosphatase) via miR-145, promoting ERK1/2 phosphorylation, augmented cell growth, and reduced apoptosis. Ribosome profiling identified a subset of mRNAs translationally controlled by 4EHP, placing 4EHP/miRISC in the ERK signaling cascade. Ribosome profiling, reporter assay, western blot for ERK phosphorylation, 4EHP knockout/knockdown with cellular phenotype readouts eLife High 29412140
2018 GIGYF2 has two distinct mechanisms of mRNA repression: one depends on 4EHP binding and mainly affects translation; the other is 4EHP-independent and involves recruitment of the CCR4/NOT complex through multiple interfaces leading to deadenylation. Three independent domains of GIGYF2 have repressive activity in tethering reporter assays. GIGYF2 is an RNA-binding protein with identifiable endogenous mRNA targets. Tethering reporter assay, domain mutagenesis, co-immunoprecipitation, RNA-binding protein assay, endogenous mRNA target identification Nucleic acids research Medium 29554310
2013 Human 4EHP/eIF4E2 binds 4E-T via the canonical YX4Lφ sequence, and this interaction recruits 4EHP to P-bodies in mammalian cells. 4EHP does not redistribute to stress granules in arsenite-treated cells or to P-bodies in Actinomycin D-treated cells (unlike eIF4E1). 4EHP shuttles through the nucleus in a Crm1-dependent but 4E-T-independent manner. Yeast two-hybrid, pull-down assay, indirect immunofluorescence, cellular fractionation, drug treatment (leptomycin B for Crm1 inhibition) PloS one Medium 23991149
2014 eIF4E2 is activated under hypoxia to drive cap-dependent translation of a subset of mRNAs in cancer cells. eIF4E2-depleted cancer cells cannot survive or proliferate in low oxygen, cannot form a hypoxic tumor core in spheroids, and fail to form tumors in xenograft assays, whereas they are indistinguishable from controls under normoxia. siRNA knockdown, in vitro spheroid assay, in vivo xenograft assay, polysome profiling under hypoxia Cancer research High 24408918
2019 Drosophila GIGYF, when in complex with 4EHP, elicits both translational repression and mRNA decay via recruitment of Me31B/DDX6 (RNA helicase), HPat (decapping activator), and the CCR4-NOT deadenylase complex. Discrete binding motifs in GIGYF conserved among metazoan GIGYF proteins are required for Me31B and HPat recruitment and for downregulation of mRNA expression. Co-immunoprecipitation, tethering reporter assay, mutagenesis of binding motifs, mRNA decay assay Nucleic acids research Medium 31114929
2019 Crystal structure (2.4 Å) of the GIGYF-Me31B/DDX6 complex reveals that the GIGYF motif arranges into a coil connected to a β hairpin, binding conserved hydrophobic patches on the Me31B RecA2 domain. Structure-guided mutants confirm that 4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated down-regulation of an AU-rich mRNA. X-ray crystallography (2.4 Å), structure-based mutagenesis, mRNA reporter assay Genes & development High 31439631
2020 4EHP and GIGYF2 form a negative feedback loop that inhibits translation initiation on mRNAs that have undergone failed translation (ribosome-associated quality control). CRISPR-Cas9 screens identified GIGYF2 and 4EHP as mediators of this feedback; loss of these factors leads to accumulation of partially synthesized toxic polypeptides from defective mRNAs. CRISPR-Cas9-based genetic screen, model substrate assays, growth-based assays, translation initiation assay Molecular cell High 32726578
2020 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay. Human cells lacking these proteins accumulate mRNAs with ribosome pausing, including transcripts encoding secretory/membrane proteins and tubulin. 4EHP-GIGYF1/2-mediated mRNA decay requires cap structure interaction, DDX6 interaction, ZNF598 interaction, and is dependent on ribosome stalling; GIGYF1/2 co-translational binding marks transcripts with perturbed elongation for decay. Ribosome profiling, mRNA stability assay, co-immunoprecipitation, knockout cell lines Cell reports High 33053355
2021 4EHP suppresses IFN-β production by mediating miR-34a-induced translational silencing of Ifnb1 mRNA. miR-34a is upregulated by RNA virus infection and IFN-β, creating a negative feedback loop that represses IFN-β expression via 4EHP. 4EHP knockout mice show elevated IFN-β and altered virus replication, establishing an in vivo role for 4EHP in antiviral immunity. 4EHP knockout mice, reporter assay, polysome profiling, in vivo viral infection, cytokine measurement Molecular cell High 33581076
2022 METTL16 interacts with 4EHP/eIF4E2 in the cytoplasm. This interaction impedes the recruitment of 4EHP to the 5' cap structure, thereby promoting cap recognition by eIF4E and selective protein synthesis. METTL16 depletion attenuates protein synthesis, and this effect is mediated through 4EHP, not METTL16's methyltransferase activity. Co-immunoprecipitation, cap-binding assay, translation reporter assay, METTL16 depletion/overexpression with polysome analysis Cell reports Medium 36840945
2022 4EHP/eIF4E2 interacts with GSK3β and maintains basal proline-directed serine/threonine (S/T-P) phosphorylation of p53 and other targets, thereby resisting cellular senescence under hypoxia. Peptides blocking the eIF4E2-GSK3β interaction inhibit S/T-P phosphorylation and induce senescence. Hypoxia inhibits this pathway through S-nitrosylation of GSK3β. Co-immunoprecipitation, kinase activity assay, peptide inhibition, senescence assays, in vivo mouse liver model, S-nitrosylation assay Cell death & disease Medium 35568694
2022 SARS-CoV-2 NSP2 physically associates with both 4EHP and GIGYF2 (binding a central segment of GIGYF2) in the cytoplasm, and impairs GIGYF2-mediated translation repression as shown by reporter-based assays. In vitro interaction assay, reporter-based translational repression assay iScience Medium 35756894
2020 4EHP is expressed in excitatory neurons and synaptosomes, and its abundance increases during development. Conditional knockout of 4EHP in excitatory forebrain neurons results in exaggerated mGluR-LTD and impaired social behavior, without affecting global protein synthesis, indicating that 4EHP regulates translation of specific mRNAs to mediate synaptic plasticity. Conditional knockout mouse model, electrophysiology (mGluR-LTD), behavioral assays, polysome profiling Molecular autism High 33225984
2017 eIF4E2 drives hypoxia-specific translation of cadherin-22 mRNA through an mTORC1-independent mechanism. Silencing eIF4E2 or cadherin-22 significantly impaired cancer cell migration and invasion only under hypoxic conditions; reintroduction of the respective exogenous gene restored normal phenotype. siRNA knockdown, rescue overexpression, migration/invasion assay under normoxia and hypoxia, spheroid formation assay Oncogene Medium 28991229
2024 4EHP controls replication of DNA viruses by mediating translational repression of Cgas mRNA (encoding the DNA viral sensor cGAS) triggered by miR-23a. 4EHP deficiency bolsters innate immune responses against HSV-1 and Vaccinia Virus and reduces their replication in vitro and in vivo. 4EHP knockout cells and mice, viral infection assays, reporter assay for miR-23a/Cgas, innate immune cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 39560640
2025 4EHP ISGylation at K134 and K222 (mediated by HERC5) enhances the eIF4E2-GSK3β interaction and suppresses proline-directed serine/threonine phosphorylation across multiple targets in the eIF4E2-GSK3β pathway, conferring cytoprotection against oxygen-glucose deprivation/reoxygenation stress. NITAC (Nanobody-based ISGylation Targeting Chimera) tool, site-specific ISGylation, kinase activity assay, OGD/R stress assay, mass spectrometry The Journal of biological chemistry Medium 41022323
2025 4EHP is required for ATF4 signaling in Drosophila larval fat body. In a TRIBE screen, NELF-E mRNA was identified as a top 4EHP-interacting target. Knockdown of either 4EHP or NELF-E reduces multiple 40S ribosomal subunit proteins and eIF3 subunits, and suppresses expression of ATF4 and its target genes, placing 4EHP in an ATF4 regulatory network with NELF-E, 40S ribosome, and eIF3. TRIBE (Targets of RNA Binding through Editing) screen, quantitative proteomics, genetic knockdown of pathway components in Drosophila Nature communications Medium 41436469
2023 Conditional knockout of 4EHP in excitatory (CaMKIIα) or inhibitory (GAD65) neurons impairs spatial working memory in the T-maze task. This impairment is associated with dramatically reduced phosphorylation of ribosomal protein S6 (a measure of mTORC1 activity) in the CA1 hippocampus of 4EHP-cKOexc mice, linking 4EHP-mediated translational control to mTORC1 regulation in working memory. Conditional knockout mouse, behavioral assays (T-maze, fear conditioning, Morris water maze), immunostaining for pS6 as mTORC1 readout Molecular brain Medium 36650535
2025 ZC3H7A and ZC3H7B RNA-binding proteins interact with the GIGYF2/4EHP translation repressor complex to block translation initiation of mRNAs enriched in non-optimal A/U3 codons. Depletion of 4EHP impairs repression of non-optimal A/U3-rich mRNAs, placing 4EHP downstream of ZC3H7A/B in a codon-optimality-linked translational control pathway. Co-immunoprecipitation, reporter assay, RNA-seq, ribosome profiling, 4EHP depletion bioRxivpreprint Low

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A new paradigm for translational control: inhibition via 5'-3' mRNA tethering by Bicoid and the eIF4E cognate 4EHP. Cell 202 15882623
2007 ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP. Genes & development 157 17289916
2012 A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Molecular and cellular biology 151 22751931
2020 GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. Molecular cell 125 32726578
1998 Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein. The Journal of biological chemistry 116 9582349
2017 Cap-binding protein 4EHP effects translation silencing by microRNAs. Proceedings of the National Academy of Sciences of the United States of America 82 28487484
2011 Knock-down of both eIF4E1 and eIF4E2 genes confers broad-spectrum resistance against potyviruses in tomato. PloS one 72 22242134
2017 GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression. Genes & development 64 28698298
2016 Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements. RNA (New York, N.Y.) 63 26763119
2014 Cancer cells exploit eIF4E2-directed synthesis of hypoxia response proteins to drive tumor progression. Cancer research 58 24408918
2007 Weak binding affinity of human 4EHP for mRNA cap analogs. RNA (New York, N.Y.) 56 17369309
2023 METTL16 promotes translation and lung tumorigenesis by sequestering cytoplasmic eIF4E2. Cell reports 53 36840945
2020 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay. Cell reports 51 33053355
2018 4EHP-independent repression of endogenous mRNAs by the RNA-binding protein GIGYF2. Nucleic acids research 44 29554310
2018 Translational control of ERK signaling through miRNA/4EHP-directed silencing. eLife 42 29412140
2009 Cytoplasmic Prep1 interacts with 4EHP inhibiting Hoxb4 translation. PloS one 41 19365557
2003 Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP. FEBS letters 39 14623119
2015 The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. Molecular and cellular biology 35 25624349
1991 Expression of a synthetic gene for human cap binding protein (human IF-4E) in Escherichia coli and fluorescence studies on interaction with mRNA cap structure analogues. Journal of biochemistry 35 1939010
2017 Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion. Oncogene 30 28991229
2019 Knock-out mutation of eukaryotic initiation factor 4E2 (eIF4E2) confers resistance to pepper veinal mottle virus in tomato. Virology 28 31622792
1991 Combination of Trp and Glu residues for recognition of mRNA cap structure. Analysis of m7G base recognition site of human cap binding protein (IF-4E) by site-directed mutagenesis. FEBS letters 27 1672854
2021 eIF4E-homologous protein (4EHP): a multifarious cap-binding protein. The FEBS journal 25 34758096
2021 microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP. Molecular cell 24 33581076
2019 Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression. Nucleic acids research 24 31114929
2017 The eIF4E2-Directed Hypoxic Cap-Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment. Oxidative medicine and cellular longevity 24 29317983
2019 Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression. Genes & development 23 31439631
2004 Characterizing the interaction of the mammalian eIF4E-related protein 4EHP with 4E-BP1. FEBS letters 23 15094042
2017 MicroRNAs recruit eIF4E2 to repress translation of target mRNAs. Protein & cell 22 28755203
2013 Investigating the consequences of eIF4E2 (4EHP) interaction with 4E-transporter on its cellular distribution in HeLa cells. PloS one 22 23991149
2022 The SARS-CoV-2 protein NSP2 impairs the silencing capacity of the human 4EHP-GIGYF2 complex. iScience 20 35756894
2021 CRISPR-based knock-out of eIF4E2 in a cherry tomato background successfully recapitulates resistance to pepper veinal mottle virus. Plant science : an international journal of experimental plant biology 17 35151441
2017 Trypanosoma brucei EIF4E2 cap-binding protein binds a homolog of the histone-mRNA stem-loop-binding protein. Current genetics 17 29288414
2015 Drosophila 4EHP is essential for the larval-pupal transition and required in the prothoracic gland for ecdysone biosynthesis. Developmental biology 16 26721418
2020 The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior. Molecular autism 15 33225984
2021 Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition. Computational and structural biotechnology journal 10 33995900
2020 A newly identified Leishmania IF4E-interacting protein, Leish4E-IP2, modulates the activity of cap-binding protein paralogs. Nucleic acids research 9 32232353
2022 Roles and interactions of the specialized initiation factors EIF4E2, EIF4E5, and EIF4E6 in Trypanosoma brucei: EIF4E2 maintains the abundances of S-phase mRNAs. Molecular microbiology 7 36056730
2022 Mammalian eIF4E2-GSK3β maintains basal phosphorylation of p53 to resist senescence under hypoxia. Cell death & disease 4 35568694
2024 The 4EHP-mediated translational repression of cGAS impedes the host immune response against DNA viruses. Proceedings of the National Academy of Sciences of the United States of America 3 39560640
2023 Cell-type-specific translational control of spatial working memory by the cap-binding protein 4EHP. Molecular brain 3 36650535
2025 4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila. Nature communications 1 41436469
2025 NITAC-mediated ISGylation of eIF4E2 attenuates GSK3β proline-directed kinase activity, conferring cytoprotection. The Journal of biological chemistry 0 41022323

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