Affinage

EIF4A1

Eukaryotic initiation factor 4A-I · UniProt P60842

Length
406 aa
Mass
46.2 kDa
Annotated
2026-06-09
77 papers in source corpus 26 papers cited in narrative 27 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

EIF4A1 is an ATP-dependent DEAD-box RNA helicase that serves as the engine of cap-dependent translation initiation by unwinding structured 5' UTRs to permit ribosomal scanning (PMID:1378397, PMID:8131750). Mutagenesis of recombinant eIF-4A established that its conserved motifs partition catalysis: the ATPase A motif binds ATP, the DEAD motif couples ATP hydrolysis to unwinding, the HRIGRXXR motif performs hydrolysis, and the SAT region executes RNA strand separation (PMID:1378397). eIF4A1 functions principally as a subunit of the eIF4F complex rather than as a free factor, cycling through eIF4F during each round of initiation (PMID:8131750) via a conserved central binding interface on eIF4G (PMID:11256967). Its helicase activity is stimulated by binding partners that promote eIF4F assembly and ATPase output, including PKP1 (PMID:20156963) and PHGDH (PMID:30744688), and is further activated by multimerization on AG-rich (purine-rich) 5'-UTR motifs, where distinct subunits perform separable enzymatic steps to reposition RNA for efficient unwinding (PMID:36727461). eIF4A1-dependent mRNAs are characterized by long, structured, C/CG-rich or G-quadruplex-prone 5' leaders (PMID:32766783, PMID:25611378), and inhibitor studies dissect two activities—eIF4F-mediated mRNA loading versus start-site selection—linked to C/CG-rich versus AG-rich UTR features. The factor is preferentially required for translation of oncogenic mRNAs encoding cyclins, kinases, MYC, BRD2 and CDK6, driving proliferation and cell-cycle progression across cancer contexts (PMID:35361883, PMID:27879264, PMID:25611378, PMID:37983610) and is essential for B-cell development and germinal-centre responses through control of global protein synthesis (PMID:39516355, PMID:38011999). eIF4A1 activity is regulated post-translationally by non-degradative ubiquitination via the CRL3-IBTK ligase downstream of mTORC1/S6K1 signaling (PMID:38738857) and by USP15-mediated deubiquitination, which stabilizes it to support keratinocyte proliferation and wound re-epithelialization (PMID:32671073, PMID:34422211). Beyond canonical initiation, eIF4A1 has non-canonical RNA-handling roles: it stabilizes CtIP mRNA to regulate DNA end resection (PMID:32392243), represses TOP-mRNA translation in concert with LARP1 upon mTORC1 inactivation (PMID:38773334), and acts as an RNA chaperone during mitotic exit to dissolve perichromatin condensates and enable chromatin decondensation, a function dependent on RNA binding but not ATPase activity (PMID:40069174). eIF4A1 is the target of multiple chemically distinct inhibitors—hippuristanol, elatol, and rocaglate/amidino-rocaglate compounds that clamp it onto polypurine RNA—which abrogate translation and tumor growth (PMID:32766783, PMID:29844128, PMID:39989799, PMID:40529213).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 High

    Established the catalytic logic of eIF4A1 by assigning discrete functions to conserved DEAD-box motifs, defining how ATP binding, hydrolysis, and RNA unwinding are mechanically coupled.

    Evidence In vitro reconstitution of helicase activity with recombinant eIF-4A/eIF-4B plus site-directed mutagenesis of conserved motifs

    PMID:1378397

    Open questions at the time
    • Did not establish how the helicase operates within the intact eIF4F complex in cells
    • No structural model of the catalytic cycle
  2. 1993 Medium

    Provided early evidence that eIF4A1 contacts specific cis-regulatory 5'-UTR elements, foreshadowing its sequence/structure-selective roles.

    Evidence T1 RNase footprinting and immunoprecipitation on human asparagine synthetase mRNA 5' UTR

    PMID:8093451

    Open questions at the time
    • Limited mechanistic depth; binding specificity determinants not defined
    • Functional consequence for translation not directly tested
  3. 1994 High

    Resolved whether eIF4A1 acts free or complexed, showing eIF4F is the primary functional unit and that eIF4A1 must cycle through eIF4F during translation.

    Evidence Dominant-negative eIF-4A in rabbit reticulocyte lysate with rescue and helicase assays

    PMID:8131750

    Open questions at the time
    • Molecular basis of the cycling mechanism not resolved
    • Stoichiometry of eIF4A within eIF4F in vivo not defined
  4. 2001 High

    Defined the conserved eIF4A-binding interface on eIF4G as essential for translation in vivo, while revealing species-specific functional incompatibility.

    Evidence Yeast genetics, in vitro binding, and rescue experiments comparing mammalian and yeast eIF4A/eIF4G

    PMID:11256967

    Open questions at the time
    • Structural basis of the incompatibility unresolved
    • Did not address regulation of the interaction
  5. 2010 High

    Identified PKP1 as a direct activator of eIF4A1 ATPase and eIF4F recruitment, linking eIF4A1 stimulation to proliferation and cell size.

    Evidence Co-IP, cap-complex co-purification, in vitro ATPase and IRES-dependent translation assays in MCF7 cells

    PMID:20156963

    Open questions at the time
    • Whether PKP1 modulates target-mRNA selectivity not addressed
    • Structural mode of ATPase stimulation unknown
  6. 2015 Medium

    Defined the eIF4A1-dependent translatome, showing preferential dependence of oncogenic, G/C-rich, G-quadruplex-prone mRNAs.

    Evidence siRNA knockdown plus polysome profiling and cell-cycle assays in MCF7 cells

    PMID:25611378

    Open questions at the time
    • Causal link between G-quadruplex unwinding and translation not directly demonstrated
    • Single cell-line context
  7. 2016 Medium

    Separated the shared versus divergent regulatory contributions of eIF4A1 and eIF4E, localizing eIF4A1-specific effects to the 5' UTR.

    Evidence Parallel siRNA silencing with quantitative proteomics, RNA-seq, and polysome profiling in melanoma cells

    PMID:27879264

    Open questions at the time
    • Mechanistic basis of 5'-UTR-specific divergence not resolved
    • Single tumor type
  8. 2018 High

    Validated eIF4A1 as a druggable target with elatol, demonstrating direct ATPase/helicase inhibition and an unexpected 2:1 binding stoichiometry.

    Evidence In vitro ATPase/helicase assays, binding/mutagenesis, and xenograft model

    PMID:29844128

    Open questions at the time
    • Structural basis of 2:1 stoichiometry not defined
    • Selectivity over eIF4A2 not fully resolved
  9. 2020 High

    Pinned down the molecular and structural features dictating eIF4A1 dependence and target engagement, defining hippuristanol's mechanism and the structured/C-rich nature of dependent mRNAs.

    Evidence CRISPR/Cas9 variomics, genome-wide ribosome profiling, and mRNA structural analysis

    PMID:32766783

    Open questions at the time
    • Did not resolve how conformational locking translates to translatome changes mechanistically
  10. 2020 Medium

    Revealed a non-canonical eIF4A1 function in mRNA stabilization, linking it to DNA end resection independently of helicase initiation activity.

    Evidence Co-IP, siRNA knockdown of ALC1/eIF4A1, and CtIP 5'-UTR reporter and RT-PCR stability assays

    PMID:32392243

    Open questions at the time
    • Whether ATPase activity is required not tested
    • Direct RNA contact vs. complex-mediated effect not distinguished
  11. 2020 Medium

    Identified USP15 as a deubiquitinase of eIF4A1 that stabilizes it to promote translation and wound re-epithelialization, establishing reversible ubiquitin control.

    Evidence Co-IP/MS, USP15 knockout mouse, keratinocyte knockdown, and wound-healing assays; corroborated by PRP-exosome study

    PMID:32671073 PMID:34422211

    Open questions at the time
    • The cognate ubiquitin ligase opposing USP15 not identified here
    • Ubiquitin site(s) not mapped
  12. 2023 High

    Mechanistically defined how AG-rich motifs drive eIF4A1 multimerization, with distinct subunits performing different enzymatic steps to reposition RNA for unwinding.

    Evidence In vitro unwinding assays, mutant analysis, structural studies, and ribosome profiling

    PMID:36727461

    Open questions at the time
    • Precise architecture and stoichiometry of the active multimer not fully resolved
    • Coupling to scanning in vivo not directly visualized
  13. 2024 High

    Revealed a repressive non-canonical role: eIF4A1 promotes LARP1-dependent binding of TOP mRNAs to repress their translation upon mTORC1 inhibition.

    Evidence RNA pulldown-seq, ribosome profiling, EIF4A1 deletion, and LARP1 co-IP under mTORC1 inhibition

    PMID:38773334

    Open questions at the time
    • Whether helicase catalysis is required for repression not resolved
    • Structural basis of TOP-motif recognition unknown
  14. 2024 High

    Connected mTORC1/S6K1 signaling to eIF4A1 activity through CRL3-IBTK-mediated non-degradative ubiquitination that enhances cap-dependent initiation and oncogene expression.

    Evidence Co-IP, in vitro ubiquitination/phosphorylation assays, IBTK knockout, ribosome profiling, and xenograft

    PMID:38738857

    Open questions at the time
    • How ubiquitination biochemically alters helicase/eIF4F activity not defined
    • Ubiquitin acceptor lysines not mapped
  15. 2024 High

    Distinguished eIF4A1 from eIF4A2 in vivo, showing eIF4A1 controls global synthesis and is essential for B-cell development and germinal-centre responses.

    Evidence Mouse conditional knockouts with ribosome/polysome and rRNA biogenesis assays; Hippuristanol co-inhibition

    PMID:38011999 PMID:39516355

    Open questions at the time
    • Functional redundancy with eIF4A2 in non-immune tissues not fully mapped
    • Target-mRNA sets distinguishing the isoforms incompletely defined
  16. 2024 Medium

    Showed eIF4A1 can be recruited to specific mRNAs by RNA-binding adaptors (IGF2BP2) for m6A-dependent translation of CDK6, expanding modes of selective recruitment.

    Evidence Co-IP, RIP, polysome fractionation, and stability assays in TNBC cell lines

    PMID:37983610

    Open questions at the time
    • Direct vs. bridged eIF4A1-mRNA contact not resolved
    • Generality beyond CDK6 untested
  17. 2025 High

    Established an ATPase-independent RNA-chaperone function for eIF4A1 in dissolving perichromatin condensates to drive chromatin decondensation at mitotic exit.

    Evidence Cell-free condensation assay, live imaging, knockdown/gain-of-function, and ATPase-dead mutant analysis

    PMID:40069174

    Open questions at the time
    • How eIF4A1 is targeted to mitotic chromosomes not defined
    • Relationship to its translation role mechanistically unconnected
  18. 2025 High

    Provided high-resolution structural insight into how rocaglate-class compounds clamp eIF4A1 onto polypurine RNA, rationalizing inhibitor potency.

    Evidence X-ray crystal structure of an amidino-rocaglate with eIF4A1, AMPPNP, and poly r(AG)5 at 1.69 Å

    PMID:39989799

    Open questions at the time
    • Structure of apo or eIF4F-embedded eIF4A1 not provided here
    • Does not address multimeric assembly on AG-rich RNA
  19. 2025 Medium

    Extended therapeutic targeting of eIF4A1 to cholangiocarcinoma and fibrosis models, linking inhibition to reduced glycolysis, MYC loss, autophagic disruption, and tumor regression.

    Evidence PDX and organoid models with eFT226/zotatifin; CETSA-MS target ID and knockdown with P7C3 in hepatic stellate cells

    PMID:40529213 PMID:41761033

    Open questions at the time
    • On-target specificity versus off-target effects of new compounds not fully resolved
    • Mechanistic basis of metabolic and autophagy effects incompletely defined
  20. 2025 Medium

    Mapped isoform-specific ATPase determinants and showed eIF4A1's higher ATP affinity over eIF4A2, also identifying a bacterial toxin (BLF1) that modulates its ATPase.

    Evidence In vitro ATPase assays with N-terminal domain swapping and L98/A100 point mutations

    PMID:40423315

    Open questions at the time
    • Single lab, limited replication
    • Physiological relevance of BLF1 modulation in human cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How eIF4A1's distinct canonical (mRNA loading vs. start-site selection), repressive (LARP1/TOP), mRNA-stabilizing, and ATPase-independent chaperone functions are coordinated within a single protein, and how ubiquitination biochemically reconfigures its activity, remains unresolved.
  • No unified structural framework linking helicase, multimerization, and chaperone modes
  • Ubiquitin acceptor sites and their effect on catalysis unmapped
  • Mechanism directing eIF4A1 to non-translation roles (chromatin, mRNA stability) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140657 ATP-dependent activity 5 GO:0045182 translation regulator activity 4 GO:0140098 catalytic activity, acting on RNA 4 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2
Partners
EIF4EEIF4GIBTKIGF2BP2LARP1PHGDHPKP1USP15
Complex memberships
CRL3-IBTK ubiquitin ligase complexeIF4F cap-binding complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Site-directed mutagenesis of recombinant eIF-4A defined functional roles for conserved DEAD-box motifs: the ATPase A motif (AXXXXGKT) is required for ATP binding; the DEAD motif couples ATP hydrolysis to RNA helicase activity; the HRIGRXXR motif is involved in ATP hydrolysis; and the SAT region is essential for RNA unwinding. Recombinant eIF-4A together with recombinant eIF-4B exhibit RNA helicase activity in vitro. In vitro reconstitution of RNA helicase activity with recombinant proteins; site-directed mutagenesis of conserved motifs; ATPase and helicase assays The EMBO journal High 1378397
1994 Dominant-negative eIF-4A mutants potently inhibit translation by blocking recycling through the eIF-4F complex. eIF-4A functions primarily as a subunit of eIF-4F rather than as a free factor; eIF-4F (not free eIF-4A) is the primary functional unit and is six-fold more effective than free eIF-4A at rescuing translation. Mutant eIF-4A also inhibits eIF-4F-dependent but not eIF-4A-dependent RNA helicase activity, indicating that eIF-4A must cycle through eIF-4F during translation. Dominant-negative mutant eIF-4A added to rabbit reticulocyte translation system; rescue experiments with eIF-4A, eIF-4F, eIF-4B; kinetic and helicase assays The EMBO journal High 8131750
2001 The central eIF4A-binding domain of mammalian eIF4G and the eIF4A-binding domain of yeast eIF4G share conserved amino acid motifs required for eIF4A interaction. Yeast eIF4G mutants defective in eIF4A binding show strongly impaired translation and growth in vivo. Mammalian eIF4A binds tightly to yeast eIF4G1, but mammalian eIF4A cannot substitute for yeast eIF4A in vivo despite high sequence conservation. Yeast genetics (temperature-sensitive mutants), in vitro binding assays, yeast in vitro translation system, rescue experiments The Biochemical journal High 11256967
2010 Plakophilin 1 (PKP1) directly associates with eIF4A1, co-purifies with eIF4A1 in cap-binding complexes, and stimulates eIF4A1 ATPase activity at the molecular level. PKP1 overexpression promotes eIF4A1 recruitment into cap-binding complexes and stimulates eIF4A1-dependent (cap- and EMCV IRES-mediated) translation but not eIF4A1-independent (HCV IRES-mediated) translation. PKP1 stimulation of translation correlates with increased cell proliferation and cell size. Co-immunoprecipitation, co-purification in cap complex, in vitro ATPase assay, IRES-dependent translation assays, overexpression/knockdown in MCF7 cells The Journal of cell biology High 20156963
2019 PHGDH (phosphoglycerate dehydrogenase) interacts with eIF4A1 and eIF4E, and this interaction facilitates assembly of the eIF4F complex on 5' mRNA structures to promote cap-dependent translation initiation in pancreatic cancer cells. PHGDH knockdown disrupts eIF4F complex assembly and inhibits translation of relevant target proteins. Co-immunoprecipitation, pulldown, knockdown experiments with translation readout in PANC-1 cells, xenograft model Journal of experimental & clinical cancer research : CR Medium 30744688
2020 Hippuristanol (Hipp) binds to the carboxyl-terminal domain of eIF4A1, locks it in a closed conformation, and inhibits its RNA binding. Using CRISPR/Cas9-based variomics, functional Hipp-resistant EIF4A1 alleles were identified, linking Hipp's translation-inhibitory and cytotoxic properties directly to eIF4A1 target engagement. Genome-wide translational profiling showed that eIF4A1-dependent mRNAs are characterized by longer 5' leaders, greater overall secondary structure, and higher cytosine content. CRISPR/Cas9 variomics screen, genome-wide ribosome profiling, mRNA structural analysis, cell viability assays Nucleic acids research High 32766783
2020 ALC1 (chromatin remodeler) cooperates with eIF4A1 to stabilize the most abundant splicing form of CtIP mRNA, through a specific RNA sequence in the 5' UTR of CtIP. This mRNA stabilization function of eIF4A1 is independent of ALC1's chromatin-remodeling activity, representing a non-canonical role for eIF4A1 in regulating DNA end resection by controlling CtIP mRNA levels. Co-immunoprecipitation, siRNA knockdown of ALC1 and eIF4A1, reporter assays with CtIP 5' UTR sequences, RT-PCR for mRNA stability PLoS genetics Medium 32392243
2020 USP15 interacts with eIF4A1 and deubiquitinates it, promoting translational efficacy in keratinocytes. USP15 knockout in mice delays wound re-epithelialization, and USP15-silenced keratinocytes show inhibited migration and proliferation. The USP15-EIF4A1 complex accelerates re-epithelialization. Co-immunoprecipitation, mass spectrometry, USP15 knockout mouse model, USP15 siRNA knockdown in HaCaT cells, wound healing assays, RNA-sequencing Frontiers in cell and developmental biology Medium 32671073
2021 PRP-derived exosomes promote wound healing via USP15, which deubiquitinates EIF4A1, stabilizing it and enhancing its function in keratinocyte proliferation and migration. In vitro CCK-8, EdU, scratch wound and transwell assays; in vivo wound healing mouse model; functional validation of USP15-EIF4A1 deubiquitination axis Oxidative medicine and cellular longevity Medium 34422211
2018 The marine natural product elatol specifically inhibits eIF4A1 ATPase activity in vitro, inhibits eIF4A1 helicase activity, and binds the helicase core of eIF4A1 with an unexpected 2:1 stoichiometry. Elatol-sensitive tumor cells show acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. Target-based ATPase inhibition assay, helicase inhibition assay, binding/mutagenesis studies, cell-based mechanistic studies, xenograft in vivo model Clinical cancer research High 29844128
2023 eIF4A1-dependent mRNAs contain AG-rich (purine-rich) motifs in their 5' UTRs that specifically activate eIF4A1 unwinding of local RNA structure. Binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1, with distinct subunits performing different enzymatic activities. Structural data suggest that RNA-binding by multimeric eIF4A1 induces conformational changes in RNA for optimal positioning proximal to RNA duplexes enabling efficient unwinding. In vitro RNA unwinding assays, eIF4A1 mutant analysis, structural studies, ribosome profiling, cell-based translation reporters, identification of AG-rich 5' UTR motifs Nucleic acids research High 36727461
2024 eIF4A1 preferentially binds mRNAs containing terminal oligopyrimidine (TOP) motifs in an interaction that depends on the La-related RNA-binding protein LARP1. Upon mTORC1 inhibition, eIF4A1 increases interaction between TOP mRNAs and LARP1, thereby enhancing translational repression of TOP mRNAs. Deletion of EIF4A1 attenuates translational repression of TOP mRNAs upon mTORC1 inactivation, revealing a repressive non-canonical role for eIF4A1. RNA pulldown followed by sequencing (RNA-seq), ribosome profiling, EIF4A1 deletion cell lines, mTORC1 inhibitor treatment, co-immunoprecipitation of LARP1 with TOP mRNAs Nature structural & molecular biology High 38773334
2024 The CRL3IBTK ubiquitin ligase complex (with IBTK as substrate-binding adaptor) interacts with eIF4A1 and catalyzes non-degradative ubiquitination of eIF4A1. This ubiquitination promotes cap-dependent translational initiation, nascent protein synthesis, and oncogene expression. mTORC1 and S6K1 directly phosphorylate IBTK to augment eIF4A1 ubiquitination, linking the mTORC1/S6K1 signaling axis to eIF4A1 activity. Co-immunoprecipitation, in vitro ubiquitination assay, phosphorylation assay, IBTK knockout/knockdown, ribosome profiling, xenograft in vivo model eLife High 38738857
2024 EIF4A1 and EIF4A2 play distinct molecular roles in B cells: eIF4A1 controls global protein synthesis while eIF4A2 regulates biogenesis of 18S ribosomal RNA and the 40S ribosome subunit. EIF4A1 is essential for B-cell development and the germinal centre response; its loss impairs protein synthesis and MYC expression after B cell activation. Mouse genetic conditional knockouts (Cre-lox), ribosome profiling or polysome analysis, rRNA biogenesis assays, B cell developmental analysis by flow cytometry Cellular & molecular immunology High 39516355
2023 EIF4A1 is essential for B cell development and the germinal centre response in mice. After B cell activation, EIF4A1 facilitates increased rates of protein synthesis, MYC expression, and expression of cell cycle regulators. EIF4A1-deficient B cells remain viable, whereas combined inhibition of EIF4A1 and EIF4A2 by Hippuristanol induces cell death. Conditional Eif4a1 knockout in B cells (mouse model), protein synthesis assays, western blotting, Hippuristanol pharmacological inhibition, germinal centre assays Life science alliance High 38011999
2022 eIF4A1 mediates translational regulation of the oncogene BRD2, whose 5' UTR contains the most enriched eIF4A1-binding motifs. RNA immunoprecipitation followed by RNA sequencing (RIP-seq) established this eIF4A1-BRD2 translational axis in prostate cancer cells. EIF4A1 expression is epigenetically regulated by DNA methylation at a CpG-rich island, with hypomethylation correlating with elevated EIF4A1 expression in prostate cancer. RIP-sequencing, DNMT3a CRISPR-Cas9 epigenetic targeting, EIF4A1 heterozygous knockout/knockdown, western blotting, polysome profiling implied Oncogene Medium 35361883
2016 Comparative proteomic and transcriptomic analysis of eIF4A1 vs. eIF4E silencing in melanoma cells revealed that eIF4A1 and eIF4E exert common effects on translation through coding regions and 3' UTRs, while their divergent effects occur through the 5' UTR. Silencing eIF4A1 decreases melanoma proliferation and invasion, with effects on cell cycle proteins. siRNA silencing of eIF4A1/eIF4E, quantitative proteomics, RNA-seq, polysome profiling, proliferation and invasion assays Cancer research Medium 27879264
2015 eIF4A1 knockdown in MCF7 breast cancer cells restricts cell growth and cycling. Polysome profiling defined the eIF4A1-dependent translatome, which is enriched for oncogenic mRNAs encoding G-protein constituents, cyclins, and protein kinases, and for mRNAs with G/C-rich 5' UTRs with potential to form G-quadruplexes. eIF4A1 knockdown (siRNA), polysome profiling with microarray/sequencing, cell growth and cell cycle assays Cell death & disease Medium 25611378
2025 eIF4A1 directly binds to transgelin (Tagln) protein, preventing its ubiquitination and degradation, which leads to upregulation of p53 and promotes nuclear translocation of both Tagln and p53, resulting in cardiomyocyte apoptosis during ischemia/reperfusion injury. Cardiomyocyte-specific eIF4A1 knockout attenuates cardiomyocyte apoptosis and reduces infarct area in mice. Co-immunoprecipitation, cardiomyocyte-specific knockout mouse model (myocardial I/R model), overexpression/knockdown, ubiquitination assays, nuclear fractionation, western blot Acta pharmacologica Sinica Medium 39856433
2025 eIF4A1/2 acts as an RNA chaperone during mitotic exit to enable chromatin decondensation. In a cell-free condensation assay, eIF4A1/2 is crucial for chromatin decondensation, relying on its RNA-binding ability but not its ATPase activity. Reducing eIF4A1/2 levels slows chromatin decondensation during nuclear reformation, while increasing eIF4A1/2 concentration on mitotic chromosomes accelerates decondensation. eIF4A1/2 dissociates biomolecular condensates of RNA and perichromatin proteins in vitro, regulating the composition and fluidity of the perichromatin layer. Cell-free chromatin condensation assay, live cell imaging, eIF4A1/2 knockdown, overexpression targeting mitotic chromosomes, in vitro condensate dissolution assay, ATPase-dead mutant analysis Nature communications High 40069174
2024 IGF2BP2 (m6A reader) recruits EIF4A1 to promote the translation initiation of CDK6 mRNA in an m6A-dependent manner, increasing CDK6 protein levels at the level of translation rate rather than mRNA stability. This IGF2BP2-EIF4A1-CDK6 axis drives G1/S cell cycle progression in triple-negative breast cancer. Co-immunoprecipitation, RNA immunoprecipitation, polysome fractionation, mRNA stability assay, siRNA knockdown, overexpression in TNBC cell lines Advanced science Medium 37983610
1993 eIF-4A interacts with specific cis-acting regulatory elements in the 5' UTR of human asparagine synthetase mRNA (spanning -60 to -120 bases from the initiation codon). A 46 kDa trans-acting protein identified as eIF-4A by immunoprecipitation with anti-eIF-4A monoclonal antibody was shown to protect these elements from T1 RNase digestion. T1 RNase footprinting, hybrid arrest translation, immunoprecipitation with monoclonal anti-eIF-4A antibody The Journal of biological chemistry Medium 8093451
2025 X-ray crystal structure of an amidino-rocaglate (ADR) in complex with eIF4A1, AMPPNP, and poly r(AG)5 RNA at 1.69 Å resolution shows that rocaglates clamp eIF4A1 onto polypurine RNA. ADR binding pose is similar to rocaglamide A (RocA), but its rigidified scaffold is preorganized in an eIF4A1-RNA binding-competent conformation, avoiding entropic penalties and improving potency. X-ray crystallography (1.69 Å resolution), computational modeling ACS omega High 39989799
2025 BLF1 (Burkholderia lethal factor 1 toxin) modulates eIF4A1 ATPase activity. eIF4A1 has higher ATP-binding affinity (lower Km) than eIF4A2. Leucine 98 (L98) and alanine 100 (A100) play important roles in the ATPase activities of eIF4A isoforms, as revealed by N-terminal domain swapping and single amino acid mutations. In vitro ATPase assay, domain swapping, site-directed mutagenesis, temperature/pH/Mg2+ sensitivity assays Toxins Medium 40423315
2025 P7C3 compound directly binds eIF4A1 (identified by CETSA-mass spectrometry and protein microarray), inhibits eIF4A1-mediated global protein synthesis (including c-Myc), and disrupts autophagic flux by downregulating ULK1 in hepatic stellate cells. eIF4A1 knockdown mimics P7C3 effects on fibrotic markers. Cellular thermal shift assay (CETSA) coupled with mass spectrometry, protein microarray, molecular docking, eIF4A1 knockdown/overexpression, protein synthesis assay, autophagic flux assay Archives of pharmacal research Medium 41761033
2025 EIF4A1 inhibition by eFT226 significantly reduces tumor growth in intrahepatic cholangiocarcinoma PDX models. Zotatifin (eIF4A1 inhibitor) decreases glycolysis of iCCA cells without affecting mitochondrial respiration and shows synergistic apoptosis when combined with Bcl-xl inhibitors. PDX in vivo tumor model, patient-derived organoids, cell line inhibition assays, metabolic flux assays, combination drug apoptosis assays JHEP reports Medium 40529213
2025 Mechanistic characterization of eIF4A1 inhibitors revealed two distinct eIF4A1 functions linked to distinct mRNA 5' UTR features: C/CG-rich 5' UTRs require efficient mRNA loading by eIF4F (specifically targeted by hippuristanol), while AG-rich motifs plus alternative start sites direct eIF4A1 to start site selection (specifically perturbed by eFT226/zotatifin). These findings were validated by massively parallel reporter assay. Biochemical inhibitor characterization (hippuristanol vs. eFT226), machine learning model of mRNA features, massively parallel reporter assay (MPRA), ribosome profiling bioRxivpreprint Medium

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Mutational analysis of a DEAD box RNA helicase: the mammalian translation initiation factor eIF-4A. The EMBO journal 550 1378397
1994 Dominant negative mutants of mammalian translation initiation factor eIF-4A define a critical role for eIF-4F in cap-dependent and cap-independent initiation of translation. The EMBO journal 336 8131750
1988 Nuclear protein with sequence homology to translation initiation factor eIF-4A. Nature 184 2451786
1988 An eIF-4A-like protein is a suppressor of an Escherichia coli mutant defective in 50S ribosomal subunit assembly. Nature 148 2461520
1985 Cloning of eukaryotic protein synthesis initiation factor genes: isolation and characterization of cDNA clones encoding factor eIF-4A. Nucleic acids research 148 3840589
2015 The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape. Cell death & disease 128 25611378
1989 An essential yeast protein, encoded by duplicated genes TIF1 and TIF2 and homologous to the mammalian translation initiation factor eIF-4A, can suppress a mitochondrial missense mutation. Proceedings of the National Academy of Sciences of the United States of America 126 2648398
1997 Translation initiation factor eIF-4A1 mRNA is consistently overexpressed in human melanoma cells in vitro. International journal of cancer 91 9139875
1993 A new yeast translation initiation factor suppresses a mutation in the eIF-4A RNA helicase. The EMBO journal 85 8404866
2019 Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E. Journal of experimental & clinical cancer research : CR 81 30744688
2020 Circ_0008035 contributes to cell proliferation and inhibits apoptosis and ferroptosis in gastric cancer via miR-599/EIF4A1 axis. Cancer cell international 70 32190008
2010 Plakophilin 1 stimulates translation by promoting eIF4A1 activity. The Journal of cell biology 70 20156963
2020 Exosome-transmitted long non-coding RNA SENP3-EIF4A1 suppresses the progression of hepatocellular carcinoma. Aging 53 32602848
1991 Divergent genes for translation initiation factor eIF-4A are coordinately expressed in tobacco. Nucleic acids research 53 1719476
2023 IGF2BP2 Drives Cell Cycle Progression in Triple-Negative Breast Cancer by Recruiting EIF4A1 to Promote the m6A-Modified CDK6 Translation Initiation Process. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 47 37983610
1993 Identification of an essential Drosophila gene that is homologous to the translation initiation factor eIF-4A of yeast and mouse. Molecular & general genetics : MGG 42 8455559
2019 Selective targeting of the DEAD-box RNA helicase eukaryotic initiation factor (eIF) 4A by natural products. Natural product reports 41 31782447
2014 Decreased expression of EIF4A1 after preoperative brachytherapy predicts better tumor-specific survival in cervical cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 40 24844222
2013 Over-expression of human cytomegalovirus miR-US25-2-3p downregulates eIF4A1 and inhibits HCMV replication. FEBS letters 40 23747307
2002 Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1. British journal of cancer 39 12085193
2017 miR-133a acts as a tumor suppressor in colorectal cancer by targeting eIF4A1. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 28466778
2016 MiR-1284 modulates multidrug resistance of gastric cancer cells by targeting EIF4A1. Oncology reports 37 26936591
2018 Target-Based Screening against eIF4A1 Reveals the Marine Natural Product Elatol as a Novel Inhibitor of Translation Initiation with In Vivo Antitumor Activity. Clinical cancer research : an official journal of the American Association for Cancer Research 36 29844128
1995 A pollen-specific DEAD-box protein related to translation initiation factor eIF-4A from tobacco. Plant molecular biology 34 7727743
1994 Characterization of the tobacco eIF-4A gene family. Plant molecular biology 32 7858215
2021 Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling. Cancer cell international 29 34906136
2020 Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5' leader regions. Nucleic acids research 29 32766783
2016 Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E. Cancer research 26 27879264
2023 eIF4A1-dependent mRNAs employ purine-rich 5'UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation. Nucleic acids research 25 36727461
2021 Platelet-Rich Plasma-Derived Exosomal USP15 Promotes Cutaneous Wound Healing via Deubiquitinating EIF4A1. Oxidative medicine and cellular longevity 24 34422211
2019 MiR-1284 suppresses gastric cancer progression by targeting EIF4A1. OncoTargets and therapy 24 31190893
2022 Astragaloside IV exhibits anti-tumor function in gastric cancer via targeting circRNA dihydrolipoamide S-succinyltransferase (circDLST)/miR-489-3p/ eukaryotic translation initiation factor 4A1(EIF4A1) pathway. Bioengineered 23 35435117
2021 Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5. Frontiers in cardiovascular medicine 21 34859078
2020 Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells. Cancers 20 32759815
2001 Structural and functional similarities between the central eukaryotic initiation factor (eIF)4A-binding domain of mammalian eIF4G and the eIF4A-binding domain of yeast eIF4G. The Biochemical journal 20 11256967
2022 Epigenetic regulation of EIF4A1 through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling in prostate cancer. Oncogene 17 35361883
2021 Long Non-coding RNA SENP3-EIF4A1 Functions as a Sponge of miR-195-5p to Drive Triple-Negative Breast Cancer Progress by Overexpressing CCNE1. Frontiers in cell and developmental biology 17 33791304
2003 Replication fork-stimulated eIF-4A from Plasmodium cynomolgi unwinds DNA in the 3' to 5' direction and is inhibited by DNA-interacting compounds. Archives of biochemistry and biophysics 17 12745261
2020 USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair. Frontiers in cell and developmental biology 16 32671073
2019 NHX1 and eIF4A1-stacked transgenic sweetpotato shows enhanced tolerance to drought stress. Plant cell reports 16 31396684
2019 Aberrant Expression Of PDCD4/eIF4A1 Signal Predicts Postoperative Recurrence For Early-Stage Oral Squamous Cell Carcinoma. Cancer management and research 15 31807078
1993 Characterization of the ATP-dependent binding of wheat germ protein synthesis initiation factors eIF-(iso)4F and eIF-4A to mRNA. The Journal of biological chemistry 15 8360155
2022 Novel eIF4A1 inhibitors with anti-tumor activity in lymphoma. Molecular medicine (Cambridge, Mass.) 14 36058921
2024 Critical and differential roles of eIF4A1 and eIF4A2 in B-cell development and function. Cellular & molecular immunology 12 39516355
2024 eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition. Nature structural & molecular biology 11 38773334
2020 Understanding the thermal response of rice eukaryotic transcription factor eIF4A1 towards dynamic temperature stress: insights from expression profiling and molecular dynamics simulation. Journal of biomolecular structure & dynamics 11 32367760
1999 Five different genes, Eif4a1, Cd68, Supl15h, Sox15 and Fxr2h, are clustered in a 40 kb region of mouse chromosome 11. Gene 11 10524236
1995 Highly conserved genes coding for eukaryotic translation initiation factor eIF-4A of tobacco have specific alterations in functional motifs. Biochimica et biophysica acta 11 7742374
1992 Molecular cloning and analysis of an eIF-4A-related rat liver nuclear protein. The Journal of biological chemistry 11 1618789
2024 mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated ubiquitination of eIF4A1 in cancer cells. eLife 9 38738857
2020 Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study. Scientific reports 9 32978410
2024 The m6A reader IGF2BP2 promotes esophageal cell carcinoma progression by enhancing EIF4A1 translation. Cancer cell international 8 38724996
2020 Role of eIF4A1 in triple-negative breast cancer stem-like cell-mediated drug resistance. Cancer reports (Hoboken, N.J.) 8 33053607
2020 Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1. Cancer management and research 8 33299354
2022 eIF4A1 Inhibitor Suppresses Hyperactive mTOR-Associated Tumors by Inducing Necroptosis and G2/M Arrest. International journal of molecular sciences 6 35805935
2021 Molecular Dynamics Simulations Identify Tractable Lead-like Phenyl-Piperazine Scaffolds as eIF4A1 ATP-competitive Inhibitors. ACS omega 6 34604625
2020 ALC1/eIF4A1-mediated regulation of CtIP mRNA stability controls DNA end resection. PLoS genetics 6 32392243
2000 The initiation translation factor eIF-4A of Cryptosporidium parvum is encoded by two distinct mRNA forms and shows DNA sequence polymorphism distinguishing genotype 1 and 2 isolates. The Journal of parasitology 6 10958456
1993 Interaction of the eucaryotic peptide chain initiation factor eIF-4A with the specific elements at the 5'-untranslated sequence of human asparagine synthetase mRNA. The Journal of biological chemistry 5 8093451
2024 Curcumin Inhibits the Development of Pancreatic Cancer by Targeting the circ_0079440/miR-522-3p/EIF4A1 Pathway. Cell biochemistry and biophysics 4 39102088
2020 The DEAD-box RNA helicase eIF4A1 interacts with the SWI2/SNF2-related chromatin remodelling ATPase DDM1 in the moss Physcomitrella. Biochimica et biophysica acta. Proteins and proteomics 4 33359411
2003 Molecular modeling of a Leishmania antigen eIF-4A: identification of a potential epitope implicated in the adjuvant effect. Journal of biomolecular structure & dynamics 4 12854958
2025 eIF4A1 exacerbates myocardial ischemia-reperfusion injury in mice by promoting nuclear translocation of transgelin/p53. Acta pharmacologica Sinica 3 39856433
2023 Increased Expression of lncRNA AC000120.7 and SENP3-EIF4A1 in Patients with Acute Respiratory Distress Syndrome Induced by SARS-CoV-2 Infection: A Pilot Study. Microorganisms 3 37764186
2023 RNA helicase EIF4A1-mediated translation is essential for the GC response. Life science alliance 3 38011999
2012 Protein flexibility and conformational states of Leishmania antigen eIF-4A: identification of a novel plausible protein adjuvant using comparative genomics and molecular modeling. Journal of biomolecular structure & dynamics 2 22963753
2004 All trans-retinoic acid (ATRA) elevated eukaryotic translation initiation factor 4A1 (eIF4A1) mRNA in ATRA-responsive vitiliginous epidermis. Pigment cell research 2 15541024
2025 Targeting EIF4A1 is effective against human intrahepatic cholangiocarcinoma. JHEP reports : innovation in hepatology 1 40529213
2026 P7C3 alleviates hepatic fibrosis via targeting eIF4A1-mediated protein translation and autophagy in hepatic stellate cells. Archives of pharmacal research 0 41761033
2026 Proteomic characterization of intrahepatic cholangiocarcinoma identifies risk-stratifying subgroups and EIF4A1 as a therapeutic target. Nature communications 0 41872184
2026 Curcumin inhibits chondrocyte apoptosis and inflammation in osteoarthritis via the miR-338-3p/EIF4A1 signaling axis. Hereditas 0 41957683
2025 Structural Basis for the Improved RNA Clamping of Amidino-Rocaglates to eIF4A1. ACS omega 0 39989799
2025 The DEAD-box helicase eIF4A1/2 acts as RNA chaperone during mitotic exit enabling chromatin decondensation. Nature communications 0 40069174
2025 Effect and mechanism of the miR-1284/EIF4A1 axis on the cGAS-STING pathway under radiotherapy. Translational cancer research 0 40386253
2025 BLF1 Affects ATP Hydrolysis Catalyzed by Native and Mutated eIF4A1 and eIF4A2 Proteins. Toxins 0 40423315
2025 Translation element EIF4A1 is a potential divergent immune biomarker between colon cancer and rectal cancer. International journal of immunopathology and pharmacology 0 41268779
2019 [RNA Enhancement by lncRNA Promotes Translation Through Recruitment of ILF3 and EIF4A1 to the Target Mammalian mRNAs]. Molekuliarnaia biologiia 0 30895953

Missed literature

Know a paper Affinage missed for EIF4A1? Flag it for the maintainers and the community.

No submissions yet.