Affinage

EIF4H

Eukaryotic translation initiation factor 4H · UniProt Q15056

Length
248 aa
Mass
27.4 kDa
Annotated
2026-06-09
16 papers in source corpus 15 papers cited in narrative 15 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

EIF4H is an RNA-binding translation initiation accessory factor that stimulates the ATP-dependent RNA helicase eIF4A to resolve 5'UTR secondary structure during cap-dependent translation (PMID:11418588, PMID:22457067). It binds both eIF4A and loop structures within RNA, occupying a binding site on eIF4AI that is mutually exclusive with the related factor eIF4B, and expands eIF4A's preferred RNA-binding footprint to enhance affinity (PMID:18719248); together with eIF4A it drives persistent, repetitive cycles of duplex unwinding and re-annealing, each consuming a single molecule of ATP and requiring ATP hydrolysis (PMID:22457067). Through this activity EIF4H selectively enhances translation of structured 5'UTR and IRES-containing mRNAs encoding growth and survival factors such as c-Myc, cyclin D1, and BCL-xL, promoting cellular transformation and drug resistance (PMID:26498689), and its association with the eIF4F complex is modulated by binding partners including KRT14 to reprogram metabolic gene translation (PMID:41444318). EIF4H is essential in vivo: Eif4h knockout mice show growth retardation, reduced brain volume, and severe learning and memory deficits (PMID:22234171), and its ortholog acts downstream of TOR to mediate dietary-restriction lifespan extension (PMID:20456299). EIF4H is also exploited by pathogens — it is a direct interaction partner and stimulator of the HSV virion host shutoff (Vhs) endoribonuclease, targeting Vhs activity to mRNAs (PMID:16014927, PMID:15078951, PMID:18448541), and is an essential host factor for HEV replication via interaction with the viral ORF1 methyltransferase-protease region (PMID:41779781).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established the core biochemical function of eIF4H as a stimulator of eIF4A helicase activity, addressing how the initiation machinery resolves structured RNA.

    Evidence In vitro helicase assay with purified eIF4A/eIF4B/eIF4H/eIF4F on duplexes of varying stability

    PMID:11418588

    Open questions at the time
    • Did not resolve the structural basis of eIF4A binding
    • Mechanism of processivity only partially defined
  2. 2004 High

    Showed that eIF4H is hijacked by a viral nuclease, stimulating HSV Vhs RNase activity, revealing a non-canonical role beyond translation.

    Evidence In vitro RNase assay with yeast-expressed Vhs supplemented with purified eIF4H

    PMID:15078951

    Open questions at the time
    • eIF4H alone did not reconstitute IRES-directed targeting
    • Additional mammalian factors required were not identified
  3. 2005 High

    Mapped the direct tripartite physical interactions among Vhs, eIF4H, and eIF4A, defining residues for Vhs-eIF4H binding distinct from eIF4A binding.

    Evidence Y2H, GST pulldown, co-IP from mammalian cells, site-directed mutagenesis, in vitro RNase assay

    PMID:16014927

    Open questions at the time
    • Did not establish the in-cell requirement for Vhs targeting
    • Structural geometry of the ternary complex unresolved
  4. 2008 High

    Defined the molecular relationship between eIF4H and eIF4B, showing they share a mutually exclusive eIF4A binding site and expand its RNA footprint.

    Evidence EMSA, RNase footprinting, competition binding and stoichiometry analysis with eIF4AI

    PMID:18719248

    Open questions at the time
    • Did not explain functional differences between eIF4H and eIF4B in vivo
    • Weak RNA interactions not structurally localized
  5. 2008 High

    Demonstrated cellular specificity of eIF4H for Vhs-mediated mRNA degradation, distinguishing it from eIF4B.

    Evidence siRNA knockdown in HeLa with HSV infection and RT-qPCR, with eIF4B negative control

    PMID:18448541

    Open questions at the time
    • Did not define why eIF4B cannot substitute for eIF4H in cells
  6. 2012 High

    Resolved the dynamic mechanism of eIF4H/eIF4A action as repetitive, single-ATP-per-cycle unwinding/re-annealing.

    Evidence Single-molecule FRET and ATP titration with hydrolysis controls

    PMID:22457067

    Open questions at the time
    • Did not connect repetitive cycling to specific mRNA classes in cells
  7. 2010 Medium

    Placed the eIF4H ortholog in a TOR-dependent, dietary-restriction lifespan pathway, linking translational control to organismal physiology.

    Evidence Genetic epistasis, polysome fractionation, lifespan assays in C. elegans drr-2

    PMID:20456299

    Open questions at the time
    • Molecular target mRNAs governing lifespan not identified
    • Direct biochemical link to TOR signaling not established
  8. 2003 Medium

    Localized eIF4H to cytoplasmic polysomes and the perinuclear region at the nuclear pore exit, defining where it engages mRNP.

    Evidence Subcellular fractionation, immunoelectron microscopy, polysome sedimentation in Chironomus tentans

    PMID:14576346

    Open questions at the time
    • Nuclear pool function undefined
    • Insect ortholog — human relevance not directly tested
  9. 2012 Medium

    Established an essential in vivo developmental and cognitive role for eIF4H via knockout mouse phenotyping.

    Evidence Eif4h knockout mice, MRI neuroanatomy, fear conditioning, histology

    PMID:22234171

    Open questions at the time
    • No molecular mechanism linking eIF4H to the neuronal phenotypes
    • Specific mRNAs affected in brain not identified
  10. 2015 Medium

    Defined eIF4H as a selective translational regulator of structured-5'UTR growth/survival mRNAs with oncogenic consequences.

    Evidence siRNA/overexpression in lung cancer and NIH3T3, polysome profiling, xenograft and transformation assays

    PMID:26498689

    Open questions at the time
    • Direct binding to each target 5'UTR not demonstrated
    • Isoform-specific contributions not fully dissected
  11. 2019 Medium

    Identified eIF4H as a modifier of repeat-associated non-AUG (RAN) translation of C9orf72 G4C2 repeats.

    Evidence Drosophila loss-of-function screen, GR-GFP reporter, toxicity assays, patient cell/tissue validation

    PMID:31023341

    Open questions at the time
    • Mechanism by which eIF4H promotes RAN translation undefined
    • Whether it acts via helicase stimulation on repeat RNA not tested
  12. 2018 Medium

    Tracked eIF4H cytoplasmic-to-nuclear relocalization during HSV spread, correlating it with host translation shutdown.

    Evidence Single-cell HPG labeling, immunofluorescence, live imaging during HSV transmission

    PMID:30028874

    Open questions at the time
    • Relocalization is correlative, not causal, for the translational switch
    • Trigger and machinery of relocalization unknown
  13. 2025 Medium

    Revealed that KRT14 binds eIF4H and modulates its eIF4F association to selectively drive ACOX2 translation and chemoresistance.

    Evidence Co-IP, GST pulldown, domain mapping, ACOX2 5'UTR luciferase reporter, polysome profiling, xenografts in bladder cancer

    PMID:41444318

    Open questions at the time
    • Single study/single lab
    • Structural basis of KRT14-eIF4H interaction undefined
  14. 2026 Medium

    Identified eIF4H as an essential HEV host factor interacting with the ORF1 methyltransferase-protease region.

    Evidence Genome-wide CRISPR screen, co-IP with ORF1 domains, KO cell lines and rats, HEV replication assays

    PMID:41779781

    Open questions at the time
    • How eIF4H shapes ORF1 replication complex composition mechanistically unclear
    • Whether translational/helicase activity is required for HEV role untested
  15. 2026 Low

    Showed an EIF4H coding variant (R183H) confers allele-specific enhanced translation, raising the question of how variation alters eIF4H output.

    Evidence Polysomal RNA-seq allelic analysis, shotgun proteomics with PRM, dual-fluorescence ribosome-stalling reporter

    PMID:41722779

    Open questions at the time
    • Functional consequence of R183H on eIF4H helicase-stimulating activity not characterized
    • Single lab, proof-of-concept only

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how eIF4H selectively recognizes specific structured 5'UTRs in cells and how its diverse roles (TOR-linked lifespan, neuronal development, viral cofactor) connect to its core helicase-stimulating biochemistry.
  • No structural model of the eIF4H-eIF4A-RNA complex
  • Target mRNA selection rules undefined
  • Mechanistic unification of physiological and viral roles missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0098772 molecular function regulator activity 3 GO:0045182 translation regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005840 ribosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1643685 Disease 2 R-HSA-162582 Signal Transduction 1
Partners
EIF4A1EIF4BKRT14
Complex memberships
eIF4F

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 eIF4H stimulates the initial rate and amplitude of eIF4A-dependent RNA duplex unwinding in a manner dependent on duplex stability, and in combination with eIF4A confers slight processivity to the helicase. The stimulation requires single-stranded flanking regions on the substrate, and the factor combination shows differences in unwinding chemically modified duplexes compared to eIF4A alone. In vitro helicase assay with purified eIF4A, eIF4B, eIF4H, and eIF4F using RNA duplexes of varying stability and chemical modifications The Journal of biological chemistry High 11418588
2005 eIF4H physically interacts with the HSV virion host shutoff (Vhs) protein; a complex of bacterially expressed Vhs and GST-eIF4H fusion protein has RNase activity. eIF4H also interacts directly with eIF4A (yeast two-hybrid, GST pulldown, co-immunoprecipitation from mammalian cells). Vhs, eIF4H, and eIF4A each interact directly with the other two. Site-directed mutagenesis of Vhs and eIF4H identified residues required for their mutual interaction but not for their interaction with eIF4A. GST pulldown, yeast two-hybrid, co-immunoprecipitation from mammalian cells, site-directed mutagenesis, in vitro RNase assay Journal of virology High 16014927
2004 eIF4H (and the related factor eIF4B) stimulate the nuclease activity of HSV Vhs protein. Addition of purified eIF4H to yeast-expressed Vhs strongly enhanced its RNase activity, though eIF4H did not reconstitute IRES-directed targeting to EMCV IRES (which required additional mammalian factors). In vitro RNase activity assay using yeast-expressed Vhs supplemented with purified eIF4H or eIF4B; comparison with rabbit reticulocyte lysate Journal of virology High 15078951
2008 eIF4H and eIF4B share a common, mutually exclusive binding site on eIF4AI. Both accessory factors form 1:1 stable complexes with eIF4AI dependent on AMPPNP, and both expand the preferred RNA binding site of eIF4AI from ~17 nt to ~30–33 nt without changing the RNase-resistant footprint (9–10 nt), suggesting they contribute to RNA affinity through weak interactions. Electrophoretic mobility shift assay (EMSA), RNase footprinting, in vitro RNA binding with selective binding experiments, stoichiometry analysis RNA (New York, N.Y.) High 18719248
2008 siRNA depletion of eIF4H in HeLa cells impeded Vhs-mediated mRNA degradation (beta-actin mRNA levels were indistinguishable in eIF4H-depleted infected vs. mock-infected cells), while depletion of the related factor eIF4B did not affect Vhs activity, demonstrating that eIF4H binding is specifically required for Vhs-induced mRNA degradation in cells. siRNA knockdown in HeLa cells followed by HSV infection and RT-qPCR measurement of mRNA levels; comparison to eIF4B siRNA knockdown Journal of virology High 18448541
2012 eIF4H enhances eIF4AI helicase activity by binding directly to loop structures within RNA transcripts and to eIF4AI itself; in the presence of ATP, the eIF4AI/eIF4H complex performs persistent, repetitive cycles of unwinding and re-annealing consuming a single ATP per cycle. The process requires ATP hydrolysis (non-hydrolysable ATP-γS does not support unwinding). Single-molecule FRET (sm-FRET), ATP titration assays Nucleic acids research High 22457067
2010 In C. elegans, DRR-2 (eIF4H ortholog) functions downstream of TOR but in parallel to the S6K/PHA-4 pathway to mediate lifespan extension under dietary restriction; DRR-2 associates with polysomes and its knockdown decreases the rate of protein synthesis. Genetic epistasis (double mutant analysis), polysome fractionation, lifespan assays in C. elegans with drr-2 RNAi and overexpression Aging cell Medium 20456299
2003 In Chironomus tentans, eIF4H (Ct-eIF4H) is present in both cytoplasm and nucleus; the cytoplasmic fraction associates with poly(A+) RNA in polysomes. The nuclear fraction does not associate with pre-mRNPs or mRNPs within the nucleus; immunoelectron microscopy shows eIF4H associates with mRNP only in the cytoplasmic perinuclear region immediately upon exit from the nuclear pore complex. Subcellular fractionation, immunoelectron microscopy, polysome sedimentation, RNA immunoprecipitation Journal of cell science Medium 14576346
2012 Knockout of Eif4h in mice causes growth retardation, reduced body weight, smaller brain volume with altered morphology, reduced neuronal number and complexity, and severe impairments in fear-related associative learning and memory, demonstrating an essential in vivo role in development and cognition. Knockout mouse generation, MRI neuroanatomical profiling, behavioral testing (fear conditioning), histological neuron analysis The American journal of pathology Medium 22234171
2015 eIF4H depletion in lung cancer cells reduces translation of structured 5'UTR mRNAs encoding c-Myc, cyclin D1, FGF-2, CIAP-1, and BCL-xL; overexpression of eIF4H isoforms stimulates translation of IRES-containing or structured 5'UTR mRNAs and promotes cellular transformation, invasion, and drug resistance, establishing eIF4H as a selective translational regulator of growth and survival factor mRNAs. siRNA knockdown, overexpression in NIH3T3 and lung cancer cells, polysome profiling, in vivo xenograft assays, transformation assays Oncotarget Medium 26498689
2019 eIF4H mediates RAN-translation of the GR dipeptide from expanded G4C2 (C9orf72) repeats in a Drosophila model; loss-of-function of eIF4H reduces GR-GFP production and suppresses toxicity caused by G4C2 expression, identifying eIF4H as a modifier of repeat-associated non-AUG translation. Unbiased loss-of-function genetic screen in Drosophila, GR-GFP reporter assay, toxicity assays, validation in patient-derived cells and post-mortem ALS/FTD tissue Acta neuropathologica communications Medium 31023341
2018 During HSV cell-to-cell spread, eIF4H undergoes a precise relocalization from cytoplasmic to nuclear compartments that correlates temporally with the initial shutdown of host translation; however, translational recovery occurs despite sustained eIF4H nuclear accumulation, indicating this relocalization is associated with but not solely responsible for the translational switch. Single-cell bioorthogonal protein labeling (HPG incorporation), immunofluorescence imaging of eIF4H localization, live cell imaging during HSV transmission PLoS pathogens Medium 30028874
2025 KRT14 directly interacts with eIF4H through its N-terminal Head domain; this interaction modulates the association of eIF4H with the core eIF4F complex and selectively promotes translation of ACOX2 mRNA through its 5'UTR, thereby reprogramming lipid metabolism and contributing to cisplatin resistance in bladder cancer. Co-immunoprecipitation, GST pulldown, domain mapping, polysome profiling, luciferase reporter assay with ACOX2 5'UTR, xenograft models, patient-derived tissues Cell death & disease Medium 41444318
2026 EIF4H is an essential host factor for HEV replication; it interacts with the HEV ORF1 protein via ORF1's methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1-associated replication complex. EIF4H knockout rats show profound resistance to rat HEV-C1 infection. Genome-wide CRISPR/Cas9 knockout screen, co-immunoprecipitation of EIF4H with ORF1 domains, EIF4H knockout cell lines and rats, HEV replication assays across genotypes Proceedings of the National Academy of Sciences of the United States of America Medium 41779781
2026 A heterozygous R183H missense variant (rs1554710467) in EIF4H is associated with allele-specific mRNA translation: the H183 allele is over-represented in polysomal RNA and produces more abundant protein; a dual-fluorescence ribosome-stalling assay confirmed enhanced translation potential of this variant. The two allelic proteins show similar stability and subpolysomal localization. Polysomal RNA-seq allelic fraction analysis, label-free shotgun proteomics with parallel reaction monitoring using isotope-labeled peptide standards, dual-fluorescence ribosome-stalling reporter assay Molecular & cellular proteomics : MCP Low 41722779

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. The Journal of biological chemistry 263 11418588
2005 mRNA decay during herpes simplex virus (HSV) infections: protein-protein interactions involving the HSV virion host shutoff protein and translation factors eIF4H and eIF4A. Journal of virology 99 16014927
2008 Interactions between eIF4AI and its accessory factors eIF4B and eIF4H. RNA (New York, N.Y.) 81 18719248
2004 Herpes simplex virus virion host shutoff protein is stimulated by translation initiation factors eIF4B and eIF4H. Journal of virology 57 15078951
2010 drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging cell 43 20456299
2012 The eukaryotic initiation factor eIF4H facilitates loop-binding, repetitive RNA unwinding by the eIF4A DEAD-box helicase. Nucleic acids research 41 22457067
2019 eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS. Acta neuropathologica communications 38 31023341
2008 Small interfering RNAs that deplete the cellular translation factor eIF4H impede mRNA degradation by the virion host shutoff protein of herpes simplex virus. Journal of virology 33 18448541
2015 Key contribution of eIF4H-mediated translational control in tumor promotion. Oncotarget 32 26498689
2012 Growth defects and impaired cognitive-behavioral abilities in mice with knockout for Eif4h, a gene located in the mouse homolog of the Williams-Beuren syndrome critical region. The American journal of pathology 30 22234171
2003 The Chironomus tentans translation initiation factor eIF4H is present in the nucleus but does not bind to mRNA until the mRNA reaches the cytoplasmic perinuclear region. Journal of cell science 13 14576346
2017 Overexpression of miR-519d in lung adenocarcinoma inhibits cell proliferation and invasion via the association of eIF4H. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 28351305
2018 A bimodal switch in global protein translation coupled to eIF4H relocalisation during advancing cell-cell transmission of herpes simplex virus. PLoS pathogens 4 30028874
2025 Cytoskeletal protein KRT14 governs cisplatin resistance by modulating eIF4H-dependent ACOX2 translation and lipid metabolism in bladder cancer. Cell death & disease 1 41444318
2026 Polysomal Profiling Coupled to Allele-Specific Proteomics Reveals an EIF4H TranSNP Allele Possessing Higher mRNA Translation Potential. Molecular & cellular proteomics : MCP 0 41722779
2026 EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 0 41779781

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