Affinage

EEF1D

Elongation factor 1-delta · UniProt P29692

Length
281 aa
Mass
31.1 kDa
Annotated
2026-06-09
21 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EEF1D encodes eEF1Bδ, a subunit of the eEF1B guanine-nucleotide exchange complex that operates at the interface of translation elongation, the cellular stress response, and growth signaling (PMID:25686034, PMID:36576126). Alternative splicing generates functionally distinct isoforms: short isoforms participate in translation elongation, whereas the alternatively spliced long isoform functions as a transcriptional activator of heat-shock responsive genes rather than an elongation factor (PMID:25686034). Short isoforms containing exon 5 anchor the EEF1B complex to the endoplasmic reticulum through interactions with the ER scaffold proteins KTN1 and RRBP1; deletion of exon 5 causes diffuse cytoplasmic redistribution of the complex and reduced EEF1B subunit abundance in vivo without changing global protein synthesis rates (PMID:42230146). The heat-shock transcriptional activity can be antagonized by direct binding of a lncRNA, which redistributes EEF1D and represses downstream heat-shock genes (PMID:36603194). EEF1D is phosphorylated at serine 162 by protein kinase CK2 (PMID:21936567), and its abundance is controlled post-translationally — galectin LGALS9B competes with the E3 ligase HERC5 to block ubiquitin-proteasome degradation (PMID:39639171) — and post-transcriptionally by SRSF9 binding to its 3'UTR to stabilize the mRNA (PMID:38771720). Across multiple cancers EEF1D promotes proliferation, survival, and metastasis largely through activation of PI3K/Akt-mTOR signaling, and its loss sensitizes cells to chemotherapy (PMID:29510727, PMID:35672728, PMID:39639171). Biallelic loss-of-function variants targeting either the long-isoform/alternatively spliced domain or the C-terminal GEF domain cause severe autosomal recessive neurodevelopmental disorders (PMID:30787422, PMID:36576126). EEF1D also supports mammary milk lipid synthesis (PMID:33913197) and is exploited by viruses as a host factor (PMID:40578269, PMID:41805193).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2011 High

    Established that EEF1D is a direct, physiological substrate of CK2, defining a specific regulatory phosphorylation site (S162) on the elongation-factor subunit.

    Evidence 32P metabolic labeling, in vitro CK2 kinase assays, λ-phosphatase treatment, phospho-specific pS162 antibody and inhibitor-resistant CK2 mutants in HeLa cells

    PMID:21936567

    Open questions at the time
    • Functional consequence of S162 phosphorylation on GEF activity or complex assembly not resolved
    • Does not link phosphorylation to isoform-specific roles
  2. 2015 Medium

    Resolved that EEF1D isoforms have divergent functions, separating a translation-elongation role for short isoforms from a heat-shock transcriptional activation role for the long isoform.

    Evidence Review synthesizing alternative-splicing and isoform functional characterization in heat-shock response

    PMID:25686034

    Open questions at the time
    • Primary experimental detail of transcriptional activation mechanism not described
    • Target promoters and co-factors of the long isoform unspecified
  3. 2016 Medium

    Connected EEF1D to oncogenic proliferation and EMT, moving it beyond a housekeeping translation role into cancer cell biology.

    Evidence siRNA knockdown in oral squamous carcinoma cells with proliferation/invasion assays and cyclin D1/vimentin readouts

    PMID:26823560

    Open questions at the time
    • Which isoform drives the phenotype not distinguished
    • Direct molecular link between EEF1D and cyclin D1/vimentin not defined
  4. 2018 Medium

    Placed EEF1D upstream of Akt-mTOR/Akt-Bad signaling, identifying the pathway through which it drives proliferation and survival.

    Evidence siRNA knockdown in osteosarcoma cells with cell cycle analysis, signaling array, and phospho-Akt/mTOR/Bad Western blots

    PMID:29510727

    Open questions at the time
    • Mechanism by which EEF1D activates Akt not defined
    • Direct vs indirect effect on signaling unresolved
  5. 2019 Low

    Implicated the long isoform / heat-shock transcriptional pathway, rather than canonical elongation, in a human neurodevelopmental disorder.

    Evidence Linkage analysis and whole-exome sequencing of a consanguineous family with isoform-specific variant mapping

    PMID:30787422

    Open questions at the time
    • Single family; isoform-specific pathomechanism inferred from variant location, not demonstrated functionally
    • No rescue or animal model
  6. 2021 High

    Demonstrated a physiological role for EEF1D in mammary lipid metabolism, broadening its function to tissue-specific metabolic output.

    Evidence RNAi in bovine mammary epithelial cells and CRISPR/Cas9 knockout mice with lipid droplet imaging, triglyceride measurement and PI3K-Akt/AMPK/PPAR pathway readouts

    PMID:33913197

    Open questions at the time
    • Whether effect is mediated by translation or signaling function unclear
    • Isoform responsible not identified
  7. 2022 Medium

    Showed EEF1D loss sensitizes cancer cells to chemotherapy via PI3K/AKT inactivation, linking it to apoptosis and DNA-damage-repair regulation.

    Evidence siRNA and CRISPR knockout in ovarian cancer cells with apoptosis assays, xenograft model, and Western blots for p-Akt, Bcl-2/Bax, cleaved caspase-3, ERCC1, OPTN

    PMID:35672728

    Open questions at the time
    • Direct effect of EEF1D on ERCC1/OPTN not mechanistically defined
    • Single lab
  8. 2023 Medium

    Revealed that EEF1D's heat-shock transcriptional function is regulated by lncRNA sequestration, providing a mechanism for controlling its nuclear activity.

    Evidence RNA pull-down, FISH, nuclear/cytoplasmic fractionation, and lncRNA overexpression with heat-shock gene readouts

    PMID:36603194

    Open questions at the time
    • Human ortholog lncRNA equivalence not established
    • Binding region on EEF1D not mapped
  9. 2023 Low

    Identified the C-terminal GEF domain as essential for neurodevelopment, establishing a second, distinct disease mechanism from the alternatively spliced domain.

    Evidence Exome sequencing in two families with variant mapping to the GEF domain and clinical phenotyping

    PMID:36576126

    Open questions at the time
    • Effect on GEF/eEF1A reactivation activity not functionally tested
    • No animal or cellular model
  10. 2024 Medium

    Defined post-transcriptional control of EEF1D, showing SRSF9 stabilizes its mRNA to drive cancer proliferation and metastasis.

    Evidence RNA immunoprecipitation, RNA pull-down, proteomics, and EEF1D knockdown rescue of SRSF9-driven phenotypes in colorectal cancer cells

    PMID:38771720

    Open questions at the time
    • 3'UTR binding site not mapped
    • Whether stabilization is isoform-selective unknown
  11. 2024 Medium

    Defined post-translational control of EEF1D abundance through a competition between LGALS9B and the E3 ligase HERC5, linking stability directly to PI3K/AKT-driven tumor progression.

    Evidence Co-IP, competition binding assays, proteasome inhibitor experiments and in vitro/in vivo functional assays in gastric cancer

    PMID:39639171

    Open questions at the time
    • Ubiquitination site on EEF1D not mapped
    • Reciprocal validation in additional models lacking
  12. 2025 Medium

    Identified EEF1D as a proviral host factor that translocates to viral replication compartments during herpesvirus infection.

    Evidence Immunofluorescence co-localization with ICP8 and gD, siRNA knockdown, and viral titer measurement during BoAHV1 infection

    PMID:40578269

    Open questions at the time
    • Molecular function of EEF1D within replication compartments unknown
    • Direct viral protein binding not demonstrated
  13. 2026 Medium

    Showed that KSHV RTA suppresses EEF1D both by proteasomal degradation and promoter hypermethylation, establishing EEF1D as a host restriction factor for viral lytic reactivation.

    Evidence Co-IP, dual-luciferase reporters, DNMT3A-dependent methylation assays and EEF1D overexpression/knockdown with viral reactivation readouts

    PMID:41805193

    Open questions at the time
    • Mechanism by which EEF1D restricts lytic replication not defined
    • Single lab
  14. 2026 High

    Established the molecular basis of EEF1B complex localization, showing exon-5-containing short isoforms anchor the complex to the ER via KTN1/RRBP1 independent of bulk translation.

    Evidence FLAG-EEF1D pulldown/MS, exon 5 deletion mutant, exon 5 KO mice, subcellular fractionation, multi-tissue abundance and global protein synthesis assays

    PMID:42230146

    Open questions at the time
    • Functional purpose of ER anchoring (localized translation?) not established
    • Connection between ER anchoring and disease/cancer phenotypes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EEF1D's distinct biochemical activities — GEF-mediated elongation, ER anchoring, and long-isoform heat-shock transcription — are coordinated, and which activity underlies its disease, metabolic, and cancer roles, remains unresolved.
  • Isoform attribution of most cancer/metabolic phenotypes not defined
  • No structural model linking GEF and transcriptional functions
  • Direct demonstration of GEF activity loss in disease variants lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CK2HERC5KTN1LGALS9BRRBP1SRSF9
Complex memberships
eEF1B guanine nucleotide exchange complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 EEF1D is a bona fide physiological substrate of protein kinase CK2, which directly phosphorylates EEF1D at serine 162 (S162). This was demonstrated by CK2 inhibitor-dependent decreases in EEF1D phosphorylation in 32P-labeled HeLa cells, direct CK2 kinase assays with FLAG-tagged EEF1D, λ-phosphatase treatment causing dramatic increases in phosphorylation, a phospho-specific antibody recognizing EEF1D pS162, and restoration of phosphorylation using CK2 inhibitor-resistant mutants. 32P metabolic labeling, in vitro CK2 kinase assay, λ-phosphatase treatment, phospho-specific antibody (pS162), CK2 inhibitor-resistant mutants, 2D electrophoresis and mass spectrometry Journal of proteome research High 21936567
2015 EEF1D undergoes alternative splicing to produce a long isoform and short isoforms with distinct functions: the long isoform acts as a transcriptional activator of heat-shock responsive genes (not as a translational elongation factor), while the short isoforms function in translation elongation. The long isoform regulates the cellular stress response through transcriptional activation. Alternative splicing characterization, functional analysis of isoforms in heat shock response and transcriptional activation (review summarizing experimental findings) International journal of molecular sciences Medium 25686034
2016 EEF1D knockdown in oral squamous cell carcinoma (OSCC) cells reduced cell proliferation and induced epithelial-mesenchymal transition (EMT) phenotypes including cell invasion, while EEF1D and its interaction partners promote activation of cyclin D1 and vimentin proteins. siRNA knockdown, cell proliferation assay, invasion assay, Western blotting for cyclin D1 and vimentin, protein interaction partner identification Clinical science (London, England : 1979) Medium 26823560
2018 EEF1D knockdown in osteosarcoma cells inhibited proliferation, colony-forming ability, and G2/M cell cycle transition, and decreased levels of phospho-Akt, phospho-mTOR, and phospho-Bad, placing EEF1D upstream of the Akt-mTOR and Akt-Bad signaling pathways. siRNA knockdown, cell proliferation assay, colony formation assay, cell cycle analysis, PathScan intracellular signaling array, Western blotting Journal of experimental & clinical cancer research : CR Medium 29510727
2019 Biallelic loss-of-function variants in EEF1D that exclusively target the long isoform cause autosomal recessive intellectual disability, implicating the long isoform's heat shock response pathway (transcriptional activation function) rather than canonical translational elongation in the neurodevelopmental phenotype. SNP-based linkage analysis, whole exome sequencing, isoform-specific variant analysis in consanguineous family Journal of human genetics Low 30787422
2021 EEF1D regulates milk lipid synthesis in mammals: RNAi-mediated knockdown in primary bovine mammary epithelial cells caused aberrant lipid droplet formation and decreased milk triglyceride levels by 37.7%, acting via insulin (PI3K-Akt), AMPK, and PPAR pathways. CRISPR/Cas9 knockout mice showed incompletely developed mammary glands and decreased milk triglyceride by 23.4%. RNAi knockdown in primary bovine mammary epithelial cells, CRISPR/Cas9 knockout mice, lipid droplet imaging, triglyceride measurement, gene expression analysis of PI3K-Akt/AMPK/PPAR pathways FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 33913197
2022 EEF1D knockdown or knockout sensitizes ovarian cancer cells to cisplatin (DDP), partially via inactivation of the PI3K/AKT signaling pathway, leading to increased apoptosis (elevated cleaved caspase-3, altered Bcl-2/Bax) and decreased DNA damage repair (reduced ERCC1). EEF1D loss also affected OPTN levels. siRNA knockdown, CRISPR/Cas9 knockout, cell viability assay, apoptosis assay, xenograft mouse model, Western blotting for p-Akt, Bcl-2, Bax, cleaved caspase-3, ERCC1, OPTN BMC cancer Medium 35672728
2023 The lncRNA NONMMUT033452.2 directly binds Eef1D (demonstrated by RNA pull-down assay), and overexpression of this lncRNA induces redistribution of Eef1D and substantially inhibits expression of downstream heat shock genes, revealing that Eef1D's heat shock gene regulation function can be sequestered by a lncRNA binding partner. RNA pull-down assay, FISH, cytoplasmic/nuclear fractionation, lncRNA overexpression, heat shock gene expression analysis American journal of respiratory cell and molecular biology Medium 36603194
2023 Biallelic variants in the C-terminal GEF (guanine exchange factor) domain of EEF1D cause severe neurodevelopmental disorder with microcephaly and spasticity, indicating that the GEF domain—responsible for EEF1Bδ's role in catalyzing GTP/GDP exchange to reactivate eEF1A for aminoacyl-tRNA delivery—is essential for neurodevelopment, distinct from the alternatively spliced domain variants affecting the transcriptional function. Exome sequencing in two families, variant mapping to GEF domain, clinical phenotyping Clinical genetics Low 36576126
2024 SRSF9 stabilizes EEF1D mRNA by binding to the 3'UTR of EEF1D mRNA (demonstrated by RNA immunoprecipitation and RNA pull-down assay), thereby upregulating EEF1D protein levels. EEF1D knockdown reversed the malignant proliferation and metastasis phenotype induced by SRSF9 overexpression in colorectal cancer cells. RNA immunoprecipitation, RNA pull-down assay, proteomics, EEF1D knockdown/overexpression, in vitro and in vivo proliferation/metastasis assays International journal of cancer Medium 38771720
2024 LGALS9B (Galectin-9B) binds EEF1D and competes with the E3 ubiquitin ligase HERC5 for this interaction, thereby preventing ubiquitin-proteasome-mediated degradation of EEF1D. The resulting EEF1D enrichment activates the PI3K/AKT signaling pathway to promote gastric cancer progression. Co-immunoprecipitation, competition binding assay between LGALS9B and HERC5 for EEF1D, proteasome inhibitor experiments, PI3K/AKT pathway readouts, in vitro and in vivo functional assays Oncogene Medium 39639171
2025 During Bovine alpha herpesvirus 1 (BoAHV1) productive infection, EEF1D undergoes enhanced nuclear translocation and forms puncta co-localizing with viral replication compartment marker ICP8 in the nucleus, while a portion of cytoplasmic EEF1D co-localizes with virion-associated protein gD. siRNA-mediated EEF1D knockdown significantly decreases BoAHV1 productive infection, indicating a proviral role for EEF1D. Immunofluorescence assay, siRNA knockdown, viral titer measurement, co-localization analysis Veterinary microbiology Medium 40578269
2026 KSHV RTA promotes EEF1D protein degradation via the ubiquitin-proteasome pathway and represses EEF1D transcription through promoter hypermethylation. RTA interacts with EEF1D protein and induces DNMT3A-dependent hypermethylation of the EEF1D promoter, a process facilitated by transcription factor PATZ1. EEF1D acts as an inhibitory factor for KSHV lytic reactivation, as EEF1D overexpression suppresses viral lytic replication while EEF1D depletion enhances viral reactivation. Co-immunoprecipitation (RTA-EEF1D interaction), dual-luciferase reporter assays, DNMT3A-dependent methylation assays, EEF1D overexpression/knockdown with viral reactivation readouts, promoter methylation analysis Journal of virology Medium 41805193
2026 Short EEF1D isoforms containing exon 5 anchor the EEF1B complex to the endoplasmic reticulum (ER) by interacting with ER-resident scaffold proteins KTN1 and RRBP1. Deletion of exon 5 disrupts ER anchoring and causes diffuse cytoplasmic localization of the EEF1B complex, accompanied by reduced EEF1B subunit abundance in multiple tissues in vivo, without affecting global protein synthesis rates. FLAG-tagged EEF1D pulldown with mass spectrometry, exon 5 deletion mutant, exon 5 KO mice, subcellular fractionation/localization, protein abundance measurement across tissues, global protein synthesis rate assay Life science alliance High 42230146

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8. BMC cancer 62 16968546
2016 EEF1D modulates proliferation and epithelial-mesenchymal transition in oral squamous cell carcinoma. Clinical science (London, England : 1979) 34 26823560
2018 EEF1D overexpression promotes osteosarcoma cell proliferation by facilitating Akt-mTOR and Akt-bad signaling. Journal of experimental & clinical cancer research : CR 29 29510727
2011 Unbiased functional proteomics strategy for protein kinase inhibitor validation and identification of bona fide protein kinase substrates: application to identification of EEF1D as a substrate for CK2. Journal of proteome research 26 21936567
2020 EEF1D Promotes Glioma Proliferation, Migration, and Invasion through EMT and PI3K/Akt Pathway. BioMed research international 23 33029523
2021 EEF1D facilitates milk lipid synthesis by regulation of PI3K-Akt signaling in mammals. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 33913197
2015 Regulation of translation factor EEF1D gene function by alternative splicing. International journal of molecular sciences 17 25686034
2017 Regulation of DNA methylation on EEF1D and RPL8 expression in cattle. Genetica 16 28667419
2019 Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability. Journal of human genetics 13 30787422
2013 Identification and expression pattern of two novel alternative splicing variants of EEF1D gene of dairy cattle. Gene 8 24239553
2023 Prenatal LPS Exposure Promotes Allergic Airway Inflammation via Long Coding RNA NONMMUT033452.2, and Protein Binding Partner, Eef1D. American journal of respiratory cell and molecular biology 7 36603194
2021 The role of EEF1D in disease pathogenesis: a narrative review. Annals of translational medicine 7 34790806
2022 Interfering with the expression of EEF1D gene enhances the sensitivity of ovarian cancer cells to cisplatin. BMC cancer 6 35672728
2024 EEF1D stabilized by SRSF9 promotes colorectal cancer via enhancing the proliferation and metastasis. International journal of cancer 4 38771720
2016 Identification of novel isoforms of dairy goat EEF1D and their mRNA expression characterization. Gene 4 26794801
2023 Expanding the spectrum of EEF1D neurodevelopmental disorders: Biallelic variants in the guanine exchange domain. Clinical genetics 3 36576126
2024 LGALS9B stabilizes EEF1D protein and activates the PI3K/AKT signaling pathway to promote gastric cancer occurrence and metastasis. Oncogene 2 39639171
2025 EEF1D signaling contributes to Bovine alpha herpesvirus 1 productive infection, potentially through regulation of viral replication compartments. Veterinary microbiology 1 40578269
2026 Repression of EEF1D by KSHV RTA promotes viral lytic reactivation. Journal of virology 0 41805193
2026 The ER anchoring and abundance of the EEF1B complex is affected by tissue-specific alternative EEF1D splicing. Life science alliance 0 42230146
2023 Autosomal recessive intellectual disability caused by compound heterozygous variants of the EEF1D gene in a Chinese family. Molecular genetics & genomic medicine 0 38083972

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