| 2016 |
eIF3d possesses a previously unknown cap-binding activity within the 800-kDa eIF3 complex. A 1.4 Å crystal structure of the eIF3d cap-binding domain reveals unexpected homology to endonucleases involved in RNA turnover. eIF3d makes specific contacts with the mRNA 5' cap (validated by cap analogue competition), and these interactions are essential for assembly of translation initiation complexes on eIF3-specialized mRNAs such as c-Jun. The c-Jun mRNA encodes an inhibitory RNA element that blocks eIF4E recruitment, enforcing alternative cap recognition by eIF3d, defining an eIF4E-independent, cap-dependent translation initiation pathway. |
X-ray crystallography (1.4 Å resolution), cap analogue competition assay, in vitro translation initiation complex assembly, mutagenesis |
Nature |
High |
27462815
|
| 2020 |
eIF3d cap-binding activity is activated during metabolic stress (glucose deprivation) by reduced CK2-mediated phosphorylation near the eIF3d cap-binding pocket. This phosphorylation switch enables eIF3d to drive selective translation of a gene program enriched in glucose homeostasis factors including mTOR pathway members, and is essential for cell survival during chronic glucose deprivation. |
Phosphorylation site mapping, CK2 inhibitor and knockdown experiments, ribosome profiling/translation profiling, cell viability assays under glucose deprivation |
Science |
High |
33184215
|
| 2023 |
During persistent integrated stress response (ISR), eIF3d activates translation of the kinase GCN2, which induces eIF2α phosphorylation and inhibits global protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes including ATF4, increasing ribosome engagement and enhancing bypass of upstream open reading frames (uORFs) on ATF4 mRNA. |
Ribosome profiling, m6A sequencing, genetic knockdown/overexpression, uORF reporter assays, eIF2α phosphorylation assays |
Molecular cell |
High |
37683648
|
| 2001 |
In fission yeast, Moe1 (homologue of mammalian eIF3d/p66) physically associates with eIF3 core subunits and 40S ribosomal particles as part of an eIF3 complex. Deletion of moe1 reduces translation rate by 30–40% and causes loss of stable association between eIF3 subunits upon ribosome dissociation, demonstrating that eIF3d is required for maintaining eIF3 subunit complex integrity. |
Co-immunoprecipitation, sucrose gradient sedimentation, deletion mutant analysis, translation rate measurement |
The Journal of biological chemistry |
High |
11705997
|
| 2018 |
In Drosophila, eIF3d binds to the msl-2 5' UTR and is required for efficient translation of msl-2 mRNA. eIF3d also mediates translational repression of msl-2 by interacting with the co-factor Hrp48 (which binds the msl-2 3' UTR and is recruited by Sex-lethal). Depletion of eIF3d — but not of other eIF3 subunits — specifically de-represses msl-2 expression in female flies, indicating a subunit-specific role in mRNA-selective translation control. |
RNA chromatography, reporter assays, RNAi-mediated depletion in flies, co-immunoprecipitation |
Nucleic acids research |
Medium |
29635389
|
| 2021 |
In human regulatory T cells (Tregs), a non-canonical cap-dependent translation mechanism utilizes DAP5 (eIF4G2) together with eIF3d, directed by 5' noncoding regions of Treg-specific mRNAs, to support translation of Treg differentiation and immune suppression mRNAs when mTORC1/eIF4E-dependent translation is inhibited. Silencing DAP5 impairs naive CD4+ T cell differentiation into Treg cells. |
Genome-wide transcriptomic and translatomic profiling, siRNA knockdown, T cell differentiation assays, polysome profiling |
Nature communications |
Medium |
34848685
|
| 2017 |
EIF3D stabilizes GRK2 protein by blocking ubiquitin-mediated proteasomal degradation of GRK2, thereby activating PI3K/Akt signaling and promoting gallbladder cancer cell proliferation and migration. This represents a non-translational function of eIF3d. |
Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vitro and in vivo proliferation/migration assays |
Cell death & disease |
Medium |
28594409
|
| 2019 |
EIF3D interacts with GRP78 and enhances GRP78 protein stability by blocking ubiquitin-mediated proteasomal degradation of GRP78, thereby promoting sunitinib resistance in renal cell carcinoma cells via unfolded protein response activation. |
Co-immunoprecipitation, Western blot, ubiquitination assay, knockdown/overexpression, in vitro and in vivo growth assays |
EBioMedicine |
Medium |
31669222
|
| 2019 |
EIF3D is K27-polyubiquitinated at lysine residues K153 and K275 by the Cullin-3/KCTD10 ubiquitin ligase complex in human hepatocellular carcinoma HepG2 cells, as identified by mass spectrometry. |
Co-immunoprecipitation, mass spectrometry, site-directed mutagenesis of ubiquitination sites, ubiquitination assay |
Biochemical and biophysical research communications |
Medium |
31280863
|
| 2022 |
During human cytomegalovirus (HCMV) infection, protein synthesis progressively shifts from eIF4E-dependent to eIF3d-dependent cap-dependent translation. Targeting eIF3d selectively inhibits HCMV replication, reduces polyribosome abundance, and interferes with expression of essential virus genes and a host chronic ER stress gene signature that supports HCMV reproduction. |
eIF3d knockdown/targeting, polyribosome profiling, viral replication assays, gene expression analysis |
Cell reports |
Medium |
35508137
|
| 2023 |
The DAP5/eIF3d complex mediates selective cap-dependent, eIF4E-independent translation of mRNAs encoding EMT transcription factors, cell migration integrins, metalloproteinases, and angiogenesis factors in breast cancer cells. DAP5 is required for EMT, cell migration, invasion, metastasis, and angiogenesis in human and murine breast cancer models, but not for primary tumor growth. |
Genome-wide transcriptomic and translatomic profiling, siRNA knockdown, animal models of metastasis, cell migration/invasion assays |
Cell reports |
Medium |
37314929
|
| 2023 |
mTOR inhibition activates eIF3d-mediated non-canonical translation, which cooperates with mRNA-binding proteins hnRNPF, hnRNPK, and SSB to support selective translation of mRNAs in INSR/IGF1R/IRS and IL-6ST/JAK/STAT signaling pathways, enabling cell phenotype switching from proliferative to migratory. |
Ribosome profiling, quantitative proteomics, eIF3d knockdown, mTOR inhibitor treatment, co-immunoprecipitation with hnRNPF/K/SSB |
Cell reports |
Medium |
37494188
|
| 2024 |
eIF4E-independent translation of a subset of capped mRNAs is largely dependent on eIF3d cap-binding activity. Under eIF4E1 inactivation, these mRNAs preferentially release eIF4E1 and bind instead to eIF3d via its cap-binding pocket, enabling efficient translation. |
Ribosome profiling under constitutively active 4E-BP expression, eIF3d cap-binding pocket mutant, mRNA-eIF3d binding assays |
Nature communications |
High |
39107322
|
| 2025 |
eIF3d and eIF3e mediate a selective translational response to acute hypoxia that controls HIF1α accumulation and cellular invasion. This translation program is dependent on the eIF3d/eIF3e module and can be inhibited by novel small molecules targeting eIF3e. |
Ribosome profiling in hypoxia, eIF3d/eIF3e knockdown, cellular invasion assays, HIF1α measurement, small molecule inhibitor characterization |
Cell reports |
Medium |
41364558
|
| 2025 |
eIF3d quantitatively recruits itself and the eIF3d/eIF4G2 (DAP5) complex to specific capped mRNAs via its cap-binding activity, with binding affinity dependent on a fully methylated 5' mRNA cap. This eIF3d/eIF4G2 recruitment correlates with translation efficiency of these mRNAs in cap-dependent, eIF4E-independent manner as measured by in vitro translation assays. |
Fluorescence anisotropy equilibrium binding assays, in vitro luciferase reporter translation assays, cap analogue competition |
The Journal of biological chemistry |
Medium |
39971159
|
| 2025 |
EIF3D-mediated translation of ATF4 drives ATF4-dependent S100P transcription in hepatic stellate cells (HSCs), activating JNK and NLRP3 signaling to promote HSC activation, survival, proliferation, and extracellular matrix production. Genetic and pharmacological inhibition of the EIF3D-ATF4-S100P axis suppresses metabolic reprogramming (mitochondrial activity and glycolysis) and fibrogenic markers in HSCs. |
Genetic knockdown/overexpression, HSC-specific ATF4 deletion mouse models, pharmacological ISR inhibitor (ERMT1), metabolic assays, fibrosis mouse models |
Redox biology |
Medium |
41197183
|
| 2025 |
EIF3D is required for maintaining primed pluripotency by controlling translation of p53 regulators (keeping p53 activity low) and balancing pluripotency-associated signaling pathways. Loss of EIF3D disrupts this translational homeostasis, compromising the undifferentiated state. |
CRISPR interference screen, EIF3D knockdown in human PSCs, ribosome profiling, pluripotency marker analysis |
Science advances |
Medium |
40203091
|
| 2025 |
The RNA-binding domain of eIF3d mediates its recruitment to cytoplasmic stress granules and is required for stress granule assembly in response to specific stresses. Deletion of this domain blocks granule formation, decreases cell viability, and the exogenous RNA-binding domain alone rescues stress granule assembly in eIF3d-depleted cells. This function is conserved in C. elegans. |
Live-cell imaging of stress granules, eIF3d domain deletion mutants, eIF3d depletion with rescue, C. elegans in vivo experiments |
bioRxivpreprint |
Medium |
bio_10.1101_2025.11.13.688230
|
| 2024 |
Src oncogene controls eIF3d-dependent non-canonical cap-dependent translation initiation pathway in addition to the canonical mTOR/eIF4E pathway. eIF3d (together with eIF3h and eIF3e) is essential for invadosome formation and extracellular matrix degradation downstream of Src. Both eIF4E and eIF3d pathways are required for invadosome function. |
eIF3d/eIF3h/eIF3e knockdown, invadosome formation assays, ECM degradation assays, Src inhibitor experiments, expression correlation analysis |
bioRxivpreprint |
Low |
bio_10.1101_2024.08.01.606119
|