Affinage

EIF3I

Eukaryotic translation initiation factor 3 subunit I · UniProt Q13347

Length
325 aa
Mass
36.5 kDa
Annotated
2026-06-09
35 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3I (TRIP-1/eIF3-p36) is a WD40-repeat subunit of the eIF3 translation-initiation complex that operates both as a general initiation factor and as a selective translational regulator coupling growth and survival signaling to protein synthesis (PMID:20679478, PMID:25147179). Genetic dissection of the yeast ortholog establishes that eIF3i stimulates linear 43S scanning of post-termination 40S ribosomes without affecting eIF3 integrity or 43S PIC formation (PMID:20679478). Beyond bulk initiation, eIF3i directly binds and selectively enhances translation of specific mRNAs—VEGFA under hypoxia downstream of HIF1A, PHGDH (whose binding is favored by METTL3-deposited m6A), and NELFCD—thereby promoting angiogenesis, metabolic rewiring, EMT, and metastasis (PMID:25147179, PMID:37611825, PMID:41315067). EIF3I also serves as a signaling hub: it associates with the TGF-β type II receptor and is phosphorylated by it to repress Smad-driven PAI-1 transcription (PMID:9813058), and it binds the Akt1 kinase domain through its C-terminus to block PP2A-mediated dephosphorylation and sustain constitutive Akt1 activity that drives hepatocellular tumorigenesis and fibroblast-to-myofibroblast transdifferentiation (PMID:23460382, PMID:24528651). Its oncogenic activity requires mTOR-dependent serine phosphorylation (PMID:16929481), and its protein level is controlled by a SUMOylation/ubiquitination axis that, when stabilized, activates Wnt/β-catenin signaling (PMID:38374407). Pharmacologically, CRBN-bound lenalidomide sequesters eIF3i from the eIF3 complex without degrading it, producing antiangiogenic effects (PMID:36325969).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 Medium

    Established the first signaling role for EIF3I beyond translation by showing it is a receptor-associated substrate that modulates TGF-β transcriptional output.

    Evidence Co-IP receptor association, PAI-1 promoter reporter assay, and deletion mutagenesis in transfected cells

    PMID:9813058

    Open questions at the time
    • Physiological phosphorylation sites on EIF3I by TGF-βRII not mapped
    • Receptor-independent mechanism of Smad repression undefined
    • Relationship to its eIF3 role unaddressed
  2. 2006 Medium

    Connected EIF3I to growth control by identifying mTOR-dependent serine phosphorylation as a requirement for its proliferative and transforming activity.

    Evidence Overexpression with rapamycin treatment, phosphorylation and anchorage-independent growth assays in cell lines

    PMID:16929481

    Open questions at the time
    • Specific serine residue(s) not identified
    • Direct versus indirect mTOR phosphorylation not resolved
    • Mechanistic link between phosphorylation and oncogenic output unclear
  3. 2010 High

    Pinpointed the molecular contribution of eIF3i within initiation, showing it stimulates linear 40S scanning rather than complex assembly or PIC formation.

    Evidence WD40-repeat point mutation (Q258R) with in vivo translation rate, GCN4 reporter, and polysome analyses in yeast

    PMID:20679478

    Open questions at the time
    • Molecular basis of scanning stimulation by the WD40 domain unknown
    • Generality to human eIF3I not directly tested
    • No structural model of the scanning step
  4. 2013 High

    Defined a direct oncogenic mechanism in which EIF3I sustains Akt1 activity, and separately showed selective translational control of COX-2.

    Evidence Reciprocal Co-IP, C-terminal domain mapping, PP2A dephosphorylation assay, dominant-negative rescue, and tumorigenesis assays; polysome and β-catenin/TCF4 reporter assays

    PMID:23460382 PMID:24056964

    Open questions at the time
    • Structural detail of the EIF3I–Akt1 interface absent
    • How EIF3I physically excludes PP2A unresolved
    • Mechanism of selective COX-2 mRNA translation not defined
  5. 2014 High

    Established EIF3I as a HIF1A-induced selective translational regulator of VEGFA and as an Akt-acting node in fibrosis, broadening its physiological reach.

    Evidence ChIP, siRNA knockdown, polysome profiling, zebrafish mutant angiogenesis and xenograft models; fibroblast transdifferentiation with AKT epistasis

    PMID:24528651 PMID:25147179

    Open questions at the time
    • RNA features conferring VEGFA selectivity unidentified
    • Whether VEGFA binding is direct not fully resolved
    • Smad-independent route to AKT activation in fibroblasts mechanistically incomplete
  6. 2015 Medium

    Extended the EIF3I–Akt axis to metastasis by showing clusterin partners with EIF3I to drive MMP13 expression.

    Evidence Co-IP of CLU-EIF3I, invasion/metastasis assays, and CLU knockdown in HCC

    PMID:25609201

    Open questions at the time
    • Direct versus indirect CLU–EIF3I binding not established
    • No reciprocal interaction mapping
    • Link between complex formation and MMP13 induction mechanistic gap
  7. 2017 Medium

    Showed EIF3I selectively controls translation of pro-angiogenic effectors (VEGFR2/ERK) in endothelial cells and identified a physical interaction with VSV M protein affecting viral replication.

    Evidence siRNA knockdown, zebrafish mutant, proliferation/migration assays, Western blot; yeast two-hybrid, GST pull-down, co-localization, viral replication assay

    PMID:28193911 PMID:29173589

    Open questions at the time
    • Basis of VEGFR2/ERK mRNA selectivity unknown
    • Functional consequence of VSV M binding incompletely defined
    • Whether viral effect depends on the eIF3 complex unclear
  8. 2018 Medium

    Revealed a non-canonical extracellular function in which EIF3I/TRIP-1 nucleates hydroxyapatite in mineralized matrix.

    Evidence In vivo implantation, recombinant protein nucleation experiments, and TEM of mineral deposits

    PMID:29745814

    Open questions at the time
    • Mechanism of secretion to the ECM unknown
    • Relationship to its intracellular eIF3 role unexplained
    • Domain mediating mineral nucleation unmapped
  9. 2021 Medium

    Identified a PD-L1–EIF3I–IRS4 axis linking EIF3I to wound healing.

    Evidence IP-MS discovery, Co-IP validation, and in vivo/in vitro wound-healing functional assays

    PMID:34293353

    Open questions at the time
    • Direct binding interface not mapped
    • How EIF3I downregulates IRS4 mechanistically unclear
    • Translation-dependence of the effect untested
  10. 2022 High

    Demonstrated a druggable, non-degradative mechanism in which CRBN-bound lenalidomide sequesters eIF3i out of the eIF3 complex, with antiangiogenic consequences.

    Evidence Covalent lenalidomide probe with mass-spectrometry interface mapping, chemical proteomics, Co-IP for complex disruption, and cell-based assays

    PMID:36325969

    Open questions at the time
    • Quantitative effect on global translation not defined
    • Selectivity of sequestration over other eIF3 subunits unaddressed
    • In vivo relevance of the antiangiogenic effect untested
  11. 2023 High

    Connected RNA modification to selective translation by showing METTL3-deposited m6A on PHGDH mRNA promotes its binding to eIF3i and enhanced translation.

    Evidence Ribosome profiling, proteomics, m6A analysis, RIP for eIF3i-PHGDH binding, and epistasis knockdown with in vivo tumor assays

    PMID:37611825

    Open questions at the time
    • Whether eIF3i directly reads m6A marks not resolved
    • Structural basis of mRNA recognition unknown
    • Breadth of m6A-dependent target set undefined
  12. 2024 Medium

    Defined post-translational control of EIF3I abundance, showing a SENP1/lnc-TSPAN12 axis blocks its SUMOylation-dependent degradation to activate Wnt/β-catenin signaling.

    Evidence Co-IP, RNA pull-down, SUMOylation and ubiquitination assays, lncRNA manipulation, and in vivo metastasis assays

    PMID:38374407

    Open questions at the time
    • SUMOylation site(s) on EIF3I not mapped
    • E3 ligase mediating ubiquitination unidentified
    • Link between EIF3I stabilization and Wnt activation mechanistically incomplete
  13. 2025 Medium

    Added NELFCD to the set of directly bound mRNAs selectively translated by eIF3i to drive EMT and invadopodia formation in colorectal cancer.

    Evidence Polysome profiling, RIP and RNA pull-down, migration/invasion assays, in vivo metastasis models, and epistasis knockdown

    PMID:41315067

    Open questions at the time
    • Sequence/structural determinants of NELFCD mRNA selectivity unknown
    • Whether binding requires the full eIF3 complex untested
    • Generalizable rules for eIF3i target selection still lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • How eIF3i achieves selective recognition of specific mRNAs (VEGFA, PHGDH, NELFCD, COX-2) versus its general scanning role within eIF3 remains the central unresolved question.
  • No structure of human EIF3I bound to a target mRNA
  • Determinants distinguishing selective targets from bulk mRNAs undefined
  • Whether selective translation occurs within or outside the canonical eIF3 complex unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 4 GO:0003723 RNA binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-162582 Signal Transduction 3
Complex memberships
eIF3 complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 TRIP-1 (EIF3I) associates with the TGF-β type II receptor and is phosphorylated by it. TRIP-1 overexpression represses TGF-β-induced transcription from the PAI-1 promoter and inhibits PAI-1 expression induced by Smads and activated TGF-β type I receptors, acting through both receptor-dependent and receptor-independent mechanisms. Deletion mutational analysis identified two distinct non-WD40 regions required for this inhibitory activity. Co-IP/association assay, reporter gene assay (PAI-1 promoter), deletion mutagenesis, transfection overexpression The Journal of biological chemistry Medium 9813058
2010 A single-point mutation in WD40 repeat 6 of yeast eIF3i/Tif34 (Q258R) causes severe growth defects, decreases the rate of translation initiation in vivo, diminishes GCN4 induction, and impairs the rate of scanning of post-termination 40S ribosomes moving downstream from uORF1, without affecting eIF3 complex integrity or 43S PIC formation. This implicates eIF3i in stimulation of linear scanning. Genetic point mutation, in vivo translation assays, GCN4 reporter assay, polysome analysis Molecular and cellular biology High 20679478
2006 Overexpression of eIF3i in human cells causes cell size increase, proliferation enhancement, cell-cycle progression, and anchorage-independent growth in an mTOR-dependent manner; rapamycin (mTOR inhibitor) reduces serine phosphorylation of eIF3i and abolishes anchorage-independent growth, indicating mTOR phosphorylates eIF3i on serine and that this is required for its oncogenic activity. Overexpression in cell lines, rapamycin treatment, phosphorylation assay, anchorage-independent growth assay Molecular carcinogenesis Medium 16929481
2013 eIF3I physically interacts with Akt1 in HCC cell lines and tissues; the C-terminal domain of eIF3I interacts with the Akt1 kinase domain. This interaction prevents PP2A-mediated dephosphorylation of Akt1, resulting in constitutively active Akt1 oncogenic signaling. Dominant negative Akt1 or antisense eIF3I suppresses eIF3I-mediated tumorigenesis. Co-IP in cell lines and tissues, oncogenic domain mapping, dominant-negative mutant rescue, in vitro and in vivo tumorigenesis assays, PP2A dephosphorylation assay Hepatology (Baltimore, Md.) High 23460382
2013 eIF3i overexpression in intestinal epithelial cells directly upregulates COX-2 protein synthesis at the translational level and activates the β-catenin/TCF4 signaling pathway, driving colon oncogenesis. Ectopic overexpression, polysome profiling/translational assay, reporter assays for β-catenin/TCF4, in vitro oncogenesis assays Oncogene Medium 24056964
2014 eIF3i is required for VEGFA protein expression under hypoxia. HIF1A binds the eIF3i promoter and activates eIF3i transcription under hypoxia. eIF3i knockdown specifically reduces translational efficiency of VEGFA mRNA without causing general translation repression, establishing eIF3i as a selective translational regulator of VEGFA downstream of HIF1A. ChIP for HIF1A at eIF3i promoter, siRNA knockdown, polysome profiling, zebrafish eIF3i mutant angiogenesis assay, tumor xenograft angiogenesis model The Journal of biological chemistry High 25147179
2014 In primary human lung fibroblasts, knockdown of TRIP-1 (EIF3I) drives fibroblast-to-myofibroblast transdifferentiation (α-SMA induction, collagen contraction, apoptosis resistance) via enhanced AKT phosphorylation, independent of Smad3 signaling. A constitutively active AKT construct mimics TRIP-1 knockdown effects, and AKT inhibition prevents α-SMA induction in TRIP-1 knockdown cells. siRNA knockdown, plasmid overexpression, AKT inhibitor treatment, constitutively active AKT construct, α-SMA expression assay, collagen contraction assay, Smad3 knockdown epistasis Respiratory research Medium 24528651
2015 CLU (clusterin) activates Akt signaling by complexing with EIF3I; this complex promotes MMP13 expression and HCC metastasis. CLU knockdown via OGX-011 suppresses HCC metastasis through inhibiting EIF3I/Akt/MMP13 signaling. Co-IP (CLU-EIF3I complex), in vitro and in vivo invasion/metastasis assays, CLU knockdown, pathway inhibition Oncotarget Medium 25609201
2017 eIF3i knockdown in endothelial cells reduces VEGFR2 and ERK protein expression (selective translational downregulation), restraining endothelial cell proliferation and migration. In zebrafish, eIF3i mutant endothelial cells fail to respond to tumor-derived induction signals, establishing eIF3i as a selective translational regulator of VEGFR/ERK signaling in endothelial cells. siRNA knockdown, zebrafish eIF3i mutant, cell proliferation/migration assays, Western blot for VEGFR2/ERK, gene therapy shRNA model Oncotarget Medium 28193911
2017 EIF3I physically interacts with VSV matrix protein (M protein) as identified by yeast two-hybrid, validated by GST pull-down and co-localization. Mutagenesis of M (aa 122–181) impairs but does not abolish the interaction. EIF3I knockdown modulates VSV replication/transcription in a time-dependent manner and inhibits ISG expression regulated by phospho-Akt1. Yeast two-hybrid, GST pull-down, laser confocal co-localization, mutagenesis of M protein, siRNA knockdown, viral replication assay Veterinary microbiology Medium 29173589
2018 TRIP-1 (EIF3I) is localized in the extracellular matrix of bone and dentin, and promotes nucleation of calcium phosphate polymorphs including hydroxyapatite crystals. Recombinant TRIP-1 at varying concentrations orchestrates hydroxyapatite formation on demineralized dentin collagen under physiological conditions. In vivo implantation assay, recombinant protein nucleation experiments, TEM analysis of mineral deposits, overexpression/knockdown ECM analysis Connective tissue research Medium 29745814
2021 PD-L1 directly binds EIF3I and promotes cutaneous wound healing by downregulating IRS4; the EIF3I–PD-L1–IRS4 axis was identified by immunoprecipitation combined with mass spectrometry and validated by co-immunoprecipitation assays with in vivo and in vitro functional testing. Co-IP with mass spectrometry, co-immunoprecipitation validation, in vivo and in vitro functional assays for wound healing The Journal of investigative dermatology Medium 34293353
2022 Lenalidomide (via the E3 ligase adapter CRBN) recruits eIF3i but does not degrade it; instead, it sequesters eIF3i from the eIF3 complex. The binding interface on eIF3i was identified by a covalent lenalidomide probe and mass spectrometry. This sequestration drives effects on angiogenic markers, Akt1 phosphorylation, and antiangiogenesis phenotypes. Covalent chemical probe + mass spectrometry mapping of binding interface, chemical proteomics, Co-IP for eIF3 complex disruption, cell-based angiogenesis and Akt1 phosphorylation assays ACS chemical biology High 36325969
2023 eIF3i directly promotes PHGDH translation in colorectal cancer cells. METTL3-mediated m6A modification on PHGDH mRNA promotes its binding to eIF3i, leading to higher translational rate of PHGDH. PHGDH knockdown partially attenuates the excessive growth induced by eIF3i overexpression. Ribosome profiling, proteomics, m6A modification analysis, RIP assay for eIF3i-PHGDH mRNA binding, siRNA knockdown epistasis, in vivo tumor growth assay The Journal of biological chemistry High 37611825
2024 lnc-TSPAN12 acts as a scaffold that enhances the SENP1-EIF3I interaction, inhibiting SUMOylation of EIF3I and preventing its ubiquitin-mediated degradation, thereby stabilizing EIF3I protein levels and activating Wnt/β-catenin signaling to promote EMT and HCC metastasis. Co-IP (EIF3I-SENP1 interaction), RNA pull-down, SUMOylation assay, ubiquitination assay, lncRNA knockdown/overexpression, in vivo metastasis assay Oncogene Medium 38374407
2025 eIF3i directly binds NELFCD mRNA and promotes its translation, independent of transcription. eIF3i-driven NELFCD upregulation facilitates EMT and invadopodia formation, promoting CRC metastasis. NELFCD knockdown abolishes the pro-metastatic effects of eIF3i overexpression. Polysome profiling, RNA-binding assays (RIP and RNA pull-down), in vitro migration/invasion assays, in vivo mouse metastatic models, epistasis knockdown British journal of cancer Medium 41315067
2025 Loss-of-function mutations in eIF3i (yeast ortholog) reduce translation of GFP reporters with both short and long unstructured 5′ UTRs to a similar extent as mutations in other scanning factors (eIF4A, Ded1, eIF4G, eIF4B, eIF3g), and severely diminish translation of reporters with structured 5′ UTRs. This is consistent with eIF3i facilitating mRNA scanning and secondary structure unwinding rather than being the rate-limiting helicase-driven translocase. GFP reporter assay in S. cerevisiae, loss-of-function mutations in eIF3i and comparison with other initiation factor mutants bioRxivpreprint Low bio_10.1101_2024.12.30.630811

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response. The Journal of biological chemistry 101 9813058
2010 The RNA recognition motif of eukaryotic translation initiation factor 3g (eIF3g) is required for resumption of scanning of posttermination ribosomes for reinitiation on GCN4 and together with eIF3i stimulates linear scanning. Molecular and cellular biology 93 20679478
2015 Clusterin facilitates metastasis by EIF3I/Akt/MMP13 signaling in hepatocellular carcinoma. Oncotarget 56 25609201
2006 Carcinoma-associated eIF3i overexpression facilitates mTOR-dependent growth transformation. Molecular carcinogenesis 45 16929481
2013 Overexpressed-eIF3I interacted and activated oncogenic Akt1 is a theranostic target in human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 44 23460382
2013 EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and β-catenin activation. Oncogene 37 24056964
2019 Metabolic reconstruction of the genome of candidate Desulfatiglans TRIP_1 and identification of key candidate enzymes for anaerobic phenanthrene degradation. Environmental microbiology 36 30680888
2020 Engineered transient and stable overexpression of translation factors eIF3i and eIF3c in CHOK1 and HEK293 cells gives enhanced cell growth associated with increased c-Myc expression and increased recombinant protein synthesis. Metabolic engineering 26 32061967
2014 The translation initiation factor eIF3i up-regulates vascular endothelial growth factor A, accelerates cell proliferation, and promotes angiogenesis in embryonic development and tumorigenesis. The Journal of biological chemistry 24 25147179
2019 Cancer Targeted Gene Therapy for Inhibition of Melanoma Lung Metastasis with eIF3i shRNA Loaded Liposomes. Molecular pharmaceutics 22 31765158
2011 TRIP-1 regulates TGF-β1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549. American journal of physiology. Lung cellular and molecular physiology 20 21378021
2024 METTL3-mediated m6A modification of lncRNA TSPAN12 promotes metastasis of hepatocellular carcinoma through SENP1-depentent deSUMOylation of EIF3I. Oncogene 19 38374407
2023 eIF3i promotes colorectal cancer cell survival via augmenting PHGDH translation. The Journal of biological chemistry 16 37611825
2023 Circular RNA EIF3I promotes papillary thyroid cancer progression by interacting with AUF1 to increase Cyclin D1 production. Oncogene 16 37697064
2020 eIF3i regulation of protein synthesis, cell proliferation, cell cycle progression, and tumorigenesis. Cancer letters 16 33301799
2014 Penta-O-galloyl-β-D-glucose suppresses EGF-induced eIF3i expression through inhibition of the PI3K/AKT/mTOR pathway in prostate cancer cells. Journal of agricultural and food chemistry 16 25123845
2012 TRIP-1: a regulator of osteoblast function. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 16 22460930
2022 Circ-EIF3I facilitates proliferation, migration, and invasion of lung cancer via regulating the activity of Wnt/β-catenin pathway through the miR-1253/NOVA2 axis. Thoracic cancer 15 36193788
2021 A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates in Glioma Therapy. Cancers 15 33807050
1997 Expression of co-factors (SMRT and Trip-1) for retinoic acid receptors in human neuroectodermal cell lines. Biochemical and biophysical research communications 15 9169003
2009 Higher TRIP-1 level explains diminished collagen contraction ability of fetal versus adult fibroblasts. American journal of physiology. Lung cellular and molecular physiology 14 19329541
2018 Lung epithelial-specific TRIP-1 overexpression maintains epithelial integrity during hyperoxia exposure. Physiological reports 12 29484847
2014 TRIP-1 via AKT modulation drives lung fibroblast/myofibroblast trans-differentiation. Respiratory research 12 24528651
2017 eIF3i activity is critical for endothelial cells in tumor induced angiogenesis through regulating VEGFR and ERK translation. Oncotarget 11 28193911
2021 PD-L1 Triggered by Binding eIF3I Contributes to the Amelioration of Diabetes-Associated Wound Healing Defects by Regulating IRS4. The Journal of investigative dermatology 10 34293353
2018 TRIP-1 Promotes the Assembly of an ECM That Contains Extracellular Vesicles and Factors That Modulate Angiogenesis. Frontiers in physiology 9 30158875
2008 Recognition and characterization of TGF-beta receptor interacting protein 1 (TRIP-1) containing WD40 repeats from Clonorchis sinensis by bioinformatics, cloning, and expression in Escherichia coli. Parasitology research 6 18626661
2022 Molecular and Structural Characterization of Lenalidomide-Mediated Sequestration of eIF3i. ACS chemical biology 5 36325969
2017 EIF3i affects vesicular stomatitis virus growth by interacting with matrix protein. Veterinary microbiology 5 29173589
2023 Insights into the Structure and Function of TRIP-1, a Newly Identified Member in Calcified Tissues. Biomolecules 4 36979349
2018 TRIP-1 in the extracellular matrix promotes nucleation of calcium phosphate polymorphs. Connective tissue research 4 29745814
1998 Genomic structure and chromosomal location of the human TGFbeta-receptor interacting protein-1 (TRIP-1) gene to 1p34.1. FEBS letters 4 9599024
2024 Circ-EIF3I Promotes Hepatocellular Carcinoma Progression Through Modulating miR-361-3p/DUSP2 Axis. DNA and cell biology 2 38513057
2025 eIF3i facilitates NELFCD translation to promote metastasis via regulating EMT and invadopodia. British journal of cancer 1 41315067
2013 WITHDRAWN: TRIP-1 interacts with ezrin to regulate ezrin phosphorylation, cell protrusion formation and cell migration. Cellular signalling 0 24012495

Missed literature

Know a paper Affinage missed for EIF3I? Flag it for the maintainers and the community.

No submissions yet.