{"gene":"EIF3E","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1997,"finding":"EIF3E (eIF3-p48/Int-6) was identified as the 48-kDa subunit of the eIF3 translation initiation complex; recombinant eIF3-p48 comigrates with the authentic p48 subunit in purified eIF3 and co-precipitates with affinity-purified antibodies to the eIF3 p170 subunit, establishing its membership in the eIF3 complex.","method":"CDNA cloning, recombinant protein expression, co-immunoprecipitation with anti-p170 antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical validation (comigration + co-IP), foundational identification replicated by subsequent studies","pmids":["9295280"],"is_preprint":false},{"year":2001,"finding":"Human eIF3e/Int-6 binds directly to eIF3b (Prt1p in yeast) through a discrete segment of eIF3b, establishing the molecular basis for eIF3e integration into the eIF3 core complex; this interaction was demonstrated both in vivo and in vitro in a budding yeast expression system.","method":"In vivo and in vitro binding assays in S. cerevisiae, yeast two-hybrid, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding plus in vivo co-purification, domain mapping, two orthogonal methods in one study","pmids":["11457827"],"is_preprint":false},{"year":2001,"finding":"In fission yeast, spInt6 (eIF3e homologue) is required for stable association of eIF3 subunits after dissociation from ribosomes; deletion of int6 results in loss of inter-subunit eIF3 cohesion while eIF3 subunits remain bound to 40S particles, demonstrating a structural role of eIF3e in maintaining eIF3 complex integrity.","method":"Genetic deletion, ribosome fractionation, co-purification of eIF3 subunits from 40S particles","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined biochemical phenotype (fractionation + co-purification), ortholog study in fission yeast consistent with mammalian function","pmids":["11705997"],"is_preprint":false},{"year":2005,"finding":"In fission yeast, eIF3e defines a distinct eIF3 complex (separate from the eIF3m complex) that associates with a restricted subset of cellular mRNAs; eIF3e is non-essential for global protein synthesis whereas eIF3m is essential, indicating eIF3e specializes in translational regulation of specific mRNAs.","method":"Genetic deletion, polysome analysis, ribonomic mRNA-association profiling (microarray + RT-PCR)","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotype, multiple orthogonal methods (polysome, microarray, RT-PCR), ortholog study consistent with mammalian data","pmids":["15904532"],"is_preprint":false},{"year":2006,"finding":"eIF3e directly binds eIF4G-1 and constitutes the eIF4G-binding subunit of mammalian eIF3; recombinant FLAG-eIF3e competes with intact eIF3 for binding to the eIF3-binding domain of eIF4G-1 in vitro, and excess eIF3e inhibits cap-dependent translation, shifts mRNA to lighter polysomes, and displaces eIF4G and eIF2α from ~40S complexes.","method":"Proteolysis/mass spectrometry-based binding assay, competitive in vitro binding, cell-free translation system, polysome profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution + competition assay + functional cell-free translation readout, multiple orthogonal methods in one study","pmids":["16766523"],"is_preprint":false},{"year":2002,"finding":"Stable expression of a C-terminally truncated eIF3e (mimicking MMTV integration) in NIH 3T3 cells causes malignant transformation (foci formation, anchorage-independent growth, accelerated growth, loss of contact inhibition) and inhibits apoptosis onset; full-length eIF3e does not cause transformation, indicating the truncated form acts as a dominant-negative/oncogenic variant.","method":"Stable transfection of truncated vs. full-length eIF3e, transformation assays (foci, soft agar, growth curves), apoptosis assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — four independent transformation criteria tested, isogenic full-length control, clean gain-of-function experiment","pmids":["11904180"],"is_preprint":false},{"year":2004,"finding":"eIF3e/INT6 localizes partly to the nucleus in human primary fibroblasts, with reduced nuclear staining specifically in early S phase, indicating cell cycle-regulated nucleocytoplasmic shuttling; transformed cells lose this regulated redistribution, suggesting it is relevant to tumor suppressor function.","method":"Immunofluorescence microscopy, cell cycle synchronization","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence localization in primary vs. transformed cells, single method but consistent finding across cell types","pmids":["15030549"],"is_preprint":false},{"year":2007,"finding":"eIF3e/Int6 mediates activity-dependent internalization of the L-type calcium channel CaV1.2 by binding to a domain in the II-III loop of CaV1.2; electrical activity triggers CaV1.2 endocytosis and rapid endosomal trafficking in a Ca2+-dependent manner, and the eIF3e-binding domain in CaV1.2 is essential for this internalization.","method":"Co-immunoprecipitation, total internal reflection microscopy (TIRF), domain deletion mutagenesis, live-cell imaging of endosomal trafficking","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, TIRF live imaging, domain mutagenesis) in one study demonstrating direct binding and functional consequence","pmids":["17698014"],"is_preprint":false},{"year":2007,"finding":"INT6/eIF3e is required for nonsense-mediated mRNA decay (NMD); INT6 knockdown strongly inhibits NMD without affecting general translation (unlike eIF3b knockdown). INT6 co-immunoprecipitates with the cap-binding protein CBP80 and the NMD factor UPF2, placing INT6 in the NMD pathway upstream of mRNA degradation.","method":"siRNA knockdown, NMD reporter assays, co-immunoprecipitation with CBP80 and UPF2, NMD-sensitive transcript quantification","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNAi phenotypic readout (NMD inhibition) plus Co-IP identifying binding partners, two orthogonal methods in single study","pmids":["17468741"],"is_preprint":false},{"year":2008,"finding":"In fission yeast, Int6/eIF3e promotes general translation and maintains basal Atf1 (a Sty1 MAPK target transcription factor) protein levels; int6Δ slows de novo protein synthesis (pulse labeling) and reduces Atf1 protein half-life, thereby impairing Sty1 MAPK-dependent stress response to amino acid starvation.","method":"Pulse-labeling translation assay, northern/microarray analysis, protein half-life measurement, genetic epistasis with sty1Δ and gcn2Δ","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pulse labeling (Tier 1 method), genetic epistasis, microarray, multiple orthogonal methods in one study","pmids":["18502752"],"is_preprint":false},{"year":2010,"finding":"eIF3e is not required for bulk translation in breast cancer cells, but regulates translation of specific mRNAs including positive regulation of urokinase-type plasminogen activator and BCL-XL, and negative regulation of MAD2L1, as determined by microarray comparison of total vs. polysomal RNA after siRNA-mediated eIF3e knockdown.","method":"siRNA knockdown, microarray of total and polysomal RNA fractions, validation of specific targets","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome profiling + microarray with specific target validation, single lab","pmids":["20453879"],"is_preprint":false},{"year":2011,"finding":"Expression of truncated eIF3e (3e5, resulting from MMTV integration at intron 5) diminishes binding of eIF3 to eIF4G (co-IP), reduces overall protein synthesis and cell growth, increases cap-independent IRES-driven translation relative to cap-dependent translation, and shifts endogenous cap-independent mRNAs (XIAP, c-Myc, CYR61, Pim-1) to heavier polysomes while cap-dependent mRNAs shift to lighter polysomes.","method":"Co-immunoprecipitation, bicistronic IRES reporter assay, polysome profiling, single-copy knockin cell line","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP, IRES reporter, polysome profiling, controlled single-copy cell line; multiple orthogonal methods in one study","pmids":["21737453"],"is_preprint":false},{"year":2012,"finding":"HTLV-1 Tax protein inhibits NMD by binding to INT6/eIF3e and UPF1; Tax interaction with INT6 is necessary for NMD inhibition, as shown by Tax mutant analysis. Tax expression decreases INT6 abundance in P-bodies and increases phosphorylated UPF1, collectively impairing NMD of viral and cellular transcripts.","method":"Co-immunoprecipitation, Tax mutant analysis, P-body morphology and marker quantification, NMD reporter assays, western blotting","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interactions, mutant dissection of necessity, multiple orthogonal methods in one study","pmids":["22553336"],"is_preprint":false},{"year":2012,"finding":"INT6/eIF3e interacts with ATM kinase and is recruited to DNA damage sites; INT6 silencing reduces ATM retention at damage sites, impairs CHK1/CHK2 phosphorylation, attenuates ubiquitylation (K63-linked polyubiquitin) at DSBs, and prevents BRCA1 accumulation at damage sites, placing INT6 in the ATM-RNF8-BRCA1 DSB repair pathway.","method":"Co-immunoprecipitation (INT6–ATM), RNAi silencing, γ-H2AX foci, immunofluorescence of ATM/BRCA1 at damage sites, western blotting of CHK1/CHK2 phosphorylation, γ-irradiation/neocarzinostatin treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying direct interaction, multiple functional readouts (kinase phosphorylation, ubiquitylation, repair factor recruitment) in one study","pmids":["22508697"],"is_preprint":false},{"year":2012,"finding":"Decreased eIF3e expression in MCF-10A breast epithelial cells induces epithelial-to-mesenchymal transition (EMT) and increases invasion/migration; reduced eIF3e causes specific upregulation of EMT regulators Snail1 and Zeb2 at both transcriptional and post-transcriptional levels.","method":"siRNA knockdown, EMT marker analysis, invasion/migration assays, qRT-PCR and western blotting for Snail1/Zeb2","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with multiple cellular readouts and mechanistic follow-up (transcriptional + post-transcriptional Snail1/Zeb2 regulation), single lab","pmids":["22907435"],"is_preprint":false},{"year":2015,"finding":"Decreased eIF3e expression induces EMT in lung epithelial cells (A549) via overproduction of TGFβ cytokine; inhibition of TGFβ signaling reverses eIF3e-regulated EMT, and several EMT-regulator mRNAs are translated by a cap-independent mechanism when eIF3e levels are reduced.","method":"Stable shRNA knockdown, TGFβ ELISA, TGFβ inhibitor rescue, polysomal mRNA analysis for cap-independent translation","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — rescue experiment with TGFβ inhibitor establishes pathway causality, polysome analysis for translational mechanism, single lab","pmids":["26056130"],"is_preprint":false},{"year":2016,"finding":"INT6/EIF3E promotes homologous recombination-mediated DSB repair by facilitating RNF8 recruitment to DSBs and K63-linked polyubiquitin chain formation; INT6 silencing impairs RNF8 accumulation (but not RNF168 or 53BP1) at DSBs, and reduces BRCA1, BRCA2, and RAD51 recruitment, with MDC1 localization also altered, consistent with defective ATM retention reported previously.","method":"RNAi silencing, immunofluorescence of repair factors at laser-induced DSBs, ubiquitin chain analysis, HR repair assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple repair factors assessed, positive/negative controls (RNF168, 53BP1 unaffected), pathway positioning by epistasis; replication by same lab with independent mechanistic extension","pmids":["27550454"],"is_preprint":false},{"year":2021,"finding":"eIF3e depletion in breast cancer cells causes reduced PARP1 protein synthesis due to weakened translation of PARP1 mRNA, decreased poly(ADP-ribosyl)ation, and aberrant mTORC1 activation, collectively inducing cellular senescence with a pro-inflammatory secretory phenotype.","method":"siRNA knockdown, polysome profiling of PARP1 mRNA, western blotting, mTORC1 activity assay, senescence assays (SA-β-gal, SASP markers)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — translational mechanism (polysome profiling) linked to functional senescence phenotype, single lab","pmids":["33868586"],"is_preprint":false},{"year":2022,"finding":"INT6/eIF3e negatively regulates HIF2α protein stability in an oxygen-independent manner; INT6 knockdown leads to HIF2α accumulation, which binds TWIST1 and together represses the E-cadherin gene promoter, driving EMT in lung carcinoma A549 cells.","method":"siRNA knockdown, western blotting for HIF2α, co-immunoprecipitation (HIF2α–TWIST1), chromatin immunoprecipitation at E-cadherin promoter, EMT marker analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ChIP supporting mechanism, but single lab and limited replication","pmids":["36116043"],"is_preprint":false},{"year":2024,"finding":"TRIM35 E3 ubiquitin ligase promotes ubiquitination and degradation of EIF3E; TRIM35 overexpression inhibits endometrial cancer cell proliferation via CDK4/Cyclin D1 pathway suppression, and EIF3E overexpression reverses TRIM35-mediated inhibition, establishing EIF3E as a TRIM35 substrate.","method":"Co-immunoprecipitation, ubiquitination assay, lentiviral overexpression/knockdown, proliferation assays, CDK4/Cyclin D1 western blotting","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay identifies writer (TRIM35), rescue experiment establishes functional relationship, single lab","pmids":["41429342"],"is_preprint":false},{"year":2025,"finding":"ALDH2 physically interacts with eIF3E within the eIF3 complex and prevents eIF3E–eIF4G1–mRNA assembly; the ALDH2*2 loss-of-function variant disrupts this interaction, releasing eIF3E to assemble an eIF3E–eIF4G1–mRNA ternary complex that drives selective translation of mRNAs containing a GAGGACR motif (including TFRC, ACSL4, UAP1), promoting ferroptosis in cardiomyocytes during myocardial infarction.","method":"Co-immunoprecipitation (ALDH2–eIF3E), cardiomyocyte-specific AAV knockdown of eIF3E in mice, lipidomics, MS-based proteomics, motif analysis of selectively translated mRNAs","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding (Co-IP), in vivo genetic rescue (AAV eIF3E KD), mechanistic motif discovery, multiple orthogonal methods in one study","pmids":["41111418"],"is_preprint":false},{"year":2025,"finding":"eIF3e (together with eIF3d) mediates a selective translational response to acute hypoxia, controlling HIF1α accumulation and cellular invasion; small molecules targeting eIF3e specifically reduce this hypoxia-induced translational program and also suppress ER stress-dependent translation.","method":"Ribosome profiling, siRNA knockdown of eIF3e/eIF3d, small-molecule eIF3e inhibitor characterization, HIF1α protein quantification, invasion assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome profiling plus genetic (RNAi) and pharmacological (small molecule) perturbation, multiple readouts, single lab","pmids":["41364558"],"is_preprint":false},{"year":2024,"finding":"eIF3e has an RNA-binding function independent of its canonical protein synthesis activity; in t(4;14) myeloma, REIIBP-upregulated eIF3e directly binds the 3'UTR of TLR7 mRNA to upregulate TLR7, demonstrating a non-canonical role of eIF3e as an RNA-binding regulator.","method":"RNA immunoprecipitation / direct binding to 3'UTR, REIIBP knockdown/overexpression, TLR7 mRNA and protein quantification","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct 3'UTR binding assay demonstrates RNA-binding function, single lab","pmids":["38124661"],"is_preprint":false},{"year":2026,"finding":"Conditional deletion of Eif3e in B cells (Cγ1Cre) causes B cell hyperactivation, impaired proliferation/survival/differentiation, upregulation of CD80, and activation of CD4+ T cells into IL-4-producing TFH-like cells that in turn activate bystander Eif3e-sufficient B cells, establishing a feedforward loop that drives malignant lymphocyte transformation; this identifies eIF3e as a translational checkpoint maintaining immune tolerance.","method":"Conditional knockout mouse (Cγ1Cre-Eif3e), flow cytometry, B/T cell co-culture, IL-4 quantification, lymphoproliferation/transformation assessment","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype and mechanistic feedforward loop, single lab, in vivo model","pmids":["42233886"],"is_preprint":false}],"current_model":"EIF3E (eIF3e/INT6/p48) is a non-core subunit of the eIF3 translation initiation complex that directly binds eIF3b to integrate into eIF3 and contacts eIF4G-1 to mediate cap-dependent translation initiation; it additionally drives selective, cap-independent and stress-responsive translation of specific mRNA subsets (via a GAGGACR motif or eIF3d/eIF3e-dependent mechanism in hypoxia/ER stress), participates in nonsense-mediated mRNA decay by associating with CBP80 and UPF2, promotes DNA double-strand break repair through the ATM–RNF8–BRCA1 axis, is subject to ubiquitin-mediated degradation by TRIM35, undergoes cell cycle-regulated nucleocytoplasmic shuttling, mediates activity-dependent internalization of CaV1.2 calcium channels, and stabilizes HIF2α protein to regulate angiogenic and EMT programs; truncation of eIF3e (as by MMTV integration) shifts the balance from cap-dependent to cap-independent translation and causes malignant transformation, whereas full eIF3e loss triggers EMT via TGFβ, impairs immune tolerance in B cells, and disrupts mTORC1/PARP1 homeostasis leading to cellular senescence."},"narrative":{"mechanistic_narrative":"EIF3E (eIF3e/INT6/p48) is a non-core subunit of the eIF3 translation initiation complex that couples general translation initiation to selective, regulated translation of defined mRNA subsets [PMID:9295280, PMID:15904532]. It integrates into eIF3 by binding directly to eIF3b and is required to maintain inter-subunit cohesion of the eIF3 complex after ribosome dissociation [PMID:11457827, PMID:11705997]. As the eIF4G-binding subunit of mammalian eIF3, eIF3e bridges eIF3 to the cap-binding apparatus, and an excess of free eIF3e competes for eIF4G-1 and inhibits cap-dependent initiation [PMID:16766523]. Rather than driving bulk protein synthesis, eIF3e specializes in translational control of particular transcripts and can promote cap-independent initiation: C-terminal truncation mimicking MMTV integration weakens eIF3–eIF4G binding, shifts the balance from cap-dependent to IRES-driven translation, and causes malignant transformation [PMID:11904180, PMID:21737453]. eIF3e directs translation of specific targets including BCL-XL, urokinase plasminogen activator, PARP1 and HIF1α, and assembles a selective eIF3E–eIF4G1–mRNA complex that translates GAGGACR-motif mRNAs (TFRC, ACSL4, UAP1) when released from inhibitory ALDH2 binding, driving cardiomyocyte ferroptosis [PMID:20453879, PMID:33868586, PMID:41111418, PMID:41364558]. Loss of eIF3e induces epithelial-to-mesenchymal transition through TGFβ overproduction and HIF2α–TWIST1-mediated repression of E-cadherin [PMID:22907435, PMID:26056130, PMID:36116043]. Beyond translation, eIF3e functions in nonsense-mediated mRNA decay via association with CBP80 and UPF2 [PMID:17468741], promotes ATM–RNF8–BRCA1-dependent homologous-recombination repair of DNA double-strand breaks [PMID:22508697, PMID:27550454], mediates activity-dependent endocytosis of the CaV1.2 calcium channel [PMID:17698014], and acts as a translational checkpoint maintaining B-cell immune tolerance [PMID:42233886]. eIF3e abundance is controlled by TRIM35-mediated ubiquitination and degradation [PMID:41429342].","teleology":[{"year":1997,"claim":"Established that the 48-kDa eIF3 subunit is a defined gene product physically embedded in the translation initiation complex, fixing EIF3E's foundational identity.","evidence":"cDNA cloning, recombinant expression, and co-IP with anti-eIF3 p170 antibodies","pmids":["9295280"],"confidence":"High","gaps":["Did not define which subunit contacts mediate integration","No functional role beyond complex membership"]},{"year":2001,"claim":"Resolved how eIF3e physically enters eIF3 and whether it is structurally required, showing a direct eIF3b interface and a role in holding the complex together.","evidence":"Yeast in vivo/in vitro binding and domain mapping (eIF3b interaction); fission yeast int6 deletion with ribosome fractionation","pmids":["11457827","11705997"],"confidence":"High","gaps":["Structural basis of the eIF3b-eIF3e interface not solved","Did not address mRNA selectivity"]},{"year":2005,"claim":"Reframed eIF3e from a generic initiation factor to a specialized regulator by showing it is dispensable for global translation but governs a restricted mRNA set.","evidence":"Fission yeast genetic deletion, polysome analysis, and ribonomic mRNA-association profiling","pmids":["15904532"],"confidence":"High","gaps":["Identity of the selected mRNAs in mammals not defined","Mechanism of selectivity unknown"]},{"year":2006,"claim":"Identified the molecular link between eIF3e and the cap-binding machinery, defining eIF3e as the eIF4G-1-binding subunit whose stoichiometry tunes cap-dependent initiation.","evidence":"Competitive in vitro binding, cell-free translation, and polysome profiling","pmids":["16766523"],"confidence":"High","gaps":["How physiological eIF3e levels are regulated to set initiation balance not addressed","Binding interface on eIF4G-1 mapped only functionally"]},{"year":2002,"claim":"Connected eIF3e structural perturbation to cancer, showing that a C-terminally truncated form is a transforming gain-of-function variant.","evidence":"Stable expression of truncated vs full-length eIF3e in NIH 3T3 with transformation and apoptosis assays","pmids":["11904180"],"confidence":"High","gaps":["Molecular mechanism of transformation not resolved at this stage","In vivo tumorigenicity not tested"]},{"year":2011,"claim":"Provided the mechanistic explanation for truncation-driven oncogenesis by showing the truncated form weakens eIF3–eIF4G binding and shifts translation toward cap-independent mRNAs.","evidence":"Single-copy knockin cell line, co-IP, bicistronic IRES reporter, polysome profiling (XIAP, c-Myc, CYR61, Pim-1)","pmids":["21737453"],"confidence":"High","gaps":["How cap-independent mRNAs are selected not defined","Link between specific targets and transformation incomplete"]},{"year":2007,"claim":"Extended eIF3e function beyond initiation, revealing roles in NMD and in membrane-channel trafficking.","evidence":"siRNA NMD reporter assays and co-IP with CBP80/UPF2; co-IP, TIRF imaging and domain mutagenesis of CaV1.2 internalization","pmids":["17468741","17698014"],"confidence":"High","gaps":["Whether NMD and channel-trafficking roles require eIF3 complex membership unclear","Mechanism linking eIF3e to UPF1/UPF2 step undefined"]},{"year":2008,"claim":"Demonstrated that eIF3e supports stress-responsive gene expression by maintaining translation of a stress MAPK target, linking it to adaptive signaling.","evidence":"Fission yeast pulse-labeling, protein half-life, and genetic epistasis with sty1Δ/gcn2Δ (Atf1 levels)","pmids":["18502752"],"confidence":"High","gaps":["Mammalian equivalent of Atf1 control not established","Direct vs indirect effect on Atf1 mRNA unresolved"]},{"year":2010,"claim":"Defined specific mammalian translational targets of eIF3e, confirming selective rather than bulk translational control in cancer cells.","evidence":"siRNA knockdown with total vs polysomal microarray and target validation (uPA, BCL-XL, MAD2L1)","pmids":["20453879"],"confidence":"Medium","gaps":["Sequence/structural features driving target selection not identified","Single-lab dataset"]},{"year":2012,"claim":"Established eIF3e as a DNA double-strand break repair factor acting in the ATM signaling axis, distinct from its translational role; concurrent work showed viral hijacking of its NMD function.","evidence":"Co-IP (INT6–ATM), RNAi, damage-site immunofluorescence, CHK1/CHK2 phosphorylation; HTLV-1 Tax co-IP and NMD reporter assays","pmids":["22508697","22553336"],"confidence":"High","gaps":["How a translation factor is recruited to chromatin damage sites unknown","Whether repair role is eIF3-dependent unclear"]},{"year":2012,"claim":"Linked eIF3e loss to a tumor-relevant EMT program, identifying Snail1 and Zeb2 as induced effectors.","evidence":"siRNA knockdown in MCF-10A with EMT marker, invasion/migration assays and Snail1/Zeb2 quantification","pmids":["22907435"],"confidence":"Medium","gaps":["Direct vs indirect control of Snail1/Zeb2 not fully separated","Single cell-line model"]},{"year":2015,"claim":"Identified TGFβ as the causal mediator of eIF3e-loss-driven EMT and tied EMT regulators to cap-independent translation.","evidence":"shRNA knockdown, TGFβ ELISA, TGFβ inhibitor rescue, polysomal cap-independence analysis in A549","pmids":["26056130"],"confidence":"Medium","gaps":["Which EMT mRNAs use cap-independent initiation not exhaustively mapped","Single lab"]},{"year":2016,"claim":"Refined the DSB-repair mechanism, placing eIF3e upstream of RNF8-dependent K63 ubiquitination and BRCA1/BRCA2/RAD51 recruitment in homologous recombination.","evidence":"RNAi, laser-induced DSB immunofluorescence, ubiquitin chain analysis, HR repair assay with RNF168/53BP1 controls","pmids":["27550454"],"confidence":"High","gaps":["Direct molecular target of eIF3e at damage sites unidentified","Whether effect is translational or structural unresolved"]},{"year":2021,"claim":"Connected eIF3e translational control to cellular senescence through PARP1 translation and mTORC1 regulation.","evidence":"siRNA knockdown, PARP1 polysome profiling, mTORC1 activity, SA-β-gal/SASP senescence assays","pmids":["33868586"],"confidence":"Medium","gaps":["Mechanism of mTORC1 dysregulation not defined","Single lab"]},{"year":2022,"claim":"Identified HIF2α stability as an eIF3e-regulated node driving EMT via TWIST1 and E-cadherin repression.","evidence":"siRNA knockdown, HIF2α western blotting, HIF2α–TWIST1 co-IP, E-cadherin promoter ChIP","pmids":["36116043"],"confidence":"Medium","gaps":["How eIF3e controls oxygen-independent HIF2α stability mechanistically unknown","Single lab"]},{"year":2024,"claim":"Established eIF3e abundance as a regulated quantity through TRIM35-mediated ubiquitination and degradation affecting proliferation.","evidence":"Co-IP, ubiquitination assay, lentiviral perturbation, rescue, CDK4/Cyclin D1 western blotting","pmids":["41429342"],"confidence":"Medium","gaps":["Ubiquitination site and chain type on eIF3E not defined","Single lab"]},{"year":2024,"claim":"Revealed a non-canonical RNA-binding function of eIF3e distinct from initiation, binding the TLR7 3'UTR to upregulate TLR7 in myeloma.","evidence":"RNA immunoprecipitation / 3'UTR binding, REIIBP perturbation, TLR7 quantification","pmids":["38124661"],"confidence":"Medium","gaps":["Whether 3'UTR binding is direct and sequence-specific genome-wide unknown","Single lab"]},{"year":2025,"claim":"Provided a mechanistic model for selective translation, showing ALDH2 sequesters eIF3e and its release enables a GAGGACR-motif-driven eIF3E–eIF4G1–mRNA program causing cardiomyocyte ferroptosis, while a parallel study tied eIF3e/eIF3d to hypoxia- and ER-stress-selective translation controlling HIF1α.","evidence":"ALDH2–eIF3E co-IP, cardiomyocyte AAV knockdown in mice, lipidomics, motif analysis; ribosome profiling with siRNA and small-molecule eIF3e inhibition","pmids":["41111418","41364558"],"confidence":"High","gaps":["How the GAGGACR motif is recognized structurally not resolved","Breadth of the selective translatome across tissues unknown"]},{"year":2026,"claim":"Defined eIF3e as a translational checkpoint enforcing immune tolerance, with B-cell deletion triggering a feedforward hyperactivation loop and lymphocyte transformation.","evidence":"Conditional Cγ1Cre-Eif3e knockout mice, flow cytometry, B/T co-culture, IL-4 quantification","pmids":["42233886"],"confidence":"Medium","gaps":["Specific mRNAs whose translation enforces tolerance not identified","Single lab"]},{"year":null,"claim":"How eIF3e physically recognizes its selective mRNA targets (e.g., the GAGGACR motif) and how it is partitioned between canonical eIF3-dependent initiation, cap-independent translation, NMD, DSB repair and RNA-binding roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of an eIF3e–mRNA selective complex","Recruitment mechanism to DNA damage sites undefined","Unclear whether non-translational roles require eIF3 membership"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,3,4,10,11,20,21]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[20,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,13,16]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,16]}],"complexes":["eIF3"],"partners":["EIF3B","EIF4G1","CBP80","UPF2","ATM","ALDH2","TRIM35","CACNA1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60228","full_name":"Eukaryotic translation initiation factor 3 subunit E","aliases":["Eukaryotic translation initiation factor 3 subunit 6","Viral integration site protein INT-6 homolog","eIF-3 p48"],"length_aa":445,"mass_kda":52.2,"function":"Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773). Required for nonsense-mediated mRNA decay (NMD); may act in conjunction with UPF2 to divert mRNAs from translation to the NMD pathway (PubMed:17468741). May interact with MCM7 and EPAS1 and regulate the proteasome-mediated degradation of these proteins (PubMed:17310990, PubMed:17324924)","subcellular_location":"Cytoplasm; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/P60228/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3E","classification":"Common 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EIF3E","url":"https://www.omim.org/entry/602210"},{"mim_id":"600495","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 4-GAMMA, 1; EIF4G1","url":"https://www.omim.org/entry/600495"},{"mim_id":"300160","title":"DEAD-BOX HELICASE 3, X-LINKED; DDX3X","url":"https://www.omim.org/entry/300160"},{"mim_id":"113703","title":"RIBOSOMAL PROTEIN L13; RPL13","url":"https://www.omim.org/entry/113703"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3E"},"hgnc":{"alias_symbol":["eIF3-p48"],"prev_symbol":["INT6","EIF3S6"]},"alphafold":{"accession":"P60228","domains":[{"cath_id":"-","chopping":"1-92_125-145","consensus_level":"medium","plddt":61.2444,"start":1,"end":145},{"cath_id":"-","chopping":"179-324","consensus_level":"medium","plddt":66.3812,"start":179,"end":324},{"cath_id":"1.10.10.10","chopping":"348-415","consensus_level":"medium","plddt":72.2337,"start":348,"end":415}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60228","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60228-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60228-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3E","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3E"},"sequence":{"accession":"P60228","fasta_url":"https://rest.uniprot.org/uniprotkb/P60228.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60228/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60228"}},"corpus_meta":[{"pmid":"16766523","id":"PMC_16766523","title":"Translation 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the eIF3 translation initiation complex; recombinant eIF3-p48 comigrates with the authentic p48 subunit in purified eIF3 and co-precipitates with affinity-purified antibodies to the eIF3 p170 subunit, establishing its membership in the eIF3 complex.\",\n      \"method\": \"CDNA cloning, recombinant protein expression, co-immunoprecipitation with anti-p170 antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical validation (comigration + co-IP), foundational identification replicated by subsequent studies\",\n      \"pmids\": [\"9295280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human eIF3e/Int-6 binds directly to eIF3b (Prt1p in yeast) through a discrete segment of eIF3b, establishing the molecular basis for eIF3e integration into the eIF3 core complex; this interaction was demonstrated both in vivo and in vitro in a budding yeast expression system.\",\n      \"method\": \"In vivo and in vitro binding assays in S. cerevisiae, yeast two-hybrid, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding plus in vivo co-purification, domain mapping, two orthogonal methods in one study\",\n      \"pmids\": [\"11457827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In fission yeast, spInt6 (eIF3e homologue) is required for stable association of eIF3 subunits after dissociation from ribosomes; deletion of int6 results in loss of inter-subunit eIF3 cohesion while eIF3 subunits remain bound to 40S particles, demonstrating a structural role of eIF3e in maintaining eIF3 complex integrity.\",\n      \"method\": \"Genetic deletion, ribosome fractionation, co-purification of eIF3 subunits from 40S particles\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined biochemical phenotype (fractionation + co-purification), ortholog study in fission yeast consistent with mammalian function\",\n      \"pmids\": [\"11705997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In fission yeast, eIF3e defines a distinct eIF3 complex (separate from the eIF3m complex) that associates with a restricted subset of cellular mRNAs; eIF3e is non-essential for global protein synthesis whereas eIF3m is essential, indicating eIF3e specializes in translational regulation of specific mRNAs.\",\n      \"method\": \"Genetic deletion, polysome analysis, ribonomic mRNA-association profiling (microarray + RT-PCR)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype, multiple orthogonal methods (polysome, microarray, RT-PCR), ortholog study consistent with mammalian data\",\n      \"pmids\": [\"15904532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"eIF3e directly binds eIF4G-1 and constitutes the eIF4G-binding subunit of mammalian eIF3; recombinant FLAG-eIF3e competes with intact eIF3 for binding to the eIF3-binding domain of eIF4G-1 in vitro, and excess eIF3e inhibits cap-dependent translation, shifts mRNA to lighter polysomes, and displaces eIF4G and eIF2α from ~40S complexes.\",\n      \"method\": \"Proteolysis/mass spectrometry-based binding assay, competitive in vitro binding, cell-free translation system, polysome profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution + competition assay + functional cell-free translation readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16766523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Stable expression of a C-terminally truncated eIF3e (mimicking MMTV integration) in NIH 3T3 cells causes malignant transformation (foci formation, anchorage-independent growth, accelerated growth, loss of contact inhibition) and inhibits apoptosis onset; full-length eIF3e does not cause transformation, indicating the truncated form acts as a dominant-negative/oncogenic variant.\",\n      \"method\": \"Stable transfection of truncated vs. full-length eIF3e, transformation assays (foci, soft agar, growth curves), apoptosis assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four independent transformation criteria tested, isogenic full-length control, clean gain-of-function experiment\",\n      \"pmids\": [\"11904180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"eIF3e/INT6 localizes partly to the nucleus in human primary fibroblasts, with reduced nuclear staining specifically in early S phase, indicating cell cycle-regulated nucleocytoplasmic shuttling; transformed cells lose this regulated redistribution, suggesting it is relevant to tumor suppressor function.\",\n      \"method\": \"Immunofluorescence microscopy, cell cycle synchronization\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence localization in primary vs. transformed cells, single method but consistent finding across cell types\",\n      \"pmids\": [\"15030549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"eIF3e/Int6 mediates activity-dependent internalization of the L-type calcium channel CaV1.2 by binding to a domain in the II-III loop of CaV1.2; electrical activity triggers CaV1.2 endocytosis and rapid endosomal trafficking in a Ca2+-dependent manner, and the eIF3e-binding domain in CaV1.2 is essential for this internalization.\",\n      \"method\": \"Co-immunoprecipitation, total internal reflection microscopy (TIRF), domain deletion mutagenesis, live-cell imaging of endosomal trafficking\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, TIRF live imaging, domain mutagenesis) in one study demonstrating direct binding and functional consequence\",\n      \"pmids\": [\"17698014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"INT6/eIF3e is required for nonsense-mediated mRNA decay (NMD); INT6 knockdown strongly inhibits NMD without affecting general translation (unlike eIF3b knockdown). INT6 co-immunoprecipitates with the cap-binding protein CBP80 and the NMD factor UPF2, placing INT6 in the NMD pathway upstream of mRNA degradation.\",\n      \"method\": \"siRNA knockdown, NMD reporter assays, co-immunoprecipitation with CBP80 and UPF2, NMD-sensitive transcript quantification\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi phenotypic readout (NMD inhibition) plus Co-IP identifying binding partners, two orthogonal methods in single study\",\n      \"pmids\": [\"17468741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In fission yeast, Int6/eIF3e promotes general translation and maintains basal Atf1 (a Sty1 MAPK target transcription factor) protein levels; int6Δ slows de novo protein synthesis (pulse labeling) and reduces Atf1 protein half-life, thereby impairing Sty1 MAPK-dependent stress response to amino acid starvation.\",\n      \"method\": \"Pulse-labeling translation assay, northern/microarray analysis, protein half-life measurement, genetic epistasis with sty1Δ and gcn2Δ\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulse labeling (Tier 1 method), genetic epistasis, microarray, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18502752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eIF3e is not required for bulk translation in breast cancer cells, but regulates translation of specific mRNAs including positive regulation of urokinase-type plasminogen activator and BCL-XL, and negative regulation of MAD2L1, as determined by microarray comparison of total vs. polysomal RNA after siRNA-mediated eIF3e knockdown.\",\n      \"method\": \"siRNA knockdown, microarray of total and polysomal RNA fractions, validation of specific targets\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling + microarray with specific target validation, single lab\",\n      \"pmids\": [\"20453879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Expression of truncated eIF3e (3e5, resulting from MMTV integration at intron 5) diminishes binding of eIF3 to eIF4G (co-IP), reduces overall protein synthesis and cell growth, increases cap-independent IRES-driven translation relative to cap-dependent translation, and shifts endogenous cap-independent mRNAs (XIAP, c-Myc, CYR61, Pim-1) to heavier polysomes while cap-dependent mRNAs shift to lighter polysomes.\",\n      \"method\": \"Co-immunoprecipitation, bicistronic IRES reporter assay, polysome profiling, single-copy knockin cell line\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP, IRES reporter, polysome profiling, controlled single-copy cell line; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21737453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HTLV-1 Tax protein inhibits NMD by binding to INT6/eIF3e and UPF1; Tax interaction with INT6 is necessary for NMD inhibition, as shown by Tax mutant analysis. Tax expression decreases INT6 abundance in P-bodies and increases phosphorylated UPF1, collectively impairing NMD of viral and cellular transcripts.\",\n      \"method\": \"Co-immunoprecipitation, Tax mutant analysis, P-body morphology and marker quantification, NMD reporter assays, western blotting\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interactions, mutant dissection of necessity, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22553336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"INT6/eIF3e interacts with ATM kinase and is recruited to DNA damage sites; INT6 silencing reduces ATM retention at damage sites, impairs CHK1/CHK2 phosphorylation, attenuates ubiquitylation (K63-linked polyubiquitin) at DSBs, and prevents BRCA1 accumulation at damage sites, placing INT6 in the ATM-RNF8-BRCA1 DSB repair pathway.\",\n      \"method\": \"Co-immunoprecipitation (INT6–ATM), RNAi silencing, γ-H2AX foci, immunofluorescence of ATM/BRCA1 at damage sites, western blotting of CHK1/CHK2 phosphorylation, γ-irradiation/neocarzinostatin treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying direct interaction, multiple functional readouts (kinase phosphorylation, ubiquitylation, repair factor recruitment) in one study\",\n      \"pmids\": [\"22508697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Decreased eIF3e expression in MCF-10A breast epithelial cells induces epithelial-to-mesenchymal transition (EMT) and increases invasion/migration; reduced eIF3e causes specific upregulation of EMT regulators Snail1 and Zeb2 at both transcriptional and post-transcriptional levels.\",\n      \"method\": \"siRNA knockdown, EMT marker analysis, invasion/migration assays, qRT-PCR and western blotting for Snail1/Zeb2\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with multiple cellular readouts and mechanistic follow-up (transcriptional + post-transcriptional Snail1/Zeb2 regulation), single lab\",\n      \"pmids\": [\"22907435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Decreased eIF3e expression induces EMT in lung epithelial cells (A549) via overproduction of TGFβ cytokine; inhibition of TGFβ signaling reverses eIF3e-regulated EMT, and several EMT-regulator mRNAs are translated by a cap-independent mechanism when eIF3e levels are reduced.\",\n      \"method\": \"Stable shRNA knockdown, TGFβ ELISA, TGFβ inhibitor rescue, polysomal mRNA analysis for cap-independent translation\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — rescue experiment with TGFβ inhibitor establishes pathway causality, polysome analysis for translational mechanism, single lab\",\n      \"pmids\": [\"26056130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"INT6/EIF3E promotes homologous recombination-mediated DSB repair by facilitating RNF8 recruitment to DSBs and K63-linked polyubiquitin chain formation; INT6 silencing impairs RNF8 accumulation (but not RNF168 or 53BP1) at DSBs, and reduces BRCA1, BRCA2, and RAD51 recruitment, with MDC1 localization also altered, consistent with defective ATM retention reported previously.\",\n      \"method\": \"RNAi silencing, immunofluorescence of repair factors at laser-induced DSBs, ubiquitin chain analysis, HR repair assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple repair factors assessed, positive/negative controls (RNF168, 53BP1 unaffected), pathway positioning by epistasis; replication by same lab with independent mechanistic extension\",\n      \"pmids\": [\"27550454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"eIF3e depletion in breast cancer cells causes reduced PARP1 protein synthesis due to weakened translation of PARP1 mRNA, decreased poly(ADP-ribosyl)ation, and aberrant mTORC1 activation, collectively inducing cellular senescence with a pro-inflammatory secretory phenotype.\",\n      \"method\": \"siRNA knockdown, polysome profiling of PARP1 mRNA, western blotting, mTORC1 activity assay, senescence assays (SA-β-gal, SASP markers)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — translational mechanism (polysome profiling) linked to functional senescence phenotype, single lab\",\n      \"pmids\": [\"33868586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"INT6/eIF3e negatively regulates HIF2α protein stability in an oxygen-independent manner; INT6 knockdown leads to HIF2α accumulation, which binds TWIST1 and together represses the E-cadherin gene promoter, driving EMT in lung carcinoma A549 cells.\",\n      \"method\": \"siRNA knockdown, western blotting for HIF2α, co-immunoprecipitation (HIF2α–TWIST1), chromatin immunoprecipitation at E-cadherin promoter, EMT marker analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ChIP supporting mechanism, but single lab and limited replication\",\n      \"pmids\": [\"36116043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM35 E3 ubiquitin ligase promotes ubiquitination and degradation of EIF3E; TRIM35 overexpression inhibits endometrial cancer cell proliferation via CDK4/Cyclin D1 pathway suppression, and EIF3E overexpression reverses TRIM35-mediated inhibition, establishing EIF3E as a TRIM35 substrate.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, lentiviral overexpression/knockdown, proliferation assays, CDK4/Cyclin D1 western blotting\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay identifies writer (TRIM35), rescue experiment establishes functional relationship, single lab\",\n      \"pmids\": [\"41429342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDH2 physically interacts with eIF3E within the eIF3 complex and prevents eIF3E–eIF4G1–mRNA assembly; the ALDH2*2 loss-of-function variant disrupts this interaction, releasing eIF3E to assemble an eIF3E–eIF4G1–mRNA ternary complex that drives selective translation of mRNAs containing a GAGGACR motif (including TFRC, ACSL4, UAP1), promoting ferroptosis in cardiomyocytes during myocardial infarction.\",\n      \"method\": \"Co-immunoprecipitation (ALDH2–eIF3E), cardiomyocyte-specific AAV knockdown of eIF3E in mice, lipidomics, MS-based proteomics, motif analysis of selectively translated mRNAs\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding (Co-IP), in vivo genetic rescue (AAV eIF3E KD), mechanistic motif discovery, multiple orthogonal methods in one study\",\n      \"pmids\": [\"41111418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"eIF3e (together with eIF3d) mediates a selective translational response to acute hypoxia, controlling HIF1α accumulation and cellular invasion; small molecules targeting eIF3e specifically reduce this hypoxia-induced translational program and also suppress ER stress-dependent translation.\",\n      \"method\": \"Ribosome profiling, siRNA knockdown of eIF3e/eIF3d, small-molecule eIF3e inhibitor characterization, HIF1α protein quantification, invasion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome profiling plus genetic (RNAi) and pharmacological (small molecule) perturbation, multiple readouts, single lab\",\n      \"pmids\": [\"41364558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"eIF3e has an RNA-binding function independent of its canonical protein synthesis activity; in t(4;14) myeloma, REIIBP-upregulated eIF3e directly binds the 3'UTR of TLR7 mRNA to upregulate TLR7, demonstrating a non-canonical role of eIF3e as an RNA-binding regulator.\",\n      \"method\": \"RNA immunoprecipitation / direct binding to 3'UTR, REIIBP knockdown/overexpression, TLR7 mRNA and protein quantification\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct 3'UTR binding assay demonstrates RNA-binding function, single lab\",\n      \"pmids\": [\"38124661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Conditional deletion of Eif3e in B cells (Cγ1Cre) causes B cell hyperactivation, impaired proliferation/survival/differentiation, upregulation of CD80, and activation of CD4+ T cells into IL-4-producing TFH-like cells that in turn activate bystander Eif3e-sufficient B cells, establishing a feedforward loop that drives malignant lymphocyte transformation; this identifies eIF3e as a translational checkpoint maintaining immune tolerance.\",\n      \"method\": \"Conditional knockout mouse (Cγ1Cre-Eif3e), flow cytometry, B/T cell co-culture, IL-4 quantification, lymphoproliferation/transformation assessment\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype and mechanistic feedforward loop, single lab, in vivo model\",\n      \"pmids\": [\"42233886\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3E (eIF3e/INT6/p48) is a non-core subunit of the eIF3 translation initiation complex that directly binds eIF3b to integrate into eIF3 and contacts eIF4G-1 to mediate cap-dependent translation initiation; it additionally drives selective, cap-independent and stress-responsive translation of specific mRNA subsets (via a GAGGACR motif or eIF3d/eIF3e-dependent mechanism in hypoxia/ER stress), participates in nonsense-mediated mRNA decay by associating with CBP80 and UPF2, promotes DNA double-strand break repair through the ATM–RNF8–BRCA1 axis, is subject to ubiquitin-mediated degradation by TRIM35, undergoes cell cycle-regulated nucleocytoplasmic shuttling, mediates activity-dependent internalization of CaV1.2 calcium channels, and stabilizes HIF2α protein to regulate angiogenic and EMT programs; truncation of eIF3e (as by MMTV integration) shifts the balance from cap-dependent to cap-independent translation and causes malignant transformation, whereas full eIF3e loss triggers EMT via TGFβ, impairs immune tolerance in B cells, and disrupts mTORC1/PARP1 homeostasis leading to cellular senescence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3E (eIF3e/INT6/p48) is a non-core subunit of the eIF3 translation initiation complex that couples general translation initiation to selective, regulated translation of defined mRNA subsets [#0, #3]. It integrates into eIF3 by binding directly to eIF3b and is required to maintain inter-subunit cohesion of the eIF3 complex after ribosome dissociation [#1, #2]. As the eIF4G-binding subunit of mammalian eIF3, eIF3e bridges eIF3 to the cap-binding apparatus, and an excess of free eIF3e competes for eIF4G-1 and inhibits cap-dependent initiation [#4]. Rather than driving bulk protein synthesis, eIF3e specializes in translational control of particular transcripts and can promote cap-independent initiation: C-terminal truncation mimicking MMTV integration weakens eIF3\\u2013eIF4G binding, shifts the balance from cap-dependent to IRES-driven translation, and causes malignant transformation [#5, #11]. eIF3e directs translation of specific targets including BCL-XL, urokinase plasminogen activator, PARP1 and HIF1\\u03b1, and assembles a selective eIF3E\\u2013eIF4G1\\u2013mRNA complex that translates GAGGACR-motif mRNAs (TFRC, ACSL4, UAP1) when released from inhibitory ALDH2 binding, driving cardiomyocyte ferroptosis [#10, #17, #20, #21]. Loss of eIF3e induces epithelial-to-mesenchymal transition through TGF\\u03b2 overproduction and HIF2\\u03b1\\u2013TWIST1-mediated repression of E-cadherin [#14, #15, #18]. Beyond translation, eIF3e functions in nonsense-mediated mRNA decay via association with CBP80 and UPF2 [#8], promotes ATM\\u2013RNF8\\u2013BRCA1-dependent homologous-recombination repair of DNA double-strand breaks [#13, #16], mediates activity-dependent endocytosis of the CaV1.2 calcium channel [#7], and acts as a translational checkpoint maintaining B-cell immune tolerance [#23]. eIF3e abundance is controlled by TRIM35-mediated ubiquitination and degradation [#19].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that the 48-kDa eIF3 subunit is a defined gene product physically embedded in the translation initiation complex, fixing EIF3E's foundational identity.\",\n      \"evidence\": \"cDNA cloning, recombinant expression, and co-IP with anti-eIF3 p170 antibodies\",\n      \"pmids\": [\"9295280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which subunit contacts mediate integration\", \"No functional role beyond complex membership\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved how eIF3e physically enters eIF3 and whether it is structurally required, showing a direct eIF3b interface and a role in holding the complex together.\",\n      \"evidence\": \"Yeast in vivo/in vitro binding and domain mapping (eIF3b interaction); fission yeast int6 deletion with ribosome fractionation\",\n      \"pmids\": [\"11457827\", \"11705997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the eIF3b-eIF3e interface not solved\", \"Did not address mRNA selectivity\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reframed eIF3e from a generic initiation factor to a specialized regulator by showing it is dispensable for global translation but governs a restricted mRNA set.\",\n      \"evidence\": \"Fission yeast genetic deletion, polysome analysis, and ribonomic mRNA-association profiling\",\n      \"pmids\": [\"15904532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the selected mRNAs in mammals not defined\", \"Mechanism of selectivity unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the molecular link between eIF3e and the cap-binding machinery, defining eIF3e as the eIF4G-1-binding subunit whose stoichiometry tunes cap-dependent initiation.\",\n      \"evidence\": \"Competitive in vitro binding, cell-free translation, and polysome profiling\",\n      \"pmids\": [\"16766523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How physiological eIF3e levels are regulated to set initiation balance not addressed\", \"Binding interface on eIF4G-1 mapped only functionally\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected eIF3e structural perturbation to cancer, showing that a C-terminally truncated form is a transforming gain-of-function variant.\",\n      \"evidence\": \"Stable expression of truncated vs full-length eIF3e in NIH 3T3 with transformation and apoptosis assays\",\n      \"pmids\": [\"11904180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of transformation not resolved at this stage\", \"In vivo tumorigenicity not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the mechanistic explanation for truncation-driven oncogenesis by showing the truncated form weakens eIF3\\u2013eIF4G binding and shifts translation toward cap-independent mRNAs.\",\n      \"evidence\": \"Single-copy knockin cell line, co-IP, bicistronic IRES reporter, polysome profiling (XIAP, c-Myc, CYR61, Pim-1)\",\n      \"pmids\": [\"21737453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cap-independent mRNAs are selected not defined\", \"Link between specific targets and transformation incomplete\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended eIF3e function beyond initiation, revealing roles in NMD and in membrane-channel trafficking.\",\n      \"evidence\": \"siRNA NMD reporter assays and co-IP with CBP80/UPF2; co-IP, TIRF imaging and domain mutagenesis of CaV1.2 internalization\",\n      \"pmids\": [\"17468741\", \"17698014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NMD and channel-trafficking roles require eIF3 complex membership unclear\", \"Mechanism linking eIF3e to UPF1/UPF2 step undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that eIF3e supports stress-responsive gene expression by maintaining translation of a stress MAPK target, linking it to adaptive signaling.\",\n      \"evidence\": \"Fission yeast pulse-labeling, protein half-life, and genetic epistasis with sty1\\u0394/gcn2\\u0394 (Atf1 levels)\",\n      \"pmids\": [\"18502752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian equivalent of Atf1 control not established\", \"Direct vs indirect effect on Atf1 mRNA unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined specific mammalian translational targets of eIF3e, confirming selective rather than bulk translational control in cancer cells.\",\n      \"evidence\": \"siRNA knockdown with total vs polysomal microarray and target validation (uPA, BCL-XL, MAD2L1)\",\n      \"pmids\": [\"20453879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence/structural features driving target selection not identified\", \"Single-lab dataset\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established eIF3e as a DNA double-strand break repair factor acting in the ATM signaling axis, distinct from its translational role; concurrent work showed viral hijacking of its NMD function.\",\n      \"evidence\": \"Co-IP (INT6\\u2013ATM), RNAi, damage-site immunofluorescence, CHK1/CHK2 phosphorylation; HTLV-1 Tax co-IP and NMD reporter assays\",\n      \"pmids\": [\"22508697\", \"22553336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a translation factor is recruited to chromatin damage sites unknown\", \"Whether repair role is eIF3-dependent unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked eIF3e loss to a tumor-relevant EMT program, identifying Snail1 and Zeb2 as induced effectors.\",\n      \"evidence\": \"siRNA knockdown in MCF-10A with EMT marker, invasion/migration assays and Snail1/Zeb2 quantification\",\n      \"pmids\": [\"22907435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of Snail1/Zeb2 not fully separated\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified TGF\\u03b2 as the causal mediator of eIF3e-loss-driven EMT and tied EMT regulators to cap-independent translation.\",\n      \"evidence\": \"shRNA knockdown, TGF\\u03b2 ELISA, TGF\\u03b2 inhibitor rescue, polysomal cap-independence analysis in A549\",\n      \"pmids\": [\"26056130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which EMT mRNAs use cap-independent initiation not exhaustively mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the DSB-repair mechanism, placing eIF3e upstream of RNF8-dependent K63 ubiquitination and BRCA1/BRCA2/RAD51 recruitment in homologous recombination.\",\n      \"evidence\": \"RNAi, laser-induced DSB immunofluorescence, ubiquitin chain analysis, HR repair assay with RNF168/53BP1 controls\",\n      \"pmids\": [\"27550454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of eIF3e at damage sites unidentified\", \"Whether effect is translational or structural unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected eIF3e translational control to cellular senescence through PARP1 translation and mTORC1 regulation.\",\n      \"evidence\": \"siRNA knockdown, PARP1 polysome profiling, mTORC1 activity, SA-\\u03b2-gal/SASP senescence assays\",\n      \"pmids\": [\"33868586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mTORC1 dysregulation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified HIF2\\u03b1 stability as an eIF3e-regulated node driving EMT via TWIST1 and E-cadherin repression.\",\n      \"evidence\": \"siRNA knockdown, HIF2\\u03b1 western blotting, HIF2\\u03b1\\u2013TWIST1 co-IP, E-cadherin promoter ChIP\",\n      \"pmids\": [\"36116043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How eIF3e controls oxygen-independent HIF2\\u03b1 stability mechanistically unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established eIF3e abundance as a regulated quantity through TRIM35-mediated ubiquitination and degradation affecting proliferation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, lentiviral perturbation, rescue, CDK4/Cyclin D1 western blotting\",\n      \"pmids\": [\"41429342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site and chain type on eIF3E not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-canonical RNA-binding function of eIF3e distinct from initiation, binding the TLR7 3'UTR to upregulate TLR7 in myeloma.\",\n      \"evidence\": \"RNA immunoprecipitation / 3'UTR binding, REIIBP perturbation, TLR7 quantification\",\n      \"pmids\": [\"38124661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether 3'UTR binding is direct and sequence-specific genome-wide unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a mechanistic model for selective translation, showing ALDH2 sequesters eIF3e and its release enables a GAGGACR-motif-driven eIF3E\\u2013eIF4G1\\u2013mRNA program causing cardiomyocyte ferroptosis, while a parallel study tied eIF3e/eIF3d to hypoxia- and ER-stress-selective translation controlling HIF1\\u03b1.\",\n      \"evidence\": \"ALDH2\\u2013eIF3E co-IP, cardiomyocyte AAV knockdown in mice, lipidomics, motif analysis; ribosome profiling with siRNA and small-molecule eIF3e inhibition\",\n      \"pmids\": [\"41111418\", \"41364558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the GAGGACR motif is recognized structurally not resolved\", \"Breadth of the selective translatome across tissues unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined eIF3e as a translational checkpoint enforcing immune tolerance, with B-cell deletion triggering a feedforward hyperactivation loop and lymphocyte transformation.\",\n      \"evidence\": \"Conditional C\\u03b31Cre-Eif3e knockout mice, flow cytometry, B/T co-culture, IL-4 quantification\",\n      \"pmids\": [\"42233886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific mRNAs whose translation enforces tolerance not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How eIF3e physically recognizes its selective mRNA targets (e.g., the GAGGACR motif) and how it is partitioned between canonical eIF3-dependent initiation, cap-independent translation, NMD, DSB repair and RNA-binding roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of an eIF3e\\u2013mRNA selective complex\", \"Recruitment mechanism to DNA damage sites undefined\", \"Unclear whether non-translational roles require eIF3 membership\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 3, 4, 10, 11, 20, 21]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [20, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 13, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 16]}\n    ],\n    \"complexes\": [\"eIF3\"],\n    \"partners\": [\"EIF3B\", \"EIF4G1\", \"CBP80\", \"UPF2\", \"ATM\", \"ALDH2\", \"TRIM35\", \"CACNA1C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}