{"gene":"EIF3F","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2008,"finding":"MAFbx/Atrogin-1 (E3 ubiquitin ligase) directly ubiquitinates eIF3f and targets it for proteasome-mediated degradation during skeletal muscle atrophy; ectopic MAFbx expression in myotubes induces eIF3f degradation and atrophy, while shRNA knockdown of MAFbx prevents eIF3f degradation; conversely, genetic activation of eIF3f causes hypertrophy and blocks atrophy.","method":"Co-immunoprecipitation, shRNA knockdown, ectopic overexpression in myotubes, in vivo mouse skeletal muscle experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments (gain- and loss-of-function), replicated in vivo and in vitro, multiple orthogonal methods","pmids":["18354498"],"is_preprint":false},{"year":2008,"finding":"The six C-terminal lysine residues of eIF3f are required for MAFbx-directed polyubiquitination and proteasomal degradation; mutation of all six (K5-10R mutant) confers resistance to degradation, promotes hypertrophy in cellulo and in vivo, and protects against starvation-induced muscle atrophy.","method":"Deletion analysis, site-directed mutagenesis, in cellulo and in vivo overexpression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-directed mutagenesis identifying specific lysine residues, validated in vivo, multiple orthogonal methods in single rigorous study","pmids":["19073596"],"is_preprint":false},{"year":2010,"finding":"eIF3f contains a conserved TOS (TOR signaling) motif that connects mTOR/raptor complex to enable S6K1 phosphorylation; MAFbx-induced degradation of eIF3f suppresses S6K1 activation by mTOR, while an eIF3f mutant insensitive to MAFbx polyubiquitination maintains persistent S6K1 and rpS6 phosphorylation during muscle differentiation.","method":"Mutant expression, immunoprecipitation, phosphorylation assays, TOS motif functional analysis in myotubes","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — TOS motif functional validation, mutant rescue experiments, phosphorylation assays, multiple orthogonal methods","pmids":["20126553"],"is_preprint":false},{"year":2010,"finding":"eIF3f possesses intrinsic deubiquitinase (DUB) activity and deubiquitinates monoubiquitinated activated Notch1 receptor on endocytic vesicles; knockdown of eIF3f causes accumulation of monoubiquitinated Notch, an effect rescued by wild-type but not catalytically inactive eIF3f mutant; eIF3f is recruited to activated Notch by the E3 ligase Deltex1 acting as a bridging factor, and this activity is required for gamma-secretase processing and Notch transcriptional activation.","method":"shRNA library screen, immunofluorescence, co-immunoprecipitation, catalytic mutant rescue, coculture Notch activation assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — catalytically inactive mutant controls, multiple orthogonal methods, epistasis in Notch pathway established in single rigorous study","pmids":["21124883"],"is_preprint":false},{"year":2008,"finding":"eIF3f physically interacts with the N-terminal region of the SARS-CoV spike (S) protein and the IBV coronavirus S protein; this interaction inhibits translation of a reporter gene in vitro and in intact cells, suggesting eIF3f is exploited by coronavirus to suppress host gene translation.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescent staining, in vitro and cell-based translation reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (Y2H confirmed by Co-IP and reporter assay) in single lab","pmids":["18231581"],"is_preprint":false},{"year":2009,"finding":"eIF3f (and its N-terminal 91 aa fragment N91-eIF3f) inhibits HIV-1 replication by specifically blocking 3' end processing of HIV-1 pre-mRNA; this restriction involves a complex of eIF3f, the SR protein 9G8, and cyclin-dependent kinase 11 (CDK11), where eIF3f modulates sequence-specific recognition of HIV-1 pre-mRNA by 9G8.","method":"cDNA expression library screen, overexpression, in vivo and in vitro 3' end processing assays, co-factor identification","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro processing assays, partner identification, mechanistic dissection across two complementary papers","pmids":["19854136","19237569"],"is_preprint":false},{"year":2012,"finding":"eIF3f inhibits both cap-dependent and cap-independent translation, and promotes rRNA degradation through direct interaction with hnRNP K; under stress conditions eIF3f dissociates hnRNP K from rRNA, preventing hnRNP K from protecting rRNA from degradation; rRNA degradation occurs in non-P-body, non-stress-granule cytoplasmic foci containing eIF3f.","method":"Stable knockdown, co-immunoprecipitation, translation reporter assays, rRNA stability assays, subcellular fractionation/imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and functional dissociation demonstrated, multiple readouts, single lab","pmids":["22457825"],"is_preprint":false},{"year":2013,"finding":"hMSH4 interacts with eIF3f through the N-terminal regions of both proteins; this interaction promotes hMSH4 protein stabilization, sustains γ-H2AX foci, and compromises cell survival after ionizing radiation by down-regulating NHEJ-mediated DSB repair; the hMSH4-eIF3f interplay also inhibits IR-induced AKT activation.","method":"Co-immunoprecipitation, deletion mapping, knockdown, cell survival and DNA damage assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with domain mapping, functional readouts, single lab multiple methods","pmids":["23725059"],"is_preprint":false},{"year":2015,"finding":"eIF3f physically interacts with the alpha-chain (residues 1–227) of secretory clusterin (sCLU); this interaction blocks psCLU modification, decreasing CLU expression and secretion, suppresses Akt and ERK signaling, stabilizes p53, and increases p21 and Bax expression; eIF3f overexpression in a xenograft model inhibits tumor growth.","method":"Co-immunoprecipitation, overexpression, xenograft model, Western blotting","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with domain mapping, in vivo xenograft confirmation, single lab","pmids":["26988917"],"is_preprint":false},{"year":2015,"finding":"eIF3f physically interacts with the alpha 1B-adrenergic receptor (α1B-ADR) in native conditions in human and mouse cell lines; upon catecholamine stimulation, eIF3f promotes adrenoceptor activity in vitro, independently of the eIF3f proline- and alanine-rich N-terminal region.","method":"Co-immunoprecipitation in native conditions, adrenoceptor activity assay in vitro, domain deletion analysis","journal":"BMC biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up","pmids":["26497985"],"is_preprint":false},{"year":2018,"finding":"eIF3f knockdown reduces steady-state levels of SCA8 polySer RAN protein and other RAN proteins, identifying eIF3f as a modulator of repeat-associated non-ATG (RAN) translation.","method":"siRNA knockdown, Western blot/immunostaining for RAN protein levels in cells","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with specific protein readout, independently shown for multiple RAN proteins, single lab","pmids":["30206144"],"is_preprint":false},{"year":2018,"finding":"ERα represses transcription of the EIF3F gene (genomic pathway) while estrogen-bound ERα promotes eIF3f mRNA translation via activation of mTORC1, which enhances binding of eIF3 to the eIF4F complex and assembly of 48S preinitiation complexes; reduced eIF3f levels are required for proper proliferation and survival of ER-positive breast cancer cells.","method":"ERα knockdown/overexpression, mTORC1 inhibition, polysome profiling, reporter assays, Western blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transcriptional and translational regulation dissected), single lab","pmids":["30573685"],"is_preprint":false},{"year":2019,"finding":"Homozygous eIF3f knockout mice die at early embryonic stage (after pre-implantation); heterozygous mice have reduced eIF3f expression, decreased skeletal muscle mass with reduced protein synthesis rate, polysome content, and inhibited mTOR pathway; eIF3f partial depletion amplifies hindlimb immobilization-induced muscle atrophy with reduced mTOR pathway activation.","method":"Gene knockout mouse model, polysome profiling, protein synthesis rate measurement, hindlimb immobilization model","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with multiple orthogonal readouts (polysome profiling, synthesis rate, mTOR signaling) confirming mechanism","pmids":["31026345"],"is_preprint":false},{"year":2023,"finding":"eIF3f antagonizes FBXW7β-mediated ubiquitination of PHGDH (phosphoglycerate dehydrogenase) through its deubiquitinase activity, stabilizing PHGDH and enhancing the SGOC metabolic pathway; eIF3f also exerts deubiquitinase activity toward MYC, increasing MYC-mediated PHGDH transcription; both Wnt (transcriptional activation of eIF3f) and EGF (via GSK3β/FBXW7β) signaling pathways converge on this axis in colorectal cancer.","method":"Co-immunoprecipitation, ubiquitination assays, deubiquitinase activity assays, pathway inhibition, Western blotting","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DUB activity toward two substrates demonstrated, pathway dissection, single lab","pmids":["37544925"],"is_preprint":false},{"year":2025,"finding":"eIF3f directly interacts with and stabilizes ACSL4 (long-chain acyl-CoA synthetase 4) through K48-linked deubiquitination, promoting fatty acid biosynthesis in hepatocellular carcinoma; phosphorylated eIF3f enhances this eIF3f–ACSL4 interaction.","method":"Co-immunoprecipitation, ubiquitination assays, metabolomics, proteomics, metabolic flux analysis, organoid and in vivo models","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and deubiquitination demonstrated with multiple orthogonal methods, single lab","pmids":["40154622"],"is_preprint":false},{"year":2025,"finding":"Using endogenous BioID proximity labeling in human muscle cells, eIF3f was found to interact with components of the eIF3 complex, eIF4E, eIF4G, and eIF5 initiation factors in both proliferating and differentiated cells; eIF3f also displayed a previously unknown nuclear localization in myoblasts and myotubes; novel cytoplasmic partners included SYNPO2 (sarcomeric/Z-disc) and LAMP1 (lysosomal compartment).","method":"CRISPR-Cas9 endogenous BioID tagging, streptavidin pulldown, mass spectrometry, polysome profiling, immunofluorescence","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous proximity labeling with MS identification and immunofluorescence validation, single lab, novel localization finding","pmids":["41423661"],"is_preprint":false},{"year":2026,"finding":"eIF3f directly interacts with PDCD4 in an RNA-independent manner; eIF3f and PDCD4 each independently bind Bcl-xL IRES RNA; eIF3f regulates IRES-mediated translation of Bcl-xL mRNA, demonstrated by IRES reporter assay, polysome profiling, and EMSA, likely via its interaction with PDCD4.","method":"Co-immunoprecipitation, IRES reporter assay, polysome profiling, EMSA, knockdown experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-independent interaction confirmed, multiple orthogonal functional assays, single lab","pmids":["42123540"],"is_preprint":false},{"year":2026,"finding":"CCT2 interacts with eIF3f and FASN to form a ternary CCT2/eIF3f/FASN complex that enhances eIF3f-mediated deubiquitination of FASN, increasing FASN protein stability and lipid synthesis in prostate cancer; disruption of the CCT2–eIF3f interaction suppresses FASN-driven tumor progression in vivo.","method":"Co-immunoprecipitation, ubiquitination assays, in vivo isograft and PDX models, small-molecule CCT2-eIF3f interaction inhibitor","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ternary complex identified, deubiquitination activity toward FASN demonstrated, in vivo validation, single lab","pmids":["42231807"],"is_preprint":false}],"current_model":"EIF3F is a multifunctional subunit of the eIF3 translation initiation complex that scaffolds mTORC1-S6K1 signaling (via a TOS motif) to promote protein synthesis and skeletal muscle hypertrophy; it is targeted for polyubiquitination at six C-terminal lysines and proteasomal degradation by the E3 ligase MAFbx/Atrogin-1 during muscle atrophy; independently, eIF3f possesses intrinsic deubiquitinase (DUB) activity that it deploys toward multiple substrates including monoubiquitinated activated Notch1 (facilitating gamma-secretase processing), PHGDH, MYC, ACSL4, and FASN; it also modulates HIV-1 mRNA 3' end processing through a complex with 9G8 and CDK11, promotes rRNA degradation via hnRNP K dissociation, regulates IRES-mediated translation of Bcl-xL through interaction with PDCD4, and localizes to both cytoplasm (ribosomal complexes, lysosomes, Z-disc) and nucleus in muscle cells."},"narrative":{"mechanistic_narrative":"EIF3F is a subunit of the eIF3 translation initiation complex that couples nutrient/growth signaling to protein synthesis and, through an independent intrinsic deubiquitinase activity, controls the stability of multiple metabolic and oncogenic substrates [PMID:41423661, PMID:21124883, PMID:37544925]. In skeletal muscle, eIF3f carries a TOS motif that bridges the mTOR/raptor complex to enable S6K1 and rpS6 phosphorylation, thereby driving translation and hypertrophy [PMID:20126553]; this output is negatively gated by the E3 ligase MAFbx/Atrogin-1, which polyubiquitinates eIF3f at six C-terminal lysines and targets it for proteasomal degradation during atrophy, while a degradation-resistant mutant sustains S6K1 signaling and protects against atrophy [PMID:18354498, PMID:19073596, PMID:20126553]. eIF3f is required for normal development and muscle mass: homozygous knockout is embryonic lethal and heterozygous loss reduces muscle protein synthesis, polysome content, and mTOR activity [PMID:31026345]. Beyond canonical initiation, eIF3f acts as a deubiquitinase that removes monoubiquitin from activated Notch1 to license gamma-secretase processing [PMID:21124883], and stabilizes the metabolic enzymes PHGDH, ACSL4, and FASN — the latter two via K48-linked chain removal — while also deubiquitinating MYC, linking it to serine/one-carbon and lipid metabolism in colorectal, hepatocellular, and prostate cancers [PMID:37544925, PMID:40154622, PMID:42231807]. eIF3f additionally tunes specialized RNA processes, restricting HIV-1 pre-mRNA 3' end processing in a complex with 9G8 and CDK11 [PMID:19854136, PMID:19237569], promoting stress-induced rRNA degradation by dissociating hnRNP K from rRNA [PMID:22457825], and regulating IRES-mediated translation of Bcl-xL through interaction with PDCD4 [PMID:42123540]. Proximity labeling places eIF3f with eIF3/eIF4E/eIF4G/eIF5 initiation machinery and assigns it nuclear, Z-disc (SYNPO2), and lysosomal (LAMP1) localizations in muscle cells [PMID:41423661].","teleology":[{"year":2008,"claim":"Established how eIF3f abundance is controlled during muscle wasting, identifying it as the degradation target that links an atrophy E3 ligase to loss of translational capacity.","evidence":"Co-IP, MAFbx shRNA knockdown and overexpression in myotubes plus in vivo mouse muscle","pmids":["18354498"],"confidence":"High","gaps":["Did not define the lysines required for ubiquitination","Did not establish the downstream signaling effector of eIF3f"]},{"year":2008,"claim":"Mapped the molecular determinant of eIF3f turnover, showing six C-terminal lysines are the ubiquitin acceptor sites whose mutation confers atrophy resistance.","evidence":"Site-directed mutagenesis (K5-10R), deletion analysis, in cellulo and in vivo overexpression","pmids":["19073596"],"confidence":"High","gaps":["Did not yet connect resistance to a specific signaling pathway"]},{"year":2010,"claim":"Defined the mechanism by which eIF3f drives hypertrophy, showing a TOS motif scaffolds mTOR/raptor to enable S6K1 activation.","evidence":"TOS motif mutagenesis, immunoprecipitation, phosphorylation assays in myotubes","pmids":["20126553"],"confidence":"High","gaps":["Did not resolve stoichiometry of the eIF3f-raptor-S6K1 interaction","Did not test requirement in vivo at this stage"]},{"year":2010,"claim":"Revealed an entirely separate enzymatic role, demonstrating eIF3f is an intrinsic deubiquitinase acting on monoubiquitinated Notch1 to permit gamma-secretase processing.","evidence":"shRNA screen, catalytically inactive mutant rescue, Notch coculture activation assay, Deltex1 bridging","pmids":["21124883"],"confidence":"High","gaps":["Did not identify the catalytic residues or structural basis of DUB activity","Did not survey the full substrate range"]},{"year":2008,"claim":"Showed eIF3f can be hijacked by coronavirus spike proteins to suppress host translation, the first link to viral pathogenesis.","evidence":"Yeast two-hybrid, Co-IP, immunofluorescence, translation reporter assays","pmids":["18231581"],"confidence":"Medium","gaps":["Mechanism of translational suppression by the S-protein interaction not resolved","Single lab"]},{"year":2009,"claim":"Identified an antiviral RNA-processing role, showing eIF3f blocks HIV-1 pre-mRNA 3' end processing within a 9G8/CDK11 complex.","evidence":"cDNA library screen, in vivo and in vitro 3' end processing assays, cofactor identification across two papers","pmids":["19854136","19237569"],"confidence":"High","gaps":["Whether this processing role generalizes to host mRNAs unclear","Catalytic vs scaffolding contribution not separated"]},{"year":2012,"claim":"Connected eIF3f to rRNA homeostasis under stress, showing it dissociates hnRNP K from rRNA to permit degradation in distinct cytoplasmic foci.","evidence":"Stable knockdown, Co-IP, translation and rRNA stability assays, subcellular imaging","pmids":["22457825"],"confidence":"Medium","gaps":["Nuclease responsible for rRNA degradation not identified","Relationship of foci to canonical RNA granules unresolved"]},{"year":2013,"claim":"Linked eIF3f to the DNA damage response through hMSH4 binding that modulates NHEJ repair and AKT activation after irradiation.","evidence":"Co-IP, deletion mapping, knockdown, cell survival and DNA damage assays","pmids":["23725059"],"confidence":"Medium","gaps":["Direct role of eIF3f at DSB sites not shown","Single lab, mechanism of NHEJ down-regulation indirect"]},{"year":2015,"claim":"Extended eIF3f's interactome to secretory clusterin and the alpha-1B-adrenergic receptor, implicating it in tumor suppression and adrenoceptor signaling.","evidence":"Co-IP with domain mapping, xenograft model; native Co-IP and adrenoceptor activity assay","pmids":["26988917","26497985"],"confidence":"Medium","gaps":["Adrenoceptor interaction rests on single low-confidence Co-IP without reciprocal validation","Mechanism of sCLU modification blockade not defined"]},{"year":2018,"claim":"Implicated eIF3f in non-canonical RAN translation, broadening its translational regulatory scope to repeat-expansion disease pathology.","evidence":"siRNA knockdown with RAN protein readouts for multiple repeat expansions","pmids":["30206144"],"confidence":"Medium","gaps":["Direct binding to repeat RNAs not demonstrated","Single lab"]},{"year":2018,"claim":"Embedded eIF3f in estrogen-receptor signaling, showing dual transcriptional repression and mTORC1-driven translational control of its own expression in breast cancer.","evidence":"ERalpha knockdown/overexpression, mTORC1 inhibition, polysome profiling, reporter assays","pmids":["30573685"],"confidence":"Medium","gaps":["Causal link between eIF3f level and proliferation correlative","Single lab"]},{"year":2019,"claim":"Provided definitive in vivo genetic proof that eIF3f is essential for development and for sustaining muscle protein synthesis through the mTOR pathway.","evidence":"Knockout mouse model, polysome profiling, synthesis rate, hindlimb immobilization atrophy model","pmids":["31026345"],"confidence":"High","gaps":["Cause of embryonic lethality not dissected","Tissue-specific contributions beyond muscle untested"]},{"year":2023,"claim":"Established eIF3f as a metabolic regulator in cancer, using DUB activity to stabilize PHGDH and MYC and amplify the serine/one-carbon pathway downstream of Wnt and EGF.","evidence":"Co-IP, ubiquitination and DUB assays, pathway inhibition in colorectal cancer","pmids":["37544925"],"confidence":"Medium","gaps":["Direct vs indirect MYC deubiquitination not fully separated","Single lab"]},{"year":2025,"claim":"Showed eIF3f drives lipid biosynthesis by K48-linked deubiquitination and stabilization of ACSL4, with phosphorylation enhancing the interaction in liver cancer.","evidence":"Co-IP, ubiquitination assays, metabolomics, metabolic flux, organoid and in vivo models","pmids":["40154622"],"confidence":"Medium","gaps":["Kinase phosphorylating eIF3f not identified","Single lab"]},{"year":2025,"claim":"Defined the endogenous eIF3f interactome and unexpected localizations, placing it with initiation machinery and at nuclear, Z-disc, and lysosomal compartments in muscle.","evidence":"CRISPR endogenous BioID, streptavidin pulldown, mass spectrometry, immunofluorescence","pmids":["41423661"],"confidence":"Medium","gaps":["Functional significance of nuclear and lysosomal pools not established","Proximity does not prove direct binding"]},{"year":2026,"claim":"Connected eIF3f to selective IRES-driven survival translation via RNA-independent interaction with PDCD4 and binding to the Bcl-xL IRES.","evidence":"Co-IP, IRES reporter, polysome profiling, EMSA, knockdown","pmids":["42123540"],"confidence":"Medium","gaps":["Whether eIF3f acts catalytically or as adaptor on the IRES unresolved","Single lab"]},{"year":2026,"claim":"Identified a chaperonin-assisted mechanism in which CCT2 forms a ternary complex enabling eIF3f-mediated deubiquitination and stabilization of FASN in prostate cancer.","evidence":"Co-IP, ubiquitination assays, isograft/PDX models, small-molecule interaction inhibitor","pmids":["42231807"],"confidence":"Medium","gaps":["Role of CCT2 chaperone function vs scaffolding not separated","Single lab"]},{"year":null,"claim":"How the same protein partitions between its eIF3 initiation role and its deubiquitinase activity — and what governs substrate selection, catalytic residues, and compartment-specific functions — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the eIF3f DUB active site or its substrate-recognition determinants","Mechanism switching initiation vs DUB roles undefined","Function of nuclear and lysosomal eIF3f pools uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,13,14,17]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,11,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,6,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,17]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[15]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,13,14,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,14,17]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,17]}],"complexes":["eIF3 translation initiation complex","eIF3f/9G8/CDK11 complex","CCT2/eIF3f/FASN ternary complex"],"partners":["MAFBX","NOTCH1","HNRNP K","PDCD4","CCT2","FASN","ACSL4","PHGDH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00303","full_name":"Eukaryotic translation initiation factor 3 subunit F","aliases":["Deubiquitinating enzyme eIF3f","Eukaryotic translation initiation factor 3 subunit 5","eIF-3-epsilon","eIF3 p47"],"length_aa":357,"mass_kda":37.6,"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) Deubiquitinates activated NOTCH1, promoting its nuclear import, thereby acting as a positive regulator of Notch signaling","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00303/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3F","classification":"Common Essential","n_dependent_lines":1174,"n_total_lines":1208,"dependency_fraction":0.9718543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"EIF4A1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"SRP14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF3F","total_profiled":1310},"omim":[{"mim_id":"618295","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 67; MRT67","url":"https://www.omim.org/entry/618295"},{"mim_id":"614729","title":"COP9 SIGNALOSOME, SUBUNIT 6; COPS6","url":"https://www.omim.org/entry/614729"},{"mim_id":"603914","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT F; EIF3F","url":"https://www.omim.org/entry/603914"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3F"},"hgnc":{"alias_symbol":["eIF3-epsilon","eIF3-p47"],"prev_symbol":["EIF3S5"]},"alphafold":{"accession":"O00303","domains":[{"cath_id":"3.40.140.10","chopping":"92-244","consensus_level":"high","plddt":82.8405,"start":92,"end":244},{"cath_id":"1.20.5","chopping":"321-357","consensus_level":"medium","plddt":94.8249,"start":321,"end":357}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00303","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00303-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00303-F1-predicted_aligned_error_v6.png","plddt_mean":73.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3F","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3F"},"sequence":{"accession":"O00303","fasta_url":"https://rest.uniprot.org/uniprotkb/O00303.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00303/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00303"}},"corpus_meta":[{"pmid":"18354498","id":"PMC_18354498","title":"The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy.","date":"2008","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18354498","citation_count":257,"is_preprint":false},{"pmid":"20126553","id":"PMC_20126553","title":"The translation regulatory subunit eIF3f controls the kinase-dependent mTOR signaling required for muscle differentiation and hypertrophy in mouse.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20126553","citation_count":83,"is_preprint":false},{"pmid":"19073596","id":"PMC_19073596","title":"MAFbx/Atrogin-1 controls the activity of the initiation factor eIF3-f in skeletal muscle atrophy by targeting multiple C-terminal lysines.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19073596","citation_count":76,"is_preprint":false},{"pmid":"21124883","id":"PMC_21124883","title":"The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation.","date":"2010","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/21124883","citation_count":75,"is_preprint":false},{"pmid":"18231581","id":"PMC_18231581","title":"Coronavirus spike protein inhibits host cell translation by interaction with eIF3f.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18231581","citation_count":69,"is_preprint":false},{"pmid":"30206144","id":"PMC_30206144","title":"SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/30206144","citation_count":65,"is_preprint":false},{"pmid":"19854136","id":"PMC_19854136","title":"HIV-1 mRNA 3' end processing is distinctively regulated by eIF3f, CDK11, and splice factor 9G8.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19854136","citation_count":46,"is_preprint":false},{"pmid":"23354061","id":"PMC_23354061","title":"The translational factor eIF3f: the ambivalent eIF3 subunit.","date":"2013","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/23354061","citation_count":44,"is_preprint":false},{"pmid":"23769948","id":"PMC_23769948","title":"eIF3f: a central regulator of the antagonism atrophy/hypertrophy in skeletal muscle.","date":"2013","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23769948","citation_count":37,"is_preprint":false},{"pmid":"19237569","id":"PMC_19237569","title":"Inhibition of HIV-1 replication by eIF3f.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19237569","citation_count":36,"is_preprint":false},{"pmid":"22457825","id":"PMC_22457825","title":"The tumor suppressive role of eIF3f and its function in translation inhibition and rRNA degradation.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22457825","citation_count":35,"is_preprint":false},{"pmid":"37544925","id":"PMC_37544925","title":"eIF3f Mediates SGOC Pathway Reprogramming by Enhancing Deubiquitinating Activity in Colorectal Cancer.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37544925","citation_count":24,"is_preprint":false},{"pmid":"18583931","id":"PMC_18583931","title":"eIF3-f function in skeletal muscles: to stand at the crossroads of atrophy and hypertrophy.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18583931","citation_count":22,"is_preprint":false},{"pmid":"40154622","id":"PMC_40154622","title":"eIF3f promotes tumour malignancy by remodelling fatty acid biosynthesis in hepatocellular carcinoma.","date":"2025","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40154622","citation_count":20,"is_preprint":false},{"pmid":"26988917","id":"PMC_26988917","title":"eIF3f reduces tumor growth by directly interrupting clusterin with anti-apoptotic property in cancer cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26988917","citation_count":18,"is_preprint":false},{"pmid":"31026345","id":"PMC_31026345","title":"eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse.","date":"2019","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31026345","citation_count":18,"is_preprint":false},{"pmid":"23725059","id":"PMC_23725059","title":"MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair.","date":"2013","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23725059","citation_count":17,"is_preprint":false},{"pmid":"30573685","id":"PMC_30573685","title":"Estrogen receptor α promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f).","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30573685","citation_count":17,"is_preprint":false},{"pmid":"33539814","id":"PMC_33539814","title":"Berberine induces anti-atopic dermatitis effects through the downregulation of cutaneous EIF3F and MALT1 in NC/Nga mice with atopy-like dermatitis.","date":"2021","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33539814","citation_count":17,"is_preprint":false},{"pmid":"33736665","id":"PMC_33736665","title":"EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.","date":"2021","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33736665","citation_count":12,"is_preprint":false},{"pmid":"26052528","id":"PMC_26052528","title":"MD11-mediated delivery of recombinant eIF3f induces melanoma and colorectal carcinoma cell death.","date":"2015","source":"Molecular therapy. Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/26052528","citation_count":12,"is_preprint":false},{"pmid":"32440143","id":"PMC_32440143","title":"Targeting eIF3f Suppresses the Growth of Prostate Cancer Cells by Inhibiting Akt Signaling.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32440143","citation_count":8,"is_preprint":false},{"pmid":"26497985","id":"PMC_26497985","title":"The eukaryotic translation initiation factor 3f (eIF3f) interacts physically with the alpha 1B-adrenergic receptor and stimulates adrenoceptor activity.","date":"2015","source":"BMC biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26497985","citation_count":3,"is_preprint":false},{"pmid":"42123540","id":"PMC_42123540","title":"Eukaryotic Initiation Factor 3F (eIF3F) Regulates the IRES-Mediated Translation of Bcl-xL via Its Interaction with Programmed Cell Death 4 (PDCD4) Protein.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42123540","citation_count":0,"is_preprint":false},{"pmid":"41423661","id":"PMC_41423661","title":"Identification of new interactors of eIF3f by endogenous proximity-dependent biotin labelling in human muscle cells.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41423661","citation_count":0,"is_preprint":false},{"pmid":"42231807","id":"PMC_42231807","title":"CCT2 Promotes Prostate Cancer Progression Through EIF3F-Dependent Stabilization of FASN.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42231807","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14590,"output_tokens":4536,"usd":0.055905,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12612,"output_tokens":5182,"usd":0.096305,"stage2_stop_reason":"end_turn"},"total_usd":0.15221,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"MAFbx/Atrogin-1 (E3 ubiquitin ligase) directly ubiquitinates eIF3f and targets it for proteasome-mediated degradation during skeletal muscle atrophy; ectopic MAFbx expression in myotubes induces eIF3f degradation and atrophy, while shRNA knockdown of MAFbx prevents eIF3f degradation; conversely, genetic activation of eIF3f causes hypertrophy and blocks atrophy.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, ectopic overexpression in myotubes, in vivo mouse skeletal muscle experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments (gain- and loss-of-function), replicated in vivo and in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"18354498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The six C-terminal lysine residues of eIF3f are required for MAFbx-directed polyubiquitination and proteasomal degradation; mutation of all six (K5-10R mutant) confers resistance to degradation, promotes hypertrophy in cellulo and in vivo, and protects against starvation-induced muscle atrophy.\",\n      \"method\": \"Deletion analysis, site-directed mutagenesis, in cellulo and in vivo overexpression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-directed mutagenesis identifying specific lysine residues, validated in vivo, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"19073596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eIF3f contains a conserved TOS (TOR signaling) motif that connects mTOR/raptor complex to enable S6K1 phosphorylation; MAFbx-induced degradation of eIF3f suppresses S6K1 activation by mTOR, while an eIF3f mutant insensitive to MAFbx polyubiquitination maintains persistent S6K1 and rpS6 phosphorylation during muscle differentiation.\",\n      \"method\": \"Mutant expression, immunoprecipitation, phosphorylation assays, TOS motif functional analysis in myotubes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TOS motif functional validation, mutant rescue experiments, phosphorylation assays, multiple orthogonal methods\",\n      \"pmids\": [\"20126553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eIF3f possesses intrinsic deubiquitinase (DUB) activity and deubiquitinates monoubiquitinated activated Notch1 receptor on endocytic vesicles; knockdown of eIF3f causes accumulation of monoubiquitinated Notch, an effect rescued by wild-type but not catalytically inactive eIF3f mutant; eIF3f is recruited to activated Notch by the E3 ligase Deltex1 acting as a bridging factor, and this activity is required for gamma-secretase processing and Notch transcriptional activation.\",\n      \"method\": \"shRNA library screen, immunofluorescence, co-immunoprecipitation, catalytic mutant rescue, coculture Notch activation assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — catalytically inactive mutant controls, multiple orthogonal methods, epistasis in Notch pathway established in single rigorous study\",\n      \"pmids\": [\"21124883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"eIF3f physically interacts with the N-terminal region of the SARS-CoV spike (S) protein and the IBV coronavirus S protein; this interaction inhibits translation of a reporter gene in vitro and in intact cells, suggesting eIF3f is exploited by coronavirus to suppress host gene translation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescent staining, in vitro and cell-based translation reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (Y2H confirmed by Co-IP and reporter assay) in single lab\",\n      \"pmids\": [\"18231581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"eIF3f (and its N-terminal 91 aa fragment N91-eIF3f) inhibits HIV-1 replication by specifically blocking 3' end processing of HIV-1 pre-mRNA; this restriction involves a complex of eIF3f, the SR protein 9G8, and cyclin-dependent kinase 11 (CDK11), where eIF3f modulates sequence-specific recognition of HIV-1 pre-mRNA by 9G8.\",\n      \"method\": \"cDNA expression library screen, overexpression, in vivo and in vitro 3' end processing assays, co-factor identification\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro processing assays, partner identification, mechanistic dissection across two complementary papers\",\n      \"pmids\": [\"19854136\", \"19237569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"eIF3f inhibits both cap-dependent and cap-independent translation, and promotes rRNA degradation through direct interaction with hnRNP K; under stress conditions eIF3f dissociates hnRNP K from rRNA, preventing hnRNP K from protecting rRNA from degradation; rRNA degradation occurs in non-P-body, non-stress-granule cytoplasmic foci containing eIF3f.\",\n      \"method\": \"Stable knockdown, co-immunoprecipitation, translation reporter assays, rRNA stability assays, subcellular fractionation/imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and functional dissociation demonstrated, multiple readouts, single lab\",\n      \"pmids\": [\"22457825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hMSH4 interacts with eIF3f through the N-terminal regions of both proteins; this interaction promotes hMSH4 protein stabilization, sustains γ-H2AX foci, and compromises cell survival after ionizing radiation by down-regulating NHEJ-mediated DSB repair; the hMSH4-eIF3f interplay also inhibits IR-induced AKT activation.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, knockdown, cell survival and DNA damage assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with domain mapping, functional readouts, single lab multiple methods\",\n      \"pmids\": [\"23725059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"eIF3f physically interacts with the alpha-chain (residues 1–227) of secretory clusterin (sCLU); this interaction blocks psCLU modification, decreasing CLU expression and secretion, suppresses Akt and ERK signaling, stabilizes p53, and increases p21 and Bax expression; eIF3f overexpression in a xenograft model inhibits tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, xenograft model, Western blotting\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with domain mapping, in vivo xenograft confirmation, single lab\",\n      \"pmids\": [\"26988917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"eIF3f physically interacts with the alpha 1B-adrenergic receptor (α1B-ADR) in native conditions in human and mouse cell lines; upon catecholamine stimulation, eIF3f promotes adrenoceptor activity in vitro, independently of the eIF3f proline- and alanine-rich N-terminal region.\",\n      \"method\": \"Co-immunoprecipitation in native conditions, adrenoceptor activity assay in vitro, domain deletion analysis\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"26497985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"eIF3f knockdown reduces steady-state levels of SCA8 polySer RAN protein and other RAN proteins, identifying eIF3f as a modulator of repeat-associated non-ATG (RAN) translation.\",\n      \"method\": \"siRNA knockdown, Western blot/immunostaining for RAN protein levels in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with specific protein readout, independently shown for multiple RAN proteins, single lab\",\n      \"pmids\": [\"30206144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ERα represses transcription of the EIF3F gene (genomic pathway) while estrogen-bound ERα promotes eIF3f mRNA translation via activation of mTORC1, which enhances binding of eIF3 to the eIF4F complex and assembly of 48S preinitiation complexes; reduced eIF3f levels are required for proper proliferation and survival of ER-positive breast cancer cells.\",\n      \"method\": \"ERα knockdown/overexpression, mTORC1 inhibition, polysome profiling, reporter assays, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transcriptional and translational regulation dissected), single lab\",\n      \"pmids\": [\"30573685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Homozygous eIF3f knockout mice die at early embryonic stage (after pre-implantation); heterozygous mice have reduced eIF3f expression, decreased skeletal muscle mass with reduced protein synthesis rate, polysome content, and inhibited mTOR pathway; eIF3f partial depletion amplifies hindlimb immobilization-induced muscle atrophy with reduced mTOR pathway activation.\",\n      \"method\": \"Gene knockout mouse model, polysome profiling, protein synthesis rate measurement, hindlimb immobilization model\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with multiple orthogonal readouts (polysome profiling, synthesis rate, mTOR signaling) confirming mechanism\",\n      \"pmids\": [\"31026345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"eIF3f antagonizes FBXW7β-mediated ubiquitination of PHGDH (phosphoglycerate dehydrogenase) through its deubiquitinase activity, stabilizing PHGDH and enhancing the SGOC metabolic pathway; eIF3f also exerts deubiquitinase activity toward MYC, increasing MYC-mediated PHGDH transcription; both Wnt (transcriptional activation of eIF3f) and EGF (via GSK3β/FBXW7β) signaling pathways converge on this axis in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, deubiquitinase activity assays, pathway inhibition, Western blotting\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DUB activity toward two substrates demonstrated, pathway dissection, single lab\",\n      \"pmids\": [\"37544925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"eIF3f directly interacts with and stabilizes ACSL4 (long-chain acyl-CoA synthetase 4) through K48-linked deubiquitination, promoting fatty acid biosynthesis in hepatocellular carcinoma; phosphorylated eIF3f enhances this eIF3f–ACSL4 interaction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, metabolomics, proteomics, metabolic flux analysis, organoid and in vivo models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and deubiquitination demonstrated with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40154622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using endogenous BioID proximity labeling in human muscle cells, eIF3f was found to interact with components of the eIF3 complex, eIF4E, eIF4G, and eIF5 initiation factors in both proliferating and differentiated cells; eIF3f also displayed a previously unknown nuclear localization in myoblasts and myotubes; novel cytoplasmic partners included SYNPO2 (sarcomeric/Z-disc) and LAMP1 (lysosomal compartment).\",\n      \"method\": \"CRISPR-Cas9 endogenous BioID tagging, streptavidin pulldown, mass spectrometry, polysome profiling, immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous proximity labeling with MS identification and immunofluorescence validation, single lab, novel localization finding\",\n      \"pmids\": [\"41423661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"eIF3f directly interacts with PDCD4 in an RNA-independent manner; eIF3f and PDCD4 each independently bind Bcl-xL IRES RNA; eIF3f regulates IRES-mediated translation of Bcl-xL mRNA, demonstrated by IRES reporter assay, polysome profiling, and EMSA, likely via its interaction with PDCD4.\",\n      \"method\": \"Co-immunoprecipitation, IRES reporter assay, polysome profiling, EMSA, knockdown experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-independent interaction confirmed, multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"42123540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT2 interacts with eIF3f and FASN to form a ternary CCT2/eIF3f/FASN complex that enhances eIF3f-mediated deubiquitination of FASN, increasing FASN protein stability and lipid synthesis in prostate cancer; disruption of the CCT2–eIF3f interaction suppresses FASN-driven tumor progression in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, in vivo isograft and PDX models, small-molecule CCT2-eIF3f interaction inhibitor\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ternary complex identified, deubiquitination activity toward FASN demonstrated, in vivo validation, single lab\",\n      \"pmids\": [\"42231807\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3F is a multifunctional subunit of the eIF3 translation initiation complex that scaffolds mTORC1-S6K1 signaling (via a TOS motif) to promote protein synthesis and skeletal muscle hypertrophy; it is targeted for polyubiquitination at six C-terminal lysines and proteasomal degradation by the E3 ligase MAFbx/Atrogin-1 during muscle atrophy; independently, eIF3f possesses intrinsic deubiquitinase (DUB) activity that it deploys toward multiple substrates including monoubiquitinated activated Notch1 (facilitating gamma-secretase processing), PHGDH, MYC, ACSL4, and FASN; it also modulates HIV-1 mRNA 3' end processing through a complex with 9G8 and CDK11, promotes rRNA degradation via hnRNP K dissociation, regulates IRES-mediated translation of Bcl-xL through interaction with PDCD4, and localizes to both cytoplasm (ribosomal complexes, lysosomes, Z-disc) and nucleus in muscle cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3F is a subunit of the eIF3 translation initiation complex that couples nutrient/growth signaling to protein synthesis and, through an independent intrinsic deubiquitinase activity, controls the stability of multiple metabolic and oncogenic substrates [#15, #3, #13]. In skeletal muscle, eIF3f carries a TOS motif that bridges the mTOR/raptor complex to enable S6K1 and rpS6 phosphorylation, thereby driving translation and hypertrophy [#2]; this output is negatively gated by the E3 ligase MAFbx/Atrogin-1, which polyubiquitinates eIF3f at six C-terminal lysines and targets it for proteasomal degradation during atrophy, while a degradation-resistant mutant sustains S6K1 signaling and protects against atrophy [#0, #1, #2]. eIF3f is required for normal development and muscle mass: homozygous knockout is embryonic lethal and heterozygous loss reduces muscle protein synthesis, polysome content, and mTOR activity [#12]. Beyond canonical initiation, eIF3f acts as a deubiquitinase that removes monoubiquitin from activated Notch1 to license gamma-secretase processing [#3], and stabilizes the metabolic enzymes PHGDH, ACSL4, and FASN — the latter two via K48-linked chain removal — while also deubiquitinating MYC, linking it to serine/one-carbon and lipid metabolism in colorectal, hepatocellular, and prostate cancers [#13, #14, #17]. eIF3f additionally tunes specialized RNA processes, restricting HIV-1 pre-mRNA 3' end processing in a complex with 9G8 and CDK11 [#5], promoting stress-induced rRNA degradation by dissociating hnRNP K from rRNA [#6], and regulating IRES-mediated translation of Bcl-xL through interaction with PDCD4 [#16]. Proximity labeling places eIF3f with eIF3/eIF4E/eIF4G/eIF5 initiation machinery and assigns it nuclear, Z-disc (SYNPO2), and lysosomal (LAMP1) localizations in muscle cells [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established how eIF3f abundance is controlled during muscle wasting, identifying it as the degradation target that links an atrophy E3 ligase to loss of translational capacity.\",\n      \"evidence\": \"Co-IP, MAFbx shRNA knockdown and overexpression in myotubes plus in vivo mouse muscle\",\n      \"pmids\": [\"18354498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the lysines required for ubiquitination\", \"Did not establish the downstream signaling effector of eIF3f\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the molecular determinant of eIF3f turnover, showing six C-terminal lysines are the ubiquitin acceptor sites whose mutation confers atrophy resistance.\",\n      \"evidence\": \"Site-directed mutagenesis (K5-10R), deletion analysis, in cellulo and in vivo overexpression\",\n      \"pmids\": [\"19073596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet connect resistance to a specific signaling pathway\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the mechanism by which eIF3f drives hypertrophy, showing a TOS motif scaffolds mTOR/raptor to enable S6K1 activation.\",\n      \"evidence\": \"TOS motif mutagenesis, immunoprecipitation, phosphorylation assays in myotubes\",\n      \"pmids\": [\"20126553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve stoichiometry of the eIF3f-raptor-S6K1 interaction\", \"Did not test requirement in vivo at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an entirely separate enzymatic role, demonstrating eIF3f is an intrinsic deubiquitinase acting on monoubiquitinated Notch1 to permit gamma-secretase processing.\",\n      \"evidence\": \"shRNA screen, catalytically inactive mutant rescue, Notch coculture activation assay, Deltex1 bridging\",\n      \"pmids\": [\"21124883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the catalytic residues or structural basis of DUB activity\", \"Did not survey the full substrate range\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed eIF3f can be hijacked by coronavirus spike proteins to suppress host translation, the first link to viral pathogenesis.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, immunofluorescence, translation reporter assays\",\n      \"pmids\": [\"18231581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of translational suppression by the S-protein interaction not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified an antiviral RNA-processing role, showing eIF3f blocks HIV-1 pre-mRNA 3' end processing within a 9G8/CDK11 complex.\",\n      \"evidence\": \"cDNA library screen, in vivo and in vitro 3' end processing assays, cofactor identification across two papers\",\n      \"pmids\": [\"19854136\", \"19237569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this processing role generalizes to host mRNAs unclear\", \"Catalytic vs scaffolding contribution not separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected eIF3f to rRNA homeostasis under stress, showing it dissociates hnRNP K from rRNA to permit degradation in distinct cytoplasmic foci.\",\n      \"evidence\": \"Stable knockdown, Co-IP, translation and rRNA stability assays, subcellular imaging\",\n      \"pmids\": [\"22457825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclease responsible for rRNA degradation not identified\", \"Relationship of foci to canonical RNA granules unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked eIF3f to the DNA damage response through hMSH4 binding that modulates NHEJ repair and AKT activation after irradiation.\",\n      \"evidence\": \"Co-IP, deletion mapping, knockdown, cell survival and DNA damage assays\",\n      \"pmids\": [\"23725059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of eIF3f at DSB sites not shown\", \"Single lab, mechanism of NHEJ down-regulation indirect\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended eIF3f's interactome to secretory clusterin and the alpha-1B-adrenergic receptor, implicating it in tumor suppression and adrenoceptor signaling.\",\n      \"evidence\": \"Co-IP with domain mapping, xenograft model; native Co-IP and adrenoceptor activity assay\",\n      \"pmids\": [\"26988917\", \"26497985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adrenoceptor interaction rests on single low-confidence Co-IP without reciprocal validation\", \"Mechanism of sCLU modification blockade not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated eIF3f in non-canonical RAN translation, broadening its translational regulatory scope to repeat-expansion disease pathology.\",\n      \"evidence\": \"siRNA knockdown with RAN protein readouts for multiple repeat expansions\",\n      \"pmids\": [\"30206144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to repeat RNAs not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Embedded eIF3f in estrogen-receptor signaling, showing dual transcriptional repression and mTORC1-driven translational control of its own expression in breast cancer.\",\n      \"evidence\": \"ERalpha knockdown/overexpression, mTORC1 inhibition, polysome profiling, reporter assays\",\n      \"pmids\": [\"30573685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between eIF3f level and proliferation correlative\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided definitive in vivo genetic proof that eIF3f is essential for development and for sustaining muscle protein synthesis through the mTOR pathway.\",\n      \"evidence\": \"Knockout mouse model, polysome profiling, synthesis rate, hindlimb immobilization atrophy model\",\n      \"pmids\": [\"31026345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of embryonic lethality not dissected\", \"Tissue-specific contributions beyond muscle untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established eIF3f as a metabolic regulator in cancer, using DUB activity to stabilize PHGDH and MYC and amplify the serine/one-carbon pathway downstream of Wnt and EGF.\",\n      \"evidence\": \"Co-IP, ubiquitination and DUB assays, pathway inhibition in colorectal cancer\",\n      \"pmids\": [\"37544925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect MYC deubiquitination not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed eIF3f drives lipid biosynthesis by K48-linked deubiquitination and stabilization of ACSL4, with phosphorylation enhancing the interaction in liver cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, metabolomics, metabolic flux, organoid and in vivo models\",\n      \"pmids\": [\"40154622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase phosphorylating eIF3f not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the endogenous eIF3f interactome and unexpected localizations, placing it with initiation machinery and at nuclear, Z-disc, and lysosomal compartments in muscle.\",\n      \"evidence\": \"CRISPR endogenous BioID, streptavidin pulldown, mass spectrometry, immunofluorescence\",\n      \"pmids\": [\"41423661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of nuclear and lysosomal pools not established\", \"Proximity does not prove direct binding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected eIF3f to selective IRES-driven survival translation via RNA-independent interaction with PDCD4 and binding to the Bcl-xL IRES.\",\n      \"evidence\": \"Co-IP, IRES reporter, polysome profiling, EMSA, knockdown\",\n      \"pmids\": [\"42123540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether eIF3f acts catalytically or as adaptor on the IRES unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a chaperonin-assisted mechanism in which CCT2 forms a ternary complex enabling eIF3f-mediated deubiquitination and stabilization of FASN in prostate cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, isograft/PDX models, small-molecule interaction inhibitor\",\n      \"pmids\": [\"42231807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of CCT2 chaperone function vs scaffolding not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same protein partitions between its eIF3 initiation role and its deubiquitinase activity — and what governs substrate selection, catalytic residues, and compartment-specific functions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the eIF3f DUB active site or its substrate-recognition determinants\", \"Mechanism switching initiation vs DUB roles undefined\", \"Function of nuclear and lysosomal eIF3f pools uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 13, 14, 17]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 11, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 6, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 17]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [2, 12, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 13, 14, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 14, 17]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 17]}\n    ],\n    \"complexes\": [\n      \"eIF3 translation initiation complex\",\n      \"eIF3f/9G8/CDK11 complex\",\n      \"CCT2/eIF3f/FASN ternary complex\"\n    ],\n    \"partners\": [\n      \"MAFbx\",\n      \"Notch1\",\n      \"hnRNP K\",\n      \"PDCD4\",\n      \"CCT2\",\n      \"FASN\",\n      \"ACSL4\",\n      \"PHGDH\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}