{"gene":"EIF3L","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2001,"finding":"The human protein HSPC021 (now known as eIF3L) was identified as a subunit of the eIF3 complex through immunoprecipitation and mass spectrometry. It directly interacts with Int-6 (eIF3e), co-elutes with eIF3 in gel filtration, coimmunoprecipitates with eIF3, and is incorporated into eIF3 in rabbit reticulocyte lysates and COS7 cells. A direct protein-protein interaction occurs between HSPC021 and Int-6, but a larger region of HSPC021 is required for full eIF3 incorporation compared to Int-6 binding alone. The protein contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat.","method":"Immunoprecipitation, mass spectrometry, gel filtration, in vitro reconstitution in reticulocyte lysates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, gel filtration, and in vitro reconstitution with domain mapping, moderate evidence","pmids":["11590142"],"is_preprint":false},{"year":2010,"finding":"Using limited proteolysis and mass spectrometry of human eIF3, eIF3l (along with eIF3e, eIF3f, and eIF3h) was found to be exposed (not protected) when the HCV IRES RNA binds eIF3, while eIF3b is protected. This defines distinct regions of eIF3 sufficient for HCV IRES binding versus 40S ribosomal subunit binding, with eIF3 binding to the 40S subunit occurring through many redundant interactions.","method":"Limited proteolysis, mass spectrometry of eIF3–HCV IRES and eIF3–40S complexes","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical footprinting with MS readout, single lab","pmids":["20816988"],"is_preprint":false},{"year":2012,"finding":"Recombinant human eIF3 was reconstituted by co-expressing all 11 subunits in a HeLa cell-derived in vitro transcription/translation system. When eIF3l was omitted, an eIF3l-deficient complex was still assembled and purified. Both the 11-subunit complex and the eIF3l-less complex were as active as native eIF3 in a reconstituted translation initiation assay, indicating that eIF3l is a nonessential subunit for bulk translation initiation activity.","method":"Cell-free co-expression reconstitution, affinity chromatography, in vitro translation initiation assay","journal":"Protein expression and purification","confidence":"High","confidence_rationale":"Tier 1 — reconstituted complex in vitro with functional translation assay; shows dispensability of eIF3l for bulk initiation","pmids":["23063735"],"is_preprint":false},{"year":2013,"finding":"eIF3L was identified as a binding partner of Yellow Fever Virus NS5 RdRp domain via yeast two-hybrid screening of a human cDNA library, confirmed by in vitro binding assays and in vivo co-immunoprecipitation. The interaction maps to a conserved region in the NS5 RdRp domain. eIF3L overexpression showed a slight facilitation of YFV replication in plaque reduction assays.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, RNAi knockdown, overexpression plaque assay","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods confirming interaction, functional follow-up with overexpression/knockdown, single lab","pmids":["23800076"],"is_preprint":false},{"year":2014,"finding":"Biophysical characterization of recombinant full-length eIF3L expressed in E. coli showed it behaves as a monomer in solution (dynamic light scattering), adopts a predominantly α-helical structure (circular dichroism), and molecular docking predicts a strong interaction interface with eIF3k. Approximately 8 putative phosphorylation sites and one N-glycosylation site were predicted, suggesting regulation by post-translational modifications.","method":"Dynamic light scattering, circular dichroism, in silico structural modeling and molecular docking","journal":"Protein and peptide letters","confidence":"Low","confidence_rationale":"Tier 4 — biophysical characterization of recombinant protein with computational docking; no functional validation of PTM sites","pmids":["23919378"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function mutations in the C. elegans ortholog eif-3.L (eIF3l) extend lifespan by ~40% and enhance resistance to ER stress without affecting growth, development, or bulk protein synthesis rates. Lifespan extension requires the DAF-16 Forkhead transcription factor, while ER stress resistance is independent of IRE-1–XBP-1, ATF-6, PEK-1, and DAF-16, revealing a non-canonical regulatory role for eIF3l in stress responses and aging separate from its translation function.","method":"C. elegans loss-of-function genetics, lifespan assays, ER stress resistance assays, bulk protein synthesis measurement, genetic epistasis with daf-16 and UPR pathway mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with specific phenotypic readouts, epistasis analysis with multiple pathway mutants, replication of phenotype","pmids":["27690135"],"is_preprint":false},{"year":2019,"finding":"Androgen treatment of human prostate LNCaP cells significantly increases the palmitoylation level of eIF3L, as detected by clickable palmitate probe (Alk-C16) palmitoylome profiling coupled with quantitative mass spectrometry, identifying eIF3L as an androgen-regulated palmitoylated protein.","method":"Clickable palmitate probe (Alk-C16) metabolic labeling, quantitative mass spectrometry, palmitoylome profiling","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — chemical biology approach with quantitative proteomics; single lab, no mutagenesis validation of palmitoylation sites","pmids":["31239713"],"is_preprint":false},{"year":2019,"finding":"eIF3L was found on the outer surface of colorectal cancer SW480-derived exosomes, sensitive to proteinase K proteolysis of intact exosomes, indicating it is peripherally associated with the exosome exterior and likely functions as an RNA-binding protein on the exosome surface.","method":"Proteinase K treatment of intact exosomes, Triton X-114 phase separation, label-free quantitative mass spectrometry","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct proteolysis experiment on intact exosomes with MS readout; single lab","pmids":["30865381"],"is_preprint":false},{"year":2020,"finding":"eIF3L interacts with the PEDV membrane (M) protein as validated by co-immunoprecipitation in PEDV-infected cells. Downregulation of eIF3L expression by siRNA significantly increased PEDV viral production, indicating eIF3L acts as a negative regulator of PEDV replication.","method":"Co-immunoprecipitation with M-specific monoclonal antibody, LC-MS/MS identification, siRNA knockdown with viral titer readout","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP validation plus functional knockdown with viral production readout; single lab","pmids":["32605758"],"is_preprint":false},{"year":2022,"finding":"Picornavirus 2Apro protease appears to interact with eIF3L and utilize the eIF3 complex to proteolytically access and cleave eIF4G during infection, representing a mechanism by which the virus inhibits host protein translation early in infection.","method":"Quantitative proteomics of 2Apro interacting partners, proteomic characterization of cleavage targets in infected cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic identification of interaction with mechanistic follow-up; single lab","pmids":["35367208"],"is_preprint":false},{"year":2022,"finding":"In a CRISPR/Cas9 knockout screen of 1,213 RNA-binding proteins, EIF3L (along with EIF3K) was validated as an inhibitor of CD138+ plasma cell accumulation in vitro, and components of the CCR4-NOT complex showed the same phenotype, placing EIF3L as a regulator of plasma cell differentiation or survival.","method":"CRISPR/Cas9 knockout screen, in vitro plasma cell differentiation assay, validation of individual knockouts","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — genome-scale CRISPR screen with individual validation; functional phenotype without full pathway placement","pmids":["35451955"],"is_preprint":false},{"year":2023,"finding":"eIF3k and eIF3l form a mRNA-specific regulatory module within eIF3. Acute depletion of eIF3k (and eIF3l, which is co-downregulated with eIF3k under ER and oxidative stress) promotes global translation, cell proliferation, tumor growth, and stress resistance by relieving repression of RPS15A mRNA translation. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA abolished these anabolic effects, and ectopic RPS15A expression mimicked eIF3k depletion. Mathematical modeling supported the model that eIF3k-l acts as a rheostat of ribosome content by controlling RPS15A synthesis.","method":"Multiomic profiling (ribosome profiling, proteomics, transcriptomics), acute subunit depletion (dTAG system), tumor growth assays, reporter assays with 5'-UTR mutations, ectopic overexpression, mathematical modeling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (multiomic profiling, functional genetics, reporter assays with mutagenesis, in vivo tumor assays) in a single study with rigorous controls","pmids":["37155573"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, reduction of eIF3l (along with eIF3h, 40S ribosomal subunits, and other eIF3 subunits downstream of the 4EHP–NELF-E axis) suppressed ATF4 expression and its target genes, placing eIF3l as a component required for stress-induced ATF4 translational upregulation in the context of the integrated stress response.","method":"Drosophila genetics (RNAi knockdown), quantitative proteomics (TRIBE screen), ATF4 reporter assays in larval fat body and disease models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with proteomics; eIF3l role in ATF4 regulation is part of a broader network study","pmids":["41436469"],"is_preprint":false}],"current_model":"EIF3L is a nonessential but functionally important accessory subunit of the eIF3 complex that, together with eIF3k, forms an mRNA-selective regulatory module controlling ribosome biogenesis by repressing RPS15A mRNA translation; its loss extends lifespan and stress resistance in C. elegans via DAF-16, it undergoes androgen-induced palmitoylation, is required for ATF4 stress-response translation in Drosophila, negatively regulates PEDV viral replication, and interacts with viral proteins (YFV NS5, picornavirus 2Apro) to influence host translation and viral replication."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that EIF3L is a bona fide subunit of the human eIF3 complex resolved the subunit composition of the largest translation initiation factor and identified its direct binding partner eIF3e (Int-6).","evidence":"Immunoprecipitation, mass spectrometry, gel filtration, and in vitro reconstitution in reticulocyte lysates with domain mapping in COS7 cells","pmids":["11590142"],"confidence":"High","gaps":["Functional contribution of eIF3L to translation was not addressed","Structural basis of eIF3L–eIF3e interaction was not resolved"]},{"year":2012,"claim":"Reconstitution of the full eIF3 complex with and without eIF3L demonstrated that eIF3L is dispensable for bulk translation initiation, raising the question of what specialized role it serves.","evidence":"Cell-free co-expression of all 11 subunits, affinity purification, and in vitro translation initiation assay comparing 11-subunit and eIF3L-deficient complexes","pmids":["23063735"],"confidence":"High","gaps":["Assay measured only bulk initiation; mRNA-selective effects were not tested","In vivo consequences of eIF3L loss were not examined"]},{"year":2016,"claim":"Discovery that C. elegans eif-3.L loss-of-function extends lifespan and confers ER stress resistance without impairing bulk translation revealed a regulatory role beyond canonical initiation, with lifespan extension requiring DAF-16.","evidence":"C. elegans loss-of-function genetics with lifespan assays, ER stress resistance assays, protein synthesis measurement, and epistasis with daf-16 and UPR mutants","pmids":["27690135"],"confidence":"High","gaps":["The specific mRNA targets mediating longevity and stress phenotypes were unknown","Mechanism linking eIF3L to DAF-16 activation was not identified"]},{"year":2023,"claim":"Identification of eIF3k–eIF3l as an mRNA-selective regulatory module that represses RPS15A translation provided the molecular mechanism by which eIF3L controls ribosome content, proliferation, and stress resistance.","evidence":"Acute dTAG-mediated depletion with ribosome profiling, proteomics, transcriptomics, 5ʹ-UTR reporter mutagenesis, tumor growth assays, and mathematical modeling","pmids":["37155573"],"confidence":"High","gaps":["Whether additional mRNAs besides RPS15A are directly regulated by the eIF3k–l module remains incompletely catalogued","Structural basis for eIF3k–l recognition of the RPS15A 5ʹ-UTR is unresolved","Whether this mechanism fully explains the C. elegans longevity phenotype is untested"]},{"year":2013,"claim":"Identification of eIF3L as a direct interaction partner of Yellow Fever Virus NS5 RdRp domain established eIF3L as a host factor co-opted during flavivirus infection.","evidence":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, and overexpression plaque assay","pmids":["23800076"],"confidence":"Medium","gaps":["Functional consequence of the interaction on viral polymerase activity was not determined","Whether the interaction is conserved across flaviviruses was not tested"]},{"year":2020,"claim":"Demonstration that eIF3L interacts with PEDV M protein and that its knockdown enhances viral replication positioned eIF3L as a host restriction factor for a coronavirus.","evidence":"Co-immunoprecipitation in PEDV-infected cells, LC-MS/MS, siRNA knockdown with viral titer measurement","pmids":["32605758"],"confidence":"Medium","gaps":["Mechanism by which eIF3L restricts PEDV replication is unknown","Relevance to other coronaviruses not examined"]},{"year":2022,"claim":"Picornavirus 2Apro was shown to interact with eIF3L and utilize the eIF3 complex as a platform to access and cleave eIF4G, revealing a virus strategy to hijack the eIF3 scaffold for host translation shutoff.","evidence":"Quantitative proteomics of 2Apro interacting partners and cleavage target characterization in infected cells","pmids":["35367208"],"confidence":"Medium","gaps":["Direct structural evidence for 2Apro–eIF3L binding interface is lacking","Whether eIF3L depletion protects eIF4G from 2Apro cleavage was not tested"]},{"year":2022,"claim":"A CRISPR screen identified EIF3L (alongside EIF3K) as an inhibitor of plasma cell accumulation, suggesting the eIF3k–l module regulates immune cell differentiation.","evidence":"CRISPR/Cas9 knockout screen of 1,213 RNA-binding proteins with in vitro plasma cell differentiation and individual knockout validation","pmids":["35451955"],"confidence":"Medium","gaps":["Target mRNAs responsible for the plasma cell phenotype are unidentified","In vivo immune function after eIF3L loss is untested"]},{"year":2025,"claim":"Placing eIF3L as a component required for stress-induced ATF4 translational upregulation in Drosophila extended its regulatory role to the integrated stress response, connecting the subunit to selective translational control under stress.","evidence":"Drosophila RNAi knockdown, TRIBE proteomics screen, ATF4 reporter assays in fat body and disease models","pmids":["41436469"],"confidence":"Medium","gaps":["Whether eIF3L's role in ATF4 regulation is direct or mediated through eIF3 complex integrity is unclear","Mammalian validation of eIF3L requirement for ATF4 translation is lacking"]},{"year":null,"claim":"Key unresolved questions include the structural basis for eIF3k–l selective mRNA recognition, the full repertoire of translationally regulated mRNAs, whether the RPS15A mechanism underlies the longevity and immune phenotypes, and the functional significance of eIF3L palmitoylation.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the eIF3k–l module bound to target mRNA","Palmitoylation sites and their functional impact are unvalidated","Mechanism connecting eIF3L to DAF-16 activation in C. elegans is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,5,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,8,9]}],"complexes":["eIF3"],"partners":["EIF3E","EIF3K","RPS15A","YFV NS5","PEDV M"],"other_free_text":[]},"mechanistic_narrative":"EIF3L is an accessory subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that, together with eIF3k, forms an mRNA-selective regulatory module controlling ribosome biogenesis by repressing translation of the ribosomal protein mRNA RPS15A [PMID:37155573]. Although dispensable for bulk translation initiation activity in reconstituted assays [PMID:23063735], eIF3L loss enhances global translation, cell proliferation, tumor growth, and stress resistance; in C. elegans, eif-3.L loss-of-function extends lifespan by ~40% through DAF-16 and confers ER stress resistance via a non-canonical, UPR-independent pathway [PMID:27690135]. EIF3L participates in stress-induced translational reprogramming, being required for ATF4 upregulation during the integrated stress response in Drosophila [PMID:41436469], and serves as a host factor co-opted by multiple viruses—it interacts with Yellow Fever Virus NS5 and PEDV M protein and is engaged by picornavirus 2Apro to facilitate eIF4G cleavage [PMID:23800076, PMID:32605758, PMID:35367208]."},"prefetch_data":{"uniprot":{"accession":"Q9Y262","full_name":"Eukaryotic translation initiation factor 3 subunit L","aliases":["Eukaryotic translation initiation factor 3 subunit 6-interacting protein","Eukaryotic translation initiation factor 3 subunit E-interacting protein"],"length_aa":564,"mass_kda":66.7,"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) (Microbial infection) In case of FCV infection, plays a role in the ribosomal termination-reinitiation event leading to the translation of VP2 (PubMed:18056426)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y262/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3L","classification":"Common Essential","n_dependent_lines":517,"n_total_lines":1208,"dependency_fraction":0.4279801324503311},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":10.0},{"gene":"EIF3K","stoichiometry":10.0},{"gene":"EIF3M","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":4.0},{"gene":"EIF3I","stoichiometry":4.0},{"gene":"RPL5","stoichiometry":4.0},{"gene":"RPS16","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EIF3L","total_profiled":1310},"omim":[{"mim_id":"619197","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT L; EIF3L","url":"https://www.omim.org/entry/619197"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3L"},"hgnc":{"alias_symbol":["HSPC021","HSPC025","EIF3S11"],"prev_symbol":["EIF3S6IP","EIF3EIP"]},"alphafold":{"accession":"Q9Y262","domains":[{"cath_id":"-","chopping":"308-444","consensus_level":"medium","plddt":74.8515,"start":308,"end":444}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y262","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y262-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y262-F1-predicted_aligned_error_v6.png","plddt_mean":68.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3L","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3L"},"sequence":{"accession":"Q9Y262","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y262.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y262/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y262"}},"corpus_meta":[{"pmid":"25805818","id":"PMC_25805818","title":"Oncogenesis 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Direct protein-protein interaction occurs between EIF3L and Int-6 (eIF3e), but a larger region of EIF3L is required for incorporation into eIF3 than for binding to Int-6 alone. EIF3L undergoes tyrosine phosphorylation in response to H2O2 treatment. EIF3L contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat.\",\n      \"method\": \"Co-immunoprecipitation, gel filtration, mass spectrometry, in vitro incorporation into eIF3 from rabbit reticulocyte lysates and COS7 cells, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, gel filtration co-elution, in vitro and in vivo reconstitution, domain mapping with mutants\",\n      \"pmids\": [\"11590142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EIF3L (eIF3l subunit) is part of human eIF3 that binds the HCV IRES RNA. Limited proteolysis and mass spectrometry showed that eIF3l is exposed (not protected) upon HCV IRES RNA binding to eIF3, whereas eIF3b is protected. EIF3 binding to the 40S ribosomal subunit occurs through many redundant interactions across multiple subunits.\",\n      \"method\": \"Limited proteolysis, mass spectrometry, HCV IRES binding assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro binding assay with proteolysis/MS structural probing, single study\",\n      \"pmids\": [\"20816988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EIF3L (eIF3l) is a nonessential subunit of eIF3: when eIF3l is omitted from co-expression of all 11 eIF3 subunits, a stable eIF3 complex lacking eIF3l is still assembled. Both the 11-subunit complex and the eIF3l-lacking complex are equally active in a reconstituted translation initiation assay.\",\n      \"method\": \"Cell-free co-expression reconstitution, affinity chromatography, reconstituted translation initiation assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with functional translation assay, demonstrating dispensability of eIF3l for basal activity\",\n      \"pmids\": [\"23063735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EIF3L interacts directly with Yellow Fever Virus NS5 RdRp domain. The interaction was mapped to a conserved interaction domain in NS5 segment 3 and confirmed by in vitro binding assays and in vivo co-immunoprecipitation. EIF3L overexpression modestly facilitates YFV replication, while RNAi knockdown reduces it.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, site-directed mutagenesis, RNAi knockdown, overexpression plaque assay\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by multiple orthogonal methods (Y2H, in vitro, Co-IP) with mutagenesis, functional readout from knockdown/overexpression\",\n      \"pmids\": [\"23800076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Recombinant human EIF3L behaves as a monomer in solution (by dynamic light scattering) and adopts a predominantly alpha-helical structure (by circular dichroism). Molecular docking predicts a strong interaction with eIF3k (the K subunit). Bioinformatics identifies approximately 8 putative phosphorylation sites and one possible N-glycosylation site on EIF3L.\",\n      \"method\": \"Dynamic light scattering, circular dichroism, in silico molecular docking and secondary structure prediction\",\n      \"journal\": \"Protein and peptide letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 for biophysical characterization but docking is computational; no mutagenesis or functional validation of PTM sites\",\n      \"pmids\": [\"23919378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans, loss-of-function mutations in eif-3.L (the EIF3L ortholog) extend lifespan by ~40% and enhance resistance to ER stress without affecting bulk protein synthesis or growth. Lifespan extension by eif-3.L deficiency is suppressed by a mutation in the DAF-16 Forkhead transcription factor. ER stress resistance conferred by eif-3.L loss is independent of IRE-1-XBP-1, ATF-6, PEK-1, and DAF-16, suggesting a distinct pathway.\",\n      \"method\": \"Loss-of-function genetics in C. elegans, lifespan assays, genetic epistasis (DAF-16, IRE-1, ATF-6, PEK-1 double mutants), bulk protein synthesis measurement\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined phenotypic readout and epistasis analysis placing eif-3.L in the DAF-16 pathway for longevity, replicated across multiple genetic backgrounds\",\n      \"pmids\": [\"27690135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Androgen treatment significantly increases the palmitoylation level of EIF3L in human prostate LNCaP cells, as identified by palmitoylome profiling using a clickable palmitate probe.\",\n      \"method\": \"Chemical biology palmitoylation profiling with clickable palmitate probe (Alk-C16) and quantitative mass spectrometry\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical proteomics directly identifies palmitoylation modification of EIF3L in response to androgen, single study\",\n      \"pmids\": [\"31239713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EIF3L interacts with the PEDV coronavirus M protein, confirmed by co-immunoprecipitation. Downregulation of EIF3L expression significantly increases PEDV viral production, establishing EIF3L as a negative regulator of PEDV replication.\",\n      \"method\": \"Co-immunoprecipitation with LC-MS/MS, siRNA knockdown, viral titer measurement\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP validation plus knockdown with defined functional readout (viral production), single study\",\n      \"pmids\": [\"32605758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF3L and EIF3K subunits act as inhibitors of CD138+ plasma cell accumulation in vitro. CRISPR/Cas9 knockout of EIF3L (and EIF3K) in a mouse RBP screen increased CD138+ plasma cell abundance.\",\n      \"method\": \"CRISPR/Cas9 knockout screen of 1213 RNA-binding proteins, flow cytometry readout for CD138+ cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen with defined cellular phenotype readout, validated hits\",\n      \"pmids\": [\"35451955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Picornavirus 2Apro interacts with EIF3L and appears to utilize the eIF3 complex as a scaffold to proteolytically access and cleave eIF4G (a critical component of the protein synthesis machinery), rather than directly cleaving EIF3L itself.\",\n      \"method\": \"Proteomic interactome analysis, protease substrate mapping, LC-MS/MS, functional translation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic interaction data combined with functional cleavage assays identifying EIF3L as a scaffold for 2Apro access to eIF4G\",\n      \"pmids\": [\"35367208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EIF3K and EIF3L form a mRNA-specific module within eIF3 that represses translation of ribosomal protein RPS15A mRNA. Depletion of EIF3K (and correspondingly EIF3L, which is co-downregulated with EIF3K under ER and oxidative stress) promotes global translation, cell proliferation, and tumor growth through increased RPS15A synthesis. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA negates these anabolic effects. EIF3K and EIF3L are selectively downregulated in response to ER and oxidative stress.\",\n      \"method\": \"Multiomic profiling (ribosome profiling + proteomics) upon acute eIF3 subunit depletion, ectopic RPS15A expression, eIF3-5'UTR binding disruption, tumor growth assays, mathematical modeling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ribosome profiling, proteomics, genetic rescue, cis-element disruption) in a single study demonstrating specific translational mechanism\",\n      \"pmids\": [\"37155573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, reduction of eIF3l suppresses ATF4 expression and its target genes, placing eIF3l as a required component of an ATF4 regulatory network that includes 4EHP, NELF-E, and 40S ribosomal subunits. Knockdown of eIF3l phenocopies loss of 4EHP and NELF-E in reducing ATF4 signaling.\",\n      \"method\": \"Genetic knockdown in Drosophila, quantitative proteomics, ATF4 reporter assays, TRIBE screen\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila ortholog with quantitative proteomics, places eIF3l in a defined ATF4 regulatory pathway\",\n      \"pmids\": [\"41436469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The PCI domain of eIF3E mediates its interaction with EIF3L; deletion of the PCI domain in eIF3E abolishes the eIF3E-EIF3L interaction as shown by AlphaFold3 structural modeling and FRET verification. PCI domain deletion or phosphosite mutagenesis (Thr417, Ser421) in eIF3E weakens eIF3E-EIF3L interactions and blocks translational activation of an mRNA reporter bearing specific coding-sequence motifs.\",\n      \"method\": \"AlphaFold3 structural modeling, FRET (Förster resonance energy transfer), domain deletion mutagenesis, phosphosite mutagenesis, mRNA reporter assay, affinity RNA immunoprecipitation sequencing\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — FRET and structural modeling combined with mutagenesis and reporter assays in plant ortholog system; cross-kingdom but eIF3E-eIF3L interaction mechanism is conserved\",\n      \"pmids\": [\"41701515\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3L is a nonessential but functionally regulatory subunit of the eIF3 translation initiation complex that, together with EIF3K, forms an mRNA-selective module controlling ribosomal protein (RPS15A) translation and thereby serving as a rheostat of ribosome content and translational capacity; EIF3L directly interacts with other eIF3 subunits (notably eIF3e/Int-6 via its PCI domain) and undergoes post-translational modifications including tyrosine phosphorylation and androgen-induced palmitoylation, and in C. elegans its loss extends lifespan and ER stress resistance in a DAF-16-dependent manner, while in mammalian contexts it interacts with viral proteins (flavivirus NS5, coronavirus M protein) and is exploited by picornavirus 2Apro as a scaffold to access eIF4G.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"The human protein HSPC021 (now known as eIF3L) was identified as a subunit of the eIF3 complex through immunoprecipitation and mass spectrometry. It directly interacts with Int-6 (eIF3e), co-elutes with eIF3 in gel filtration, coimmunoprecipitates with eIF3, and is incorporated into eIF3 in rabbit reticulocyte lysates and COS7 cells. A direct protein-protein interaction occurs between HSPC021 and Int-6, but a larger region of HSPC021 is required for full eIF3 incorporation compared to Int-6 binding alone. The protein contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, gel filtration, in vitro reconstitution in reticulocyte lysates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, gel filtration, and in vitro reconstitution with domain mapping, moderate evidence\",\n      \"pmids\": [\"11590142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Using limited proteolysis and mass spectrometry of human eIF3, eIF3l (along with eIF3e, eIF3f, and eIF3h) was found to be exposed (not protected) when the HCV IRES RNA binds eIF3, while eIF3b is protected. This defines distinct regions of eIF3 sufficient for HCV IRES binding versus 40S ribosomal subunit binding, with eIF3 binding to the 40S subunit occurring through many redundant interactions.\",\n      \"method\": \"Limited proteolysis, mass spectrometry of eIF3–HCV IRES and eIF3–40S complexes\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical footprinting with MS readout, single lab\",\n      \"pmids\": [\"20816988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Recombinant human eIF3 was reconstituted by co-expressing all 11 subunits in a HeLa cell-derived in vitro transcription/translation system. When eIF3l was omitted, an eIF3l-deficient complex was still assembled and purified. Both the 11-subunit complex and the eIF3l-less complex were as active as native eIF3 in a reconstituted translation initiation assay, indicating that eIF3l is a nonessential subunit for bulk translation initiation activity.\",\n      \"method\": \"Cell-free co-expression reconstitution, affinity chromatography, in vitro translation initiation assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted complex in vitro with functional translation assay; shows dispensability of eIF3l for bulk initiation\",\n      \"pmids\": [\"23063735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"eIF3L was identified as a binding partner of Yellow Fever Virus NS5 RdRp domain via yeast two-hybrid screening of a human cDNA library, confirmed by in vitro binding assays and in vivo co-immunoprecipitation. The interaction maps to a conserved region in the NS5 RdRp domain. eIF3L overexpression showed a slight facilitation of YFV replication in plaque reduction assays.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, RNAi knockdown, overexpression plaque assay\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods confirming interaction, functional follow-up with overexpression/knockdown, single lab\",\n      \"pmids\": [\"23800076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Biophysical characterization of recombinant full-length eIF3L expressed in E. coli showed it behaves as a monomer in solution (dynamic light scattering), adopts a predominantly α-helical structure (circular dichroism), and molecular docking predicts a strong interaction interface with eIF3k. Approximately 8 putative phosphorylation sites and one N-glycosylation site were predicted, suggesting regulation by post-translational modifications.\",\n      \"method\": \"Dynamic light scattering, circular dichroism, in silico structural modeling and molecular docking\",\n      \"journal\": \"Protein and peptide letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — biophysical characterization of recombinant protein with computational docking; no functional validation of PTM sites\",\n      \"pmids\": [\"23919378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function mutations in the C. elegans ortholog eif-3.L (eIF3l) extend lifespan by ~40% and enhance resistance to ER stress without affecting growth, development, or bulk protein synthesis rates. Lifespan extension requires the DAF-16 Forkhead transcription factor, while ER stress resistance is independent of IRE-1–XBP-1, ATF-6, PEK-1, and DAF-16, revealing a non-canonical regulatory role for eIF3l in stress responses and aging separate from its translation function.\",\n      \"method\": \"C. elegans loss-of-function genetics, lifespan assays, ER stress resistance assays, bulk protein synthesis measurement, genetic epistasis with daf-16 and UPR pathway mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with specific phenotypic readouts, epistasis analysis with multiple pathway mutants, replication of phenotype\",\n      \"pmids\": [\"27690135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Androgen treatment of human prostate LNCaP cells significantly increases the palmitoylation level of eIF3L, as detected by clickable palmitate probe (Alk-C16) palmitoylome profiling coupled with quantitative mass spectrometry, identifying eIF3L as an androgen-regulated palmitoylated protein.\",\n      \"method\": \"Clickable palmitate probe (Alk-C16) metabolic labeling, quantitative mass spectrometry, palmitoylome profiling\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical biology approach with quantitative proteomics; single lab, no mutagenesis validation of palmitoylation sites\",\n      \"pmids\": [\"31239713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"eIF3L was found on the outer surface of colorectal cancer SW480-derived exosomes, sensitive to proteinase K proteolysis of intact exosomes, indicating it is peripherally associated with the exosome exterior and likely functions as an RNA-binding protein on the exosome surface.\",\n      \"method\": \"Proteinase K treatment of intact exosomes, Triton X-114 phase separation, label-free quantitative mass spectrometry\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct proteolysis experiment on intact exosomes with MS readout; single lab\",\n      \"pmids\": [\"30865381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eIF3L interacts with the PEDV membrane (M) protein as validated by co-immunoprecipitation in PEDV-infected cells. Downregulation of eIF3L expression by siRNA significantly increased PEDV viral production, indicating eIF3L acts as a negative regulator of PEDV replication.\",\n      \"method\": \"Co-immunoprecipitation with M-specific monoclonal antibody, LC-MS/MS identification, siRNA knockdown with viral titer readout\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP validation plus functional knockdown with viral production readout; single lab\",\n      \"pmids\": [\"32605758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Picornavirus 2Apro protease appears to interact with eIF3L and utilize the eIF3 complex to proteolytically access and cleave eIF4G during infection, representing a mechanism by which the virus inhibits host protein translation early in infection.\",\n      \"method\": \"Quantitative proteomics of 2Apro interacting partners, proteomic characterization of cleavage targets in infected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification of interaction with mechanistic follow-up; single lab\",\n      \"pmids\": [\"35367208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In a CRISPR/Cas9 knockout screen of 1,213 RNA-binding proteins, EIF3L (along with EIF3K) was validated as an inhibitor of CD138+ plasma cell accumulation in vitro, and components of the CCR4-NOT complex showed the same phenotype, placing EIF3L as a regulator of plasma cell differentiation or survival.\",\n      \"method\": \"CRISPR/Cas9 knockout screen, in vitro plasma cell differentiation assay, validation of individual knockouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-scale CRISPR screen with individual validation; functional phenotype without full pathway placement\",\n      \"pmids\": [\"35451955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"eIF3k and eIF3l form a mRNA-specific regulatory module within eIF3. Acute depletion of eIF3k (and eIF3l, which is co-downregulated with eIF3k under ER and oxidative stress) promotes global translation, cell proliferation, tumor growth, and stress resistance by relieving repression of RPS15A mRNA translation. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA abolished these anabolic effects, and ectopic RPS15A expression mimicked eIF3k depletion. Mathematical modeling supported the model that eIF3k-l acts as a rheostat of ribosome content by controlling RPS15A synthesis.\",\n      \"method\": \"Multiomic profiling (ribosome profiling, proteomics, transcriptomics), acute subunit depletion (dTAG system), tumor growth assays, reporter assays with 5'-UTR mutations, ectopic overexpression, mathematical modeling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (multiomic profiling, functional genetics, reporter assays with mutagenesis, in vivo tumor assays) in a single study with rigorous controls\",\n      \"pmids\": [\"37155573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, reduction of eIF3l (along with eIF3h, 40S ribosomal subunits, and other eIF3 subunits downstream of the 4EHP–NELF-E axis) suppressed ATF4 expression and its target genes, placing eIF3l as a component required for stress-induced ATF4 translational upregulation in the context of the integrated stress response.\",\n      \"method\": \"Drosophila genetics (RNAi knockdown), quantitative proteomics (TRIBE screen), ATF4 reporter assays in larval fat body and disease models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with proteomics; eIF3l role in ATF4 regulation is part of a broader network study\",\n      \"pmids\": [\"41436469\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3L is a nonessential but functionally important accessory subunit of the eIF3 complex that, together with eIF3k, forms an mRNA-selective regulatory module controlling ribosome biogenesis by repressing RPS15A mRNA translation; its loss extends lifespan and stress resistance in C. elegans via DAF-16, it undergoes androgen-induced palmitoylation, is required for ATF4 stress-response translation in Drosophila, negatively regulates PEDV viral replication, and interacts with viral proteins (YFV NS5, picornavirus 2Apro) to influence host translation and viral replication.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EIF3L is a nonessential regulatory subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that, together with EIF3K, forms an mRNA-selective translational control module acting as a rheostat for ribosome biogenesis and cellular anabolic capacity. EIF3L integrates into eIF3 via its PCI domain through direct interaction with eIF3E (Int-6), though a larger region beyond the PCI domain is required for full complex incorporation, and its omission yields a stable eIF3 complex with unimpaired basal translation activity [PMID:11590142, PMID:23063735, PMID:41701515]. The EIF3K–EIF3L module selectively represses translation of the ribosomal protein RPS15A mRNA via its 5′-UTR; stress-induced downregulation of this module derepresses RPS15A synthesis, thereby increasing ribosome content and driving cell proliferation and tumor growth [PMID:37155573]. EIF3L also participates in integrated stress response signaling—promoting ATF4 expression in Drosophila—and is exploited by diverse viruses, serving as a scaffold through which picornavirus 2Apro accesses eIF4G for cleavage and interacting with flavivirus NS5 and coronavirus M proteins [PMID:41436469, PMID:35367208, PMID:23800076, PMID:32605758].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing EIF3L as a bona fide eIF3 subunit resolved the composition of the human eIF3 complex and showed that its PCI domain mediates binding to eIF3E (Int-6) while a larger region is needed for full complex incorporation.\",\n      \"evidence\": \"Co-immunoprecipitation, gel filtration co-elution, domain deletion analysis in rabbit reticulocyte lysates and COS7 cells\",\n      \"pmids\": [\"11590142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional contribution of EIF3L to translation initiation remained untested\",\n        \"Structural basis of EIF3L–eIF3E interaction was not determined at atomic resolution\",\n        \"The significance of EIF3L tyrosine phosphorylation was not explored\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstitution showed that EIF3L is dispensable for stable eIF3 assembly and basal translation initiation activity, redefining it as a regulatory rather than core subunit.\",\n      \"evidence\": \"Cell-free co-expression of all 11 eIF3 subunits with and without EIF3L, followed by affinity chromatography and reconstituted translation assay\",\n      \"pmids\": [\"23063735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether EIF3L is required for translation of specific mRNAs was unknown\",\n        \"In vivo consequences of EIF3L loss in mammalian cells were not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of a direct EIF3L–flavivirus NS5 interaction revealed that EIF3L can be co-opted by viruses, with functional consequences for viral replication.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, RNAi knockdown, and overexpression in Yellow Fever Virus system\",\n      \"pmids\": [\"23800076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which EIF3L binding to NS5 facilitates replication was not determined\",\n        \"Generality across other flaviviruses was not shown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Loss-of-function genetics in C. elegans demonstrated that EIF3L deficiency extends lifespan through DAF-16/FOXO and enhances ER stress resistance through a distinct pathway, linking a nonessential eIF3 subunit to organismal aging.\",\n      \"evidence\": \"C. elegans eif-3.L mutants, lifespan assays, genetic epistasis with DAF-16 and UPR components\",\n      \"pmids\": [\"27690135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific mRNAs whose translational regulation mediates the longevity phenotype were not identified\",\n        \"Whether this mechanism is conserved in mammals was untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two studies expanded EIF3L's functional repertoire: a CRISPR screen showed EIF3L loss increases plasma cell accumulation, and proteomic analysis revealed picornavirus 2Apro uses EIF3L as a scaffold within eIF3 to access and cleave eIF4G.\",\n      \"evidence\": \"CRISPR/Cas9 screen of 1213 RBPs with CD138+ readout; proteomic interactome and protease substrate mapping for 2Apro\",\n      \"pmids\": [\"35451955\", \"35367208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether plasma cell phenotype is a direct consequence of selective mRNA translational changes was not shown\",\n        \"The structural interface between 2Apro and EIF3L was not mapped\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiomic profiling resolved the key mechanistic question of what EIF3L selectively controls: the EIF3K–EIF3L module represses RPS15A mRNA translation via its 5′-UTR, functioning as a rheostat that tunes ribosome content and anabolic capacity, with stress-induced downregulation of this module driving proliferation and tumor growth.\",\n      \"evidence\": \"Ribosome profiling, proteomics, ectopic RPS15A expression rescue, 5′-UTR cis-element disruption, tumor growth assays\",\n      \"pmids\": [\"37155573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How EIF3K–EIF3L physically recognizes the RPS15A 5′-UTR was not structurally resolved\",\n        \"Whether additional mRNAs beyond RPS15A are major targets of this module remains open\",\n        \"Mechanism of stress-induced selective downregulation of EIF3K/EIF3L was not determined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Drosophila genetic studies placed eIF3L within an ATF4 regulatory network alongside 4EHP and NELF-E, revealing a role in integrated stress response translational control beyond the RPS15A circuit.\",\n      \"evidence\": \"Genetic knockdown in Drosophila, quantitative proteomics, ATF4 reporter assays, TRIBE screen\",\n      \"pmids\": [\"41436469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether EIF3L promotes ATF4 uORF-dependent reinitiation or acts via a different mechanism was not resolved\",\n        \"Conservation of this ATF4 regulatory function in mammalian cells was not tested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"FRET and mutagenesis in the plant ortholog system defined the PCI domain interface and phosphorylation-dependent regulation of the eIF3E–EIF3L interaction for mRNA-selective translational activation, providing the first mechanistic detail of how this subunit contact is regulated.\",\n      \"evidence\": \"AlphaFold3 modeling, FRET, PCI domain deletion and phosphosite mutagenesis (Thr417/Ser421 of eIF3E), mRNA reporter assays in Arabidopsis\",\n      \"pmids\": [\"41701515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether phosphorylation-dependent regulation of eIF3E–EIF3L interaction operates similarly in mammals\",\n        \"No high-resolution experimental structure of the eIF3E–EIF3L interface exists\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include how the EIF3K–EIF3L module physically recognizes specific 5′-UTR elements, the structural basis of EIF3L's role in ATF4 translational control, the mechanism of stress-induced selective degradation of EIF3K/EIF3L, and whether EIF3L's longevity and stress resistance functions in C. elegans are conserved in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of EIF3K–EIF3L bound to target mRNA 5′-UTR\",\n        \"Mechanism of selective EIF3K/EIF3L downregulation under stress is unknown\",\n        \"Mammalian in vivo genetic models for EIF3L loss are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [\n      \"eIF3\"\n    ],\n    \"partners\": [\n      \"EIF3E\",\n      \"EIF3K\",\n      \"EIF4G1\",\n      \"RPS15A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EIF3L is an accessory subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that, together with eIF3k, forms an mRNA-selective regulatory module controlling ribosome biogenesis by repressing translation of the ribosomal protein mRNA RPS15A [PMID:37155573]. Although dispensable for bulk translation initiation activity in reconstituted assays [PMID:23063735], eIF3L loss enhances global translation, cell proliferation, tumor growth, and stress resistance; in C. elegans, eif-3.L loss-of-function extends lifespan by ~40% through DAF-16 and confers ER stress resistance via a non-canonical, UPR-independent pathway [PMID:27690135]. EIF3L participates in stress-induced translational reprogramming, being required for ATF4 upregulation during the integrated stress response in Drosophila [PMID:41436469], and serves as a host factor co-opted by multiple viruses—it interacts with Yellow Fever Virus NS5 and PEDV M protein and is engaged by picornavirus 2Apro to facilitate eIF4G cleavage [PMID:23800076, PMID:32605758, PMID:35367208].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that EIF3L is a bona fide subunit of the human eIF3 complex resolved the subunit composition of the largest translation initiation factor and identified its direct binding partner eIF3e (Int-6).\",\n      \"evidence\": \"Immunoprecipitation, mass spectrometry, gel filtration, and in vitro reconstitution in reticulocyte lysates with domain mapping in COS7 cells\",\n      \"pmids\": [\"11590142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional contribution of eIF3L to translation was not addressed\",\n        \"Structural basis of eIF3L–eIF3e interaction was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reconstitution of the full eIF3 complex with and without eIF3L demonstrated that eIF3L is dispensable for bulk translation initiation, raising the question of what specialized role it serves.\",\n      \"evidence\": \"Cell-free co-expression of all 11 subunits, affinity purification, and in vitro translation initiation assay comparing 11-subunit and eIF3L-deficient complexes\",\n      \"pmids\": [\"23063735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Assay measured only bulk initiation; mRNA-selective effects were not tested\",\n        \"In vivo consequences of eIF3L loss were not examined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that C. elegans eif-3.L loss-of-function extends lifespan and confers ER stress resistance without impairing bulk translation revealed a regulatory role beyond canonical initiation, with lifespan extension requiring DAF-16.\",\n      \"evidence\": \"C. elegans loss-of-function genetics with lifespan assays, ER stress resistance assays, protein synthesis measurement, and epistasis with daf-16 and UPR mutants\",\n      \"pmids\": [\"27690135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific mRNA targets mediating longevity and stress phenotypes were unknown\",\n        \"Mechanism linking eIF3L to DAF-16 activation was not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of eIF3k–eIF3l as an mRNA-selective regulatory module that represses RPS15A translation provided the molecular mechanism by which eIF3L controls ribosome content, proliferation, and stress resistance.\",\n      \"evidence\": \"Acute dTAG-mediated depletion with ribosome profiling, proteomics, transcriptomics, 5ʹ-UTR reporter mutagenesis, tumor growth assays, and mathematical modeling\",\n      \"pmids\": [\"37155573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional mRNAs besides RPS15A are directly regulated by the eIF3k–l module remains incompletely catalogued\",\n        \"Structural basis for eIF3k–l recognition of the RPS15A 5ʹ-UTR is unresolved\",\n        \"Whether this mechanism fully explains the C. elegans longevity phenotype is untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of eIF3L as a direct interaction partner of Yellow Fever Virus NS5 RdRp domain established eIF3L as a host factor co-opted during flavivirus infection.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, and overexpression plaque assay\",\n      \"pmids\": [\"23800076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the interaction on viral polymerase activity was not determined\",\n        \"Whether the interaction is conserved across flaviviruses was not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that eIF3L interacts with PEDV M protein and that its knockdown enhances viral replication positioned eIF3L as a host restriction factor for a coronavirus.\",\n      \"evidence\": \"Co-immunoprecipitation in PEDV-infected cells, LC-MS/MS, siRNA knockdown with viral titer measurement\",\n      \"pmids\": [\"32605758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which eIF3L restricts PEDV replication is unknown\",\n        \"Relevance to other coronaviruses not examined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Picornavirus 2Apro was shown to interact with eIF3L and utilize the eIF3 complex as a platform to access and cleave eIF4G, revealing a virus strategy to hijack the eIF3 scaffold for host translation shutoff.\",\n      \"evidence\": \"Quantitative proteomics of 2Apro interacting partners and cleavage target characterization in infected cells\",\n      \"pmids\": [\"35367208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct structural evidence for 2Apro–eIF3L binding interface is lacking\",\n        \"Whether eIF3L depletion protects eIF4G from 2Apro cleavage was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A CRISPR screen identified EIF3L (alongside EIF3K) as an inhibitor of plasma cell accumulation, suggesting the eIF3k–l module regulates immune cell differentiation.\",\n      \"evidence\": \"CRISPR/Cas9 knockout screen of 1,213 RNA-binding proteins with in vitro plasma cell differentiation and individual knockout validation\",\n      \"pmids\": [\"35451955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Target mRNAs responsible for the plasma cell phenotype are unidentified\",\n        \"In vivo immune function after eIF3L loss is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing eIF3L as a component required for stress-induced ATF4 translational upregulation in Drosophila extended its regulatory role to the integrated stress response, connecting the subunit to selective translational control under stress.\",\n      \"evidence\": \"Drosophila RNAi knockdown, TRIBE proteomics screen, ATF4 reporter assays in fat body and disease models\",\n      \"pmids\": [\"41436469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether eIF3L's role in ATF4 regulation is direct or mediated through eIF3 complex integrity is unclear\",\n        \"Mammalian validation of eIF3L requirement for ATF4 translation is lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for eIF3k–l selective mRNA recognition, the full repertoire of translationally regulated mRNAs, whether the RPS15A mechanism underlies the longevity and immune phenotypes, and the functional significance of eIF3L palmitoylation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of the eIF3k–l module bound to target mRNA\",\n        \"Palmitoylation sites and their functional impact are unvalidated\",\n        \"Mechanism connecting eIF3L to DAF-16 activation in C. elegans is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 8, 9]}\n    ],\n    \"complexes\": [\n      \"eIF3\"\n    ],\n    \"partners\": [\n      \"EIF3E\",\n      \"EIF3K\",\n      \"RPS15A\",\n      \"YFV NS5\",\n      \"PEDV M\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}