{"gene":"EIF3L","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"HSPC021 (EIF3L) was identified as a protein associated with eIF3 subunit Int-6 (EIF3E). Direct protein-protein interaction occurs between HSPC021 and Int-6. HSPC021 coelutes with Int-6 and eIF3 in gel filtration, coimmunoprecipitates with eIF3, and is incorporated into eIF3 both in rabbit reticulocyte lysates and in COS7 cells. A larger region of HSPC021 is required for incorporation into eIF3 than for binding to Int-6 alone. The protein contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat. Exposure to H2O2 triggers tyrosine phosphorylation of HSPC021.","method":"Immunoprecipitation, mass spectrometry, gel filtration, cell-based coimmunoprecipitation (rabbit reticulocyte lysates and COS7 cells), deletion mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, gel filtration, multiple cell systems, deletion mutagenesis, multiple orthogonal methods in a single focused study","pmids":["11590142"],"is_preprint":false},{"year":2010,"finding":"eIF3l (along with other eIF3 subunits) is exposed (not protected) when eIF3 binds the HCV IRES RNA, whereas eIF3b is protected by HCV IRES RNA binding. Limited proteolysis revealed that eIF3l is among the subunits exposed upon HCV IRES binding but is involved in broader redundant interactions with the 40S ribosomal subunit.","method":"Limited proteolysis combined with mass spectrometry of human eIF3 in complex with HCV IRES RNA and 40S ribosomal subunit","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay with mass spectrometry, single lab, single study","pmids":["20816988"],"is_preprint":false},{"year":2012,"finding":"eIF3l is a nonessential subunit of the eIF3 complex: when eIF3l was omitted from a cell-free reconstitution of the 11-subunit human eIF3 complex, an eIF3l-deficient complex was still assembled and was as active as the native 11-subunit complex in a reconstituted translation initiation assay.","method":"Cell-free co-expression reconstitution in HeLa-derived in vitro transcription/translation system, affinity chromatography purification, reconstituted translation initiation activity assay","journal":"Protein expression and purification","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in vitro with functional activity assay; demonstrates nonessential role mechanistically","pmids":["23063735"],"is_preprint":false},{"year":2013,"finding":"eIF3L interacts directly with Yellow Fever Virus (YFV) NS5 protein (RdRp domain). The interaction was confirmed by yeast two-hybrid, in vitro binding assay, and in vivo coimmunoprecipitation. The interaction domain on NS5 is conserved across several flaviviruses. eIF3L overexpression showed a slight facilitating effect on YFV replication in plaque assays.","method":"Yeast two-hybrid screen, in vitro binding assay, coimmunoprecipitation, site-directed mutagenesis of NS5 interaction domain, eIF3L overexpression and RNAi knockdown with plaque reduction assay","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro binding, mutagenesis, and functional assay in one study; single lab","pmids":["23800076"],"is_preprint":false},{"year":2014,"finding":"Recombinant full-length human eIF3L produced in E. coli behaves as a monomer when not interacting with other molecular partners (by dynamic light scattering). Circular dichroism revealed predominantly α-helical secondary structure. In silico molecular docking predicted strong interaction between eIF3L and eIF3K. Multiple putative phosphorylation sites (~8) and one N-glycosylation site were predicted bioinformatically.","method":"Dynamic light scattering, circular dichroism spectroscopy, in silico structural modeling and molecular docking","journal":"Protein and peptide letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — biophysical characterization of recombinant protein, docking is computational; no mutagenesis or functional validation","pmids":["23919378"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function mutations in eif-3.L (the C. elegans ortholog of EIF3L) result in ~40% lifespan extension and enhanced resistance to ER stress, without affecting bulk protein synthesis rates or growth. Lifespan extension from 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 signaling.","method":"C. elegans loss-of-function genetics, lifespan assays, ER stress resistance assays, bulk protein synthesis measurement, epistasis analysis with daf-16, ire-1, atf-6, pek-1 mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function genetics with defined cellular phenotypes, epistasis analysis with multiple pathway components, multiple orthogonal readouts","pmids":["27690135"],"is_preprint":false},{"year":2011,"finding":"EIF3S6IP (EIF3L) was identified as a host factor required for influenza virus polymerase replication and transcriptional activity. RNAi-mediated depletion of EIF3L reduced viral polymerase transcriptional activity in a functional screen.","method":"Yeast two-hybrid screen for influenza polymerase interactors, RNAi knockdown with viral polymerase transcriptional activity assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional RNAi knockdown with specific viral transcription readout, single lab, part of larger screen","pmids":["21994455"],"is_preprint":false},{"year":2020,"finding":"eIF3L interacts with PEDV (porcine epidemic diarrhea virus) membrane (M) protein, validated by coimmunoprecipitation. Downregulation of eIF3L expression significantly increased PEDV viral production, indicating eIF3L acts as a negative regulator of PEDV replication.","method":"Co-immunoprecipitation with LC-MS/MS, RNAi knockdown with viral titer measurement","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP validation plus functional knockdown with specific viral production readout; single lab","pmids":["32605758"],"is_preprint":false},{"year":2022,"finding":"eIF3L is utilized by picornavirus 2Apro to gain proteolytic access to eIF4G: the protease appears to interact with eIF3L, using the eIF3 complex as a scaffold to reach and cleave eIF4G, rather than directly binding eIF4G. This was established through proteomic characterization of 2Apro interacting partners.","method":"Proteomic analysis of 2Apro interacting partners, cleavage assays, proteomic identification of cleavage targets","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proteomic interaction mapping with functional cleavage data; single lab; mechanistic model supported but not fully reconstituted","pmids":["35367208"],"is_preprint":false},{"year":2022,"finding":"EIF3K and EIF3L subunits function as inhibitors of CD138+ plasma cell accumulation in vitro. CRISPR/Cas9 knockout of EIF3L in mouse B cells promoted accumulation of CD138+ plasma cells, validated in an in vitro differentiation system.","method":"CRISPR/Cas9 knockout screen of 1213 RNA binding proteins, flow cytometry for CD138+ cell abundance, in vitro B cell differentiation","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional KO with defined cellular phenotype (CD138+ accumulation), part of broader screen but validated for EIF3L specifically","pmids":["35451955"],"is_preprint":false},{"year":2023,"finding":"eIF3k and eIF3l form a mRNA-specific regulatory module within the eIF3 complex. Depletion of eIF3k or eIF3l promoted global translation, cell proliferation, tumor growth, and stress resistance by relieving repression of ribosomal protein RPS15A synthesis. eIF3k and eIF3l are selectively downregulated in response to ER stress and oxidative stress. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA negated the anabolic effects of eIF3k depletion. eIF3l depletion phenocopied eIF3k depletion in this context.","method":"Multiomic profiling (ribosome profiling, proteomics, transcriptomics) upon acute eIF3 subunit depletion, tumor growth assays, RPS15A ectopic expression rescue, 5'-UTR reporter mutagenesis, mathematical modeling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (ribosome profiling, proteomics, mutagenesis of cis-element, rescue experiments, in vivo tumor assays) in single rigorous study","pmids":["37155573"],"is_preprint":false},{"year":2019,"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.","method":"Palmitoylome profiling using clickable palmitate probe (Alk-C16) with mass spectrometry in androgen-treated vs. untreated LNCaP cells","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — chemical biology palmitoylation profiling with quantitative MS; identifies PTM but no writer/eraser validated; single lab","pmids":["31239713"],"is_preprint":false},{"year":2015,"finding":"EIF3L is among the proteins with elevated SUMOylation in KRAS mutant colorectal cancer cells. EIF3L (along with KAP1 and CHD1) collectively supports anchorage-independent growth in KRAS mutant cells.","method":"Quantitative proteomics of SUMOylated proteins in KRAS mutant cells, RNAi knockdown of EIF3L with anchorage-independent 3D growth assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proteomics identification of SUMOylation plus RNAi functional assay; EIF3L's individual contribution not fully dissected from KAP1/CHD1","pmids":["25805818"],"is_preprint":false},{"year":2015,"finding":"eIF3L is ubiquitinated during oncogene-induced senescence (OIS) in primary human fibroblasts, as part of a broader pattern of ubiquitination affecting translation machinery components.","method":"Ubiquitinated peptide enrichment by immune affinity purification followed by LC-MS/MS in RAS-induced OIS cells","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mass spectrometry identification of ubiquitination site in proteome-scale screen; no functional follow-up specific to EIF3L","pmids":["25785348"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, reduction of eIF3l (along with 4EHP, NELF-E, RpS12, and eIF3h) suppressed ATF4 expression and ATF4 target gene induction, placing eIF3l as a component of an ATF4 regulatory network that also includes 4EHP and NELF-E. Quantitative proteomics showed that knockdown of NELF-E or 4EHP reduced levels of eIF3 subunits including eIF3l.","method":"Drosophila genetics (knockdown), quantitative proteomics, ATF4 reporter assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Drosophila in vivo genetics with specific ATF4 reporter readout; eIF3l is one of several factors tested; single study","pmids":["41436469"],"is_preprint":false},{"year":2026,"finding":"In plant eIF3, the PCI domain of eIF3E is required for eIF3E–eIF3L interaction: deletion of the PCI domain or mutation of PCI phosphosites (Thr417, Ser421) weakened eIF3E–eIF3L interaction (by FRET) and blocked translational activation of an mRNA reporter bearing a coding-sequence motif (MC2). This establishes eIF3L as a binding partner of eIF3E whose interaction is phosphorylation-dependent and functionally required for selective mRNA translation.","method":"Affinity RNA immunoprecipitation sequencing, AlphaFold3 structural modeling, FRET (Förster resonance energy transfer), mRNA reporter assay, domain deletion and phosphosite mutagenesis","journal":"The Plant cell","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural modeling with FRET validation and functional reporter assay; plant system (not mammalian); single lab","pmids":["41701515"],"is_preprint":false}],"current_model":"EIF3L is a nonessential accessory subunit of the 13-subunit human eIF3 translation initiation complex that directly binds eIF3E (Int-6) via its PCI domain; it is dispensable for bulk eIF3 assembly and general translation activity but forms a functionally important eIF3k–eIF3l module that selectively represses translation of specific mRNAs including RPS15A (thereby acting as a rheostat of ribosome content and stress resistance), undergoes tyrosine phosphorylation and androgen-induced palmitoylation as post-translational regulatory modifications, is subject to ubiquitination and SUMOylation in specific cellular contexts, and is co-opted by multiple RNA viruses (influenza, flaviviruses, picornaviruses, PEDV) as a host factor that modulates viral replication."},"narrative":{"mechanistic_narrative":"EIF3L is an accessory subunit of the human eIF3 translation initiation complex that integrates into eIF3 through a direct interaction with the eIF3E (Int-6) subunit, an association mediated by the PCI domain and dependent on phosphorylation [PMID:11590142, PMID:41701515]. A larger region of EIF3L is needed for incorporation into the assembled complex than for eIF3E binding alone, and the protein carries TPR, PCI, and Pumilio FBF repeats [PMID:11590142]. EIF3L is dispensable for both bulk eIF3 assembly and general translation initiation: an eIF3l-deficient complex reconstituted in vitro remains fully active [PMID:23063735]. Its principal regulatory role is as part of an eIF3k–eIF3l module that selectively represses translation of specific mRNAs, notably RPS15A, by binding the RPS15A 5'-UTR; loss of either subunit relieves this repression to drive global translation, proliferation, tumor growth, and stress resistance, and these subunits are selectively downregulated under ER and oxidative stress [PMID:37155573]. Consistent with this anti-anabolic, pro-survival rheostat function, loss of the C. elegans ortholog extends lifespan in a DAF-16–dependent manner and confers ER-stress resistance without altering bulk protein synthesis [PMID:27690135]. EIF3L is regulated by post-translational modifications including H2O2-induced tyrosine phosphorylation [PMID:11590142] and androgen-induced palmitoylation [PMID:31239713]. Beyond its endogenous role, EIF3L is co-opted by multiple RNA viruses: it interacts directly with the flavivirus NS5 RdRp domain [PMID:23800076] and the PEDV M protein [PMID:32605758], is required for influenza polymerase activity [PMID:21994455], and serves as a scaffold through which picornavirus 2Apro reaches and cleaves eIF4G [PMID:35367208].","teleology":[{"year":2001,"claim":"Established EIF3L as a bona fide eIF3-associated protein, answering whether this uncharacterized protein physically joins the translation initiation machinery and through which subunit.","evidence":"Reciprocal Co-IP, gel filtration co-elution, and deletion mapping in reticulocyte lysate and COS7 cells identifying direct binding to Int-6/eIF3E","pmids":["11590142"],"confidence":"High","gaps":["Did not define the functional consequence of EIF3L within eIF3","Role of the TPR/PCI/Pumilio repeats not functionally dissected","Significance of H2O2-induced tyrosine phosphorylation left open"]},{"year":2010,"claim":"Mapped EIF3L's spatial relationship within eIF3 bound to an IRES and the 40S subunit, distinguishing exposed accessory subunits from those protected upon RNA engagement.","evidence":"Limited proteolysis with mass spectrometry of human eIF3–HCV IRES–40S complexes","pmids":["20816988"],"confidence":"Medium","gaps":["Topology inferred indirectly from proteolytic accessibility","Functional role of EIF3L in IRES-driven initiation not tested"]},{"year":2011,"claim":"Showed EIF3L is required for influenza polymerase activity, opening its role as a virus-utilized host factor.","evidence":"Yeast two-hybrid screen for polymerase interactors plus RNAi knockdown with viral polymerase transcription readout","pmids":["21994455"],"confidence":"Medium","gaps":["Direct binding to polymerase not biochemically confirmed","Whether the effect reflects eIF3 function or a distinct activity unclear"]},{"year":2012,"claim":"Demonstrated that EIF3L is a nonessential subunit, resolving whether it is required for eIF3 assembly and core initiation activity.","evidence":"Cell-free co-expression reconstitution of human eIF3 with and without eIF3l plus a reconstituted translation initiation activity assay","pmids":["23063735"],"confidence":"High","gaps":["Did not address selective/mRNA-specific roles missed by a bulk activity assay","Stress-dependent functions not examined"]},{"year":2013,"claim":"Identified direct EIF3L–flavivirus NS5 interaction, broadening the catalogue of viral proteins that engage EIF3L.","evidence":"Yeast two-hybrid, in vitro binding, Co-IP, NS5 domain mutagenesis, and overexpression/RNAi plaque assays for Yellow Fever Virus","pmids":["23800076"],"confidence":"Medium","gaps":["Functional effect on replication only slight","Mechanism by which NS5 binding aids replication unresolved","Single lab"]},{"year":2014,"claim":"Provided biophysical characterization of recombinant EIF3L and computationally predicted an eIF3K partnership.","evidence":"Dynamic light scattering, circular dichroism, and in silico docking of recombinant human eIF3L","pmids":["23919378"],"confidence":"Low","gaps":["eIF3K interaction is computational, not experimentally validated here","Predicted phosphorylation and glycosylation sites not confirmed"]},{"year":2015,"claim":"Linked EIF3L to oncogenic phenotypes and stress states via post-translational modification, raising regulatory complexity beyond constitutive eIF3 membership.","evidence":"SUMO proteomics with anchorage-independent growth RNAi in KRAS-mutant cells; ubiquitinated-peptide LC-MS/MS in oncogene-induced senescent fibroblasts","pmids":["25805818","25785348"],"confidence":"Medium","gaps":["EIF3L's individual contribution to growth not separated from KAP1/CHD1","SUMO and ubiquitin sites lack writer/eraser and functional follow-up"]},{"year":2016,"claim":"Established an organismal phenotype for EIF3L loss, showing it normally limits longevity and stress resistance independent of bulk translation.","evidence":"C. elegans loss-of-function genetics with lifespan/ER-stress assays and epistasis against daf-16, ire-1, atf-6, pek-1","pmids":["27690135"],"confidence":"High","gaps":["Molecular target through which eif-3.L loss extends lifespan not identified","DAF-16-dependence of lifespan vs DAF-16-independence of ER-stress resistance left mechanistically unexplained"]},{"year":2019,"claim":"Identified androgen-induced palmitoylation as a hormone-responsive modification of EIF3L.","evidence":"Clickable-palmitate palmitoylome profiling with MS in androgen-treated LNCaP cells","pmids":["31239713"],"confidence":"Medium","gaps":["Palmitoylation site and enzyme not identified","Functional consequence for EIF3L activity unknown"]},{"year":2022,"claim":"Defined two distinct roles: EIF3L as a scaffold exploited by picornavirus 2Apro to cleave eIF4G, and as a regulator of plasma cell differentiation.","evidence":"Proteomic mapping of 2Apro partners with cleavage assays; CRISPR/Cas9 knockout with flow cytometry in an in vitro B cell differentiation system","pmids":["35367208","35451955"],"confidence":"Medium","gaps":["2Apro–eIF3L scaffolding model not reconstituted","Mechanism linking EIF3L to CD138+ plasma cell suppression unresolved"]},{"year":2023,"claim":"Defined EIF3L's core endogenous mechanism as a selective translational repressor acting with eIF3k to suppress RPS15A and tune ribosome content and stress resistance.","evidence":"Ribosome profiling, proteomics, transcriptomics on acute eIF3 subunit depletion with RPS15A rescue, 5'-UTR reporter mutagenesis, and in vivo tumor assays","pmids":["37155573"],"confidence":"High","gaps":["How EIF3L confers mRNA selectivity at the molecular level not fully resolved","Signal coupling stress to eIF3k/eIF3l downregulation not defined"]},{"year":2020,"claim":"Showed EIF3L acts as a negative regulator of PEDV replication through interaction with the viral M protein.","evidence":"Co-IP with LC-MS/MS plus RNAi knockdown with viral titer measurement","pmids":["32605758"],"confidence":"Medium","gaps":["Mechanism of replication restriction unknown","Direct binding interface not mapped"]},{"year":2025,"claim":"Placed EIF3L within an ATF4 regulatory network alongside 4EHP and NELF-E, connecting it to stress-responsive gene induction.","evidence":"Drosophila knockdown genetics, quantitative proteomics, and ATF4 reporter assays","pmids":["41436469"],"confidence":"Medium","gaps":["Whether EIF3L acts directly on ATF4 mRNA translation unclear","One of several factors tested; specificity not isolated"]},{"year":2026,"claim":"Confirmed the eIF3E PCI-domain, phosphorylation-dependent basis of the eIF3E–eIF3L interaction and its requirement for selective mRNA translation in a conserved system.","evidence":"AlphaFold3 modeling, FRET, PCI-domain deletion and phosphosite mutagenesis, and mRNA reporter assays in plant eIF3","pmids":["41701515"],"confidence":"Medium","gaps":["Demonstrated in plants, not human; transferability assumed","Kinase controlling the PCI phosphosites not identified"]},{"year":null,"claim":"How EIF3L confers transcript selectivity, what signals trigger its stress-induced downregulation, and the functional consequences of its multiple post-translational modifications remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human EIF3L within the selective repression module","Enzymes writing/erasing palmitoylation, SUMOylation, ubiquitination, and tyrosine phosphorylation unidentified","Whether viral host-factor roles are separable from the endogenous eIF3k–eIF3l module is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,10]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,10]}],"complexes":["eIF3"],"partners":["EIF3E","EIF3K"],"other_free_text":[]}},"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 driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25805818","citation_count":68,"is_preprint":false},{"pmid":"21994455","id":"PMC_21994455","title":"Generation and comprehensive analysis of an influenza virus polymerase cellular interaction network.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21994455","citation_count":63,"is_preprint":false},{"pmid":"30865381","id":"PMC_30865381","title":"Surfaceome of Exosomes Secreted from the Colorectal Cancer Cell Line SW480: Peripheral and Integral Membrane Proteins Analyzed by Proteolysis and TX114.","date":"2019","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/30865381","citation_count":45,"is_preprint":false},{"pmid":"27690135","id":"PMC_27690135","title":"Mutations in Nonessential eIF3k and eIF3l Genes Confer Lifespan Extension and Enhanced Resistance to ER Stress in Caenorhabditis elegans.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27690135","citation_count":44,"is_preprint":false},{"pmid":"28225027","id":"PMC_28225027","title":"Variable salinity responses of 12 alfalfa genotypes and comparative expression analyses of salt-response genes.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28225027","citation_count":44,"is_preprint":false},{"pmid":"30402224","id":"PMC_30402224","title":"Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population.","date":"2018","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/30402224","citation_count":31,"is_preprint":false},{"pmid":"20816988","id":"PMC_20816988","title":"Distinct regions of human eIF3 are sufficient for binding to the HCV IRES and the 40S ribosomal subunit.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20816988","citation_count":30,"is_preprint":false},{"pmid":"11590142","id":"PMC_11590142","title":"The human protein HSPC021 interacts with Int-6 and is associated with eukaryotic translation initiation factor 3.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11590142","citation_count":26,"is_preprint":false},{"pmid":"23800076","id":"PMC_23800076","title":"The eukaryotic translation initiation factor 3 subunit L protein interacts with Flavivirus NS5 and may modulate yellow fever virus replication.","date":"2013","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/23800076","citation_count":23,"is_preprint":false},{"pmid":"32605758","id":"PMC_32605758","title":"Identification of host cell proteins that interact with the M protein of porcine epidemic diarrhea virus.","date":"2020","source":"Veterinary 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Direct protein-protein interaction occurs between HSPC021 and Int-6. HSPC021 coelutes with Int-6 and eIF3 in gel filtration, coimmunoprecipitates with eIF3, and is incorporated into eIF3 both in rabbit reticulocyte lysates and in COS7 cells. A larger region of HSPC021 is required for incorporation into eIF3 than for binding to Int-6 alone. The protein contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat. Exposure to H2O2 triggers tyrosine phosphorylation of HSPC021.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, gel filtration, cell-based coimmunoprecipitation (rabbit reticulocyte lysates and COS7 cells), deletion mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, gel filtration, multiple cell systems, deletion mutagenesis, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"11590142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eIF3l (along with other eIF3 subunits) is exposed (not protected) when eIF3 binds the HCV IRES RNA, whereas eIF3b is protected by HCV IRES RNA binding. Limited proteolysis revealed that eIF3l is among the subunits exposed upon HCV IRES binding but is involved in broader redundant interactions with the 40S ribosomal subunit.\",\n      \"method\": \"Limited proteolysis combined with mass spectrometry of human eIF3 in complex with HCV IRES RNA and 40S ribosomal subunit\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assay with mass spectrometry, single lab, single study\",\n      \"pmids\": [\"20816988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"eIF3l is a nonessential subunit of the eIF3 complex: when eIF3l was omitted from a cell-free reconstitution of the 11-subunit human eIF3 complex, an eIF3l-deficient complex was still assembled and was as active as the native 11-subunit complex in a reconstituted translation initiation assay.\",\n      \"method\": \"Cell-free co-expression reconstitution in HeLa-derived in vitro transcription/translation system, affinity chromatography purification, reconstituted translation initiation activity assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in vitro with functional activity assay; demonstrates nonessential role mechanistically\",\n      \"pmids\": [\"23063735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"eIF3L interacts directly with Yellow Fever Virus (YFV) NS5 protein (RdRp domain). The interaction was confirmed by yeast two-hybrid, in vitro binding assay, and in vivo coimmunoprecipitation. The interaction domain on NS5 is conserved across several flaviviruses. eIF3L overexpression showed a slight facilitating effect on YFV replication in plaque assays.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, coimmunoprecipitation, site-directed mutagenesis of NS5 interaction domain, eIF3L overexpression and RNAi knockdown with plaque reduction assay\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro binding, mutagenesis, and functional assay in one study; single lab\",\n      \"pmids\": [\"23800076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Recombinant full-length human eIF3L produced in E. coli behaves as a monomer when not interacting with other molecular partners (by dynamic light scattering). Circular dichroism revealed predominantly α-helical secondary structure. In silico molecular docking predicted strong interaction between eIF3L and eIF3K. Multiple putative phosphorylation sites (~8) and one N-glycosylation site were predicted bioinformatically.\",\n      \"method\": \"Dynamic light scattering, circular dichroism spectroscopy, in silico structural modeling and molecular docking\",\n      \"journal\": \"Protein and peptide letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — biophysical characterization of recombinant protein, docking is computational; no mutagenesis or functional validation\",\n      \"pmids\": [\"23919378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function mutations in eif-3.L (the C. elegans ortholog of EIF3L) result in ~40% lifespan extension and enhanced resistance to ER stress, without affecting bulk protein synthesis rates or growth. Lifespan extension from 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 signaling.\",\n      \"method\": \"C. elegans loss-of-function genetics, lifespan assays, ER stress resistance assays, bulk protein synthesis measurement, epistasis analysis with daf-16, ire-1, atf-6, pek-1 mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function genetics with defined cellular phenotypes, epistasis analysis with multiple pathway components, multiple orthogonal readouts\",\n      \"pmids\": [\"27690135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EIF3S6IP (EIF3L) was identified as a host factor required for influenza virus polymerase replication and transcriptional activity. RNAi-mediated depletion of EIF3L reduced viral polymerase transcriptional activity in a functional screen.\",\n      \"method\": \"Yeast two-hybrid screen for influenza polymerase interactors, RNAi knockdown with viral polymerase transcriptional activity assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional RNAi knockdown with specific viral transcription readout, single lab, part of larger screen\",\n      \"pmids\": [\"21994455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eIF3L interacts with PEDV (porcine epidemic diarrhea virus) membrane (M) protein, validated by coimmunoprecipitation. Downregulation of eIF3L expression significantly increased PEDV viral production, indicating eIF3L acts as a negative regulator of PEDV replication.\",\n      \"method\": \"Co-immunoprecipitation with LC-MS/MS, RNAi knockdown with viral titer measurement\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP validation plus functional knockdown with specific viral production readout; single lab\",\n      \"pmids\": [\"32605758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eIF3L is utilized by picornavirus 2Apro to gain proteolytic access to eIF4G: the protease appears to interact with eIF3L, using the eIF3 complex as a scaffold to reach and cleave eIF4G, rather than directly binding eIF4G. This was established through proteomic characterization of 2Apro interacting partners.\",\n      \"method\": \"Proteomic analysis of 2Apro interacting partners, cleavage assays, proteomic identification of cleavage targets\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proteomic interaction mapping with functional cleavage data; single lab; mechanistic model supported but not fully reconstituted\",\n      \"pmids\": [\"35367208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EIF3K and EIF3L subunits function as inhibitors of CD138+ plasma cell accumulation in vitro. CRISPR/Cas9 knockout of EIF3L in mouse B cells promoted accumulation of CD138+ plasma cells, validated in an in vitro differentiation system.\",\n      \"method\": \"CRISPR/Cas9 knockout screen of 1213 RNA binding proteins, flow cytometry for CD138+ cell abundance, in vitro B cell differentiation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional KO with defined cellular phenotype (CD138+ accumulation), part of broader screen but validated for EIF3L specifically\",\n      \"pmids\": [\"35451955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"eIF3k and eIF3l form a mRNA-specific regulatory module within the eIF3 complex. Depletion of eIF3k or eIF3l promoted global translation, cell proliferation, tumor growth, and stress resistance by relieving repression of ribosomal protein RPS15A synthesis. eIF3k and eIF3l are selectively downregulated in response to ER stress and oxidative stress. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA negated the anabolic effects of eIF3k depletion. eIF3l depletion phenocopied eIF3k depletion in this context.\",\n      \"method\": \"Multiomic profiling (ribosome profiling, proteomics, transcriptomics) upon acute eIF3 subunit depletion, tumor growth assays, RPS15A ectopic expression rescue, 5'-UTR reporter mutagenesis, mathematical modeling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (ribosome profiling, proteomics, mutagenesis of cis-element, rescue experiments, in vivo tumor assays) in single rigorous study\",\n      \"pmids\": [\"37155573\"],\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\": \"Palmitoylome profiling using clickable palmitate probe (Alk-C16) with mass spectrometry in androgen-treated vs. untreated LNCaP cells\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — chemical biology palmitoylation profiling with quantitative MS; identifies PTM but no writer/eraser validated; single lab\",\n      \"pmids\": [\"31239713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EIF3L is among the proteins with elevated SUMOylation in KRAS mutant colorectal cancer cells. EIF3L (along with KAP1 and CHD1) collectively supports anchorage-independent growth in KRAS mutant cells.\",\n      \"method\": \"Quantitative proteomics of SUMOylated proteins in KRAS mutant cells, RNAi knockdown of EIF3L with anchorage-independent 3D growth assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proteomics identification of SUMOylation plus RNAi functional assay; EIF3L's individual contribution not fully dissected from KAP1/CHD1\",\n      \"pmids\": [\"25805818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"eIF3L is ubiquitinated during oncogene-induced senescence (OIS) in primary human fibroblasts, as part of a broader pattern of ubiquitination affecting translation machinery components.\",\n      \"method\": \"Ubiquitinated peptide enrichment by immune affinity purification followed by LC-MS/MS in RAS-induced OIS cells\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mass spectrometry identification of ubiquitination site in proteome-scale screen; no functional follow-up specific to EIF3L\",\n      \"pmids\": [\"25785348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, reduction of eIF3l (along with 4EHP, NELF-E, RpS12, and eIF3h) suppressed ATF4 expression and ATF4 target gene induction, placing eIF3l as a component of an ATF4 regulatory network that also includes 4EHP and NELF-E. Quantitative proteomics showed that knockdown of NELF-E or 4EHP reduced levels of eIF3 subunits including eIF3l.\",\n      \"method\": \"Drosophila genetics (knockdown), quantitative proteomics, ATF4 reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Drosophila in vivo genetics with specific ATF4 reporter readout; eIF3l is one of several factors tested; single study\",\n      \"pmids\": [\"41436469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In plant eIF3, the PCI domain of eIF3E is required for eIF3E–eIF3L interaction: deletion of the PCI domain or mutation of PCI phosphosites (Thr417, Ser421) weakened eIF3E–eIF3L interaction (by FRET) and blocked translational activation of an mRNA reporter bearing a coding-sequence motif (MC2). This establishes eIF3L as a binding partner of eIF3E whose interaction is phosphorylation-dependent and functionally required for selective mRNA translation.\",\n      \"method\": \"Affinity RNA immunoprecipitation sequencing, AlphaFold3 structural modeling, FRET (Förster resonance energy transfer), mRNA reporter assay, domain deletion and phosphosite mutagenesis\",\n      \"journal\": \"The Plant cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural modeling with FRET validation and functional reporter assay; plant system (not mammalian); single lab\",\n      \"pmids\": [\"41701515\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3L is a nonessential accessory subunit of the 13-subunit human eIF3 translation initiation complex that directly binds eIF3E (Int-6) via its PCI domain; it is dispensable for bulk eIF3 assembly and general translation activity but forms a functionally important eIF3k–eIF3l module that selectively represses translation of specific mRNAs including RPS15A (thereby acting as a rheostat of ribosome content and stress resistance), undergoes tyrosine phosphorylation and androgen-induced palmitoylation as post-translational regulatory modifications, is subject to ubiquitination and SUMOylation in specific cellular contexts, and is co-opted by multiple RNA viruses (influenza, flaviviruses, picornaviruses, PEDV) as a host factor that modulates viral replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3L is an accessory subunit of the human eIF3 translation initiation complex that integrates into eIF3 through a direct interaction with the eIF3E (Int-6) subunit, an association mediated by the PCI domain and dependent on phosphorylation [#0, #15]. A larger region of EIF3L is needed for incorporation into the assembled complex than for eIF3E binding alone, and the protein carries TPR, PCI, and Pumilio FBF repeats [#0]. EIF3L is dispensable for both bulk eIF3 assembly and general translation initiation: an eIF3l-deficient complex reconstituted in vitro remains fully active [#2]. Its principal regulatory role is as part of an eIF3k–eIF3l module that selectively represses translation of specific mRNAs, notably RPS15A, by binding the RPS15A 5'-UTR; loss of either subunit relieves this repression to drive global translation, proliferation, tumor growth, and stress resistance, and these subunits are selectively downregulated under ER and oxidative stress [#10]. Consistent with this anti-anabolic, pro-survival rheostat function, loss of the C. elegans ortholog extends lifespan in a DAF-16–dependent manner and confers ER-stress resistance without altering bulk protein synthesis [#5]. EIF3L is regulated by post-translational modifications including H2O2-induced tyrosine phosphorylation [#0] and androgen-induced palmitoylation [#11]. Beyond its endogenous role, EIF3L is co-opted by multiple RNA viruses: it interacts directly with the flavivirus NS5 RdRp domain [#3] and the PEDV M protein [#7], is required for influenza polymerase activity [#6], and serves as a scaffold through which picornavirus 2Apro reaches and cleaves eIF4G [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established EIF3L as a bona fide eIF3-associated protein, answering whether this uncharacterized protein physically joins the translation initiation machinery and through which subunit.\",\n      \"evidence\": \"Reciprocal Co-IP, gel filtration co-elution, and deletion mapping in reticulocyte lysate and COS7 cells identifying direct binding to Int-6/eIF3E\",\n      \"pmids\": [\"11590142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the functional consequence of EIF3L within eIF3\", \"Role of the TPR/PCI/Pumilio repeats not functionally dissected\", \"Significance of H2O2-induced tyrosine phosphorylation left open\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped EIF3L's spatial relationship within eIF3 bound to an IRES and the 40S subunit, distinguishing exposed accessory subunits from those protected upon RNA engagement.\",\n      \"evidence\": \"Limited proteolysis with mass spectrometry of human eIF3–HCV IRES–40S complexes\",\n      \"pmids\": [\"20816988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topology inferred indirectly from proteolytic accessibility\", \"Functional role of EIF3L in IRES-driven initiation not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed EIF3L is required for influenza polymerase activity, opening its role as a virus-utilized host factor.\",\n      \"evidence\": \"Yeast two-hybrid screen for polymerase interactors plus RNAi knockdown with viral polymerase transcription readout\",\n      \"pmids\": [\"21994455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to polymerase not biochemically confirmed\", \"Whether the effect reflects eIF3 function or a distinct activity unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that EIF3L is a nonessential subunit, resolving whether it is required for eIF3 assembly and core initiation activity.\",\n      \"evidence\": \"Cell-free co-expression reconstitution of human eIF3 with and without eIF3l plus a reconstituted translation initiation activity assay\",\n      \"pmids\": [\"23063735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address selective/mRNA-specific roles missed by a bulk activity assay\", \"Stress-dependent functions not examined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified direct EIF3L–flavivirus NS5 interaction, broadening the catalogue of viral proteins that engage EIF3L.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, Co-IP, NS5 domain mutagenesis, and overexpression/RNAi plaque assays for Yellow Fever Virus\",\n      \"pmids\": [\"23800076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect on replication only slight\", \"Mechanism by which NS5 binding aids replication unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided biophysical characterization of recombinant EIF3L and computationally predicted an eIF3K partnership.\",\n      \"evidence\": \"Dynamic light scattering, circular dichroism, and in silico docking of recombinant human eIF3L\",\n      \"pmids\": [\"23919378\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"eIF3K interaction is computational, not experimentally validated here\", \"Predicted phosphorylation and glycosylation sites not confirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked EIF3L to oncogenic phenotypes and stress states via post-translational modification, raising regulatory complexity beyond constitutive eIF3 membership.\",\n      \"evidence\": \"SUMO proteomics with anchorage-independent growth RNAi in KRAS-mutant cells; ubiquitinated-peptide LC-MS/MS in oncogene-induced senescent fibroblasts\",\n      \"pmids\": [\"25805818\", \"25785348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EIF3L's individual contribution to growth not separated from KAP1/CHD1\", \"SUMO and ubiquitin sites lack writer/eraser and functional follow-up\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established an organismal phenotype for EIF3L loss, showing it normally limits longevity and stress resistance independent of bulk translation.\",\n      \"evidence\": \"C. elegans loss-of-function genetics with lifespan/ER-stress assays and epistasis against daf-16, ire-1, atf-6, pek-1\",\n      \"pmids\": [\"27690135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target through which eif-3.L loss extends lifespan not identified\", \"DAF-16-dependence of lifespan vs DAF-16-independence of ER-stress resistance left mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified androgen-induced palmitoylation as a hormone-responsive modification of EIF3L.\",\n      \"evidence\": \"Clickable-palmitate palmitoylome profiling with MS in androgen-treated LNCaP cells\",\n      \"pmids\": [\"31239713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Palmitoylation site and enzyme not identified\", \"Functional consequence for EIF3L activity unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined two distinct roles: EIF3L as a scaffold exploited by picornavirus 2Apro to cleave eIF4G, and as a regulator of plasma cell differentiation.\",\n      \"evidence\": \"Proteomic mapping of 2Apro partners with cleavage assays; CRISPR/Cas9 knockout with flow cytometry in an in vitro B cell differentiation system\",\n      \"pmids\": [\"35367208\", \"35451955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"2Apro–eIF3L scaffolding model not reconstituted\", \"Mechanism linking EIF3L to CD138+ plasma cell suppression unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined EIF3L's core endogenous mechanism as a selective translational repressor acting with eIF3k to suppress RPS15A and tune ribosome content and stress resistance.\",\n      \"evidence\": \"Ribosome profiling, proteomics, transcriptomics on acute eIF3 subunit depletion with RPS15A rescue, 5'-UTR reporter mutagenesis, and in vivo tumor assays\",\n      \"pmids\": [\"37155573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EIF3L confers mRNA selectivity at the molecular level not fully resolved\", \"Signal coupling stress to eIF3k/eIF3l downregulation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed EIF3L acts as a negative regulator of PEDV replication through interaction with the viral M protein.\",\n      \"evidence\": \"Co-IP with LC-MS/MS plus RNAi knockdown with viral titer measurement\",\n      \"pmids\": [\"32605758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of replication restriction unknown\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed EIF3L within an ATF4 regulatory network alongside 4EHP and NELF-E, connecting it to stress-responsive gene induction.\",\n      \"evidence\": \"Drosophila knockdown genetics, quantitative proteomics, and ATF4 reporter assays\",\n      \"pmids\": [\"41436469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EIF3L acts directly on ATF4 mRNA translation unclear\", \"One of several factors tested; specificity not isolated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed the eIF3E PCI-domain, phosphorylation-dependent basis of the eIF3E–eIF3L interaction and its requirement for selective mRNA translation in a conserved system.\",\n      \"evidence\": \"AlphaFold3 modeling, FRET, PCI-domain deletion and phosphosite mutagenesis, and mRNA reporter assays in plant eIF3\",\n      \"pmids\": [\"41701515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in plants, not human; transferability assumed\", \"Kinase controlling the PCI phosphosites not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EIF3L confers transcript selectivity, what signals trigger its stress-induced downregulation, and the functional consequences of its multiple post-translational modifications remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of human EIF3L within the selective repression module\", \"Enzymes writing/erasing palmitoylation, SUMOylation, ubiquitination, and tyrosine phosphorylation unidentified\", \"Whether viral host-factor roles are separable from the endogenous eIF3k–eIF3l module is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [\"eIF3\"],\n    \"partners\": [\"EIF3E\", \"EIF3K\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}