{"gene":"EIF3K","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2004,"finding":"Crystal structure of human eIF3K was solved, revealing two distinct domains: a HEAT analogous motif (HAM) domain and a winged-helix-like (WH) domain. Structural comparison and sequence conservation analysis identified three putative protein-binding surfaces and potential RNA binding activity.","method":"X-ray crystallography with structural comparison and sequence conservation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination with functional domain mapping and surface analysis in a single rigorous study","pmids":["15180986"],"is_preprint":false},{"year":2003,"finding":"eIF3K (28 kDa) was identified as the twelfth subunit of mammalian eIF3 complex. It co-immunoprecipitates with the eIF3 complex, co-purifies with other eIF3 subunits upon affinity purification, colocalizes with eIF3 on 40S ribosomal subunits, and forms a stable complex with core eIF3 subunits when co-expressed in baculovirus-infected insect cells. Direct binary interactions were established with eIF3c, eIF3g, and eIF3j by GST pull-down assays.","method":"Co-immunoprecipitation, affinity purification, sucrose gradient sedimentation, baculovirus co-expression, GST pull-down assay","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, affinity purification, ribosome cosedimentation, baculovirus reconstitution, GST pulldown) in a single focused study","pmids":["14519125"],"is_preprint":false},{"year":2004,"finding":"eIF3K (p28 subunit) interacts with cyclin D3. The interaction was identified by yeast two-hybrid screen of a human fetal liver cDNA library, confirmed by in vitro binding assay, co-immunoprecipitation in vivo, and co-localization by confocal microscopy. Cyclin D3 interacts with eIF3K through its C-terminal domain. eIF3K localizes to both nucleus and cytoplasm and co-localizes with cyclin D3. Overexpression of cyclin D3 upregulates cellular translation activity without changing mRNA levels.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, confocal immunofluorescence","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, in vitro binding, co-IP, colocalization) in a single lab study","pmids":["15327989"],"is_preprint":false},{"year":2006,"finding":"eIF3K (PLAC-24) interacts with all three isoforms of the 5-HT7 receptor. Interaction was identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation in transfected COS-7 cells. The interaction is not restricted to the receptor C-terminus. Both the HAM and WH domains of eIF3K interact with the 5-HT7(a) receptor. Overexpression of eIF3K causes a ~3-fold increase in 5-HT7(a) receptor expression levels. Co-expression with the receptor causes eIF3K to relocate from nucleus/perinuclear sites to the plasma membrane, suggesting a role in receptor transport and stabilization.","method":"Yeast two-hybrid, co-immunoprecipitation, deletion mutagenesis, immunofluorescence co-localization","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal approaches (Y2H + co-IP + domain mapping) in a single lab study","pmids":["16935469"],"is_preprint":false},{"year":2002,"finding":"PLAC-24 (eIF3K) binds directly to cytoplasmic dynein intermediate chain (DIC) and is not a dynactin subunit; the binding is independent of dynein-dynactin association. eIF3K shows a punctate perinuclear distribution in isolated cells but is specifically recruited to cortical sites of cell-cell contact in epithelial cells, where it co-localizes with adherens junction components. Cortical localization requires intact actin filaments but not microtubules (shown by latrunculin vs. nocodazole treatment). Overexpression of beta-catenin abolishes eIF3K localization to cell-cell contacts.","method":"Protein interaction screen, immunocytochemistry, cytoskeletal disruption assays (latrunculin, nocodazole), beta-catenin overexpression","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding established by screen with functional localization studies using pharmacological perturbations and overexpression, single lab","pmids":["12006665"],"is_preprint":false},{"year":2013,"finding":"eIF3K interacts with the PML tumor suppressor protein. Interaction was identified by yeast two-hybrid screen using PML isoform I (PML-I) peptide sequences as bait, and confirmed by in vitro pull-down and in vivo co-immunoprecipitation and co-immunofluorescence in human cells. A novel eIF3K isoform (eIF3K-2) was identified that specifically co-localizes to PML nuclear bodies, particularly those enriched in PML-I, while eIF3K isoform 1 associates poorly with PML NBs. This identifies eIF3K as the first known eIF3 subunit to interact directly with PML.","method":"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, co-immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, pulldown, co-IP, co-IF) in a single lab study","pmids":["24036361"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function mutations in C. elegans eif-3.K (ortholog of EIF3K) extend lifespan by ~40% and confer enhanced resistance to ER stress without affecting bulk protein synthesis or growth rates. Lifespan extension requires the DAF-16 (FOXO) transcription factor. Enhanced ER stress resistance is independent of IRE-1-XBP-1, ATF-6, and PEK-1 pathways and also independent of DAF-16, indicating eIF3K and eIF3L accessory subunits have a distinct regulatory role in ER stress and aging responses.","method":"Loss-of-function genetics, lifespan assays, epistasis analysis with DAF-16, IRE-1, XBP-1, ATF-6, PEK-1 mutants, protein synthesis measurements","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with multiple epistasis experiments, orthogonal phenotypic readouts, and mechanistic pathway placement in a rigorous study","pmids":["27690135"],"is_preprint":false},{"year":2022,"finding":"In teleost fish, eIF3K acts as a suppressor of the NF-κB pathway. Mechanistically, eIF3K expression (induced by Vibrio harveyi) enhances E3 ligase Nrdp1-mediated K27-linked ubiquitination of MyD88. eIF3K then bridges ubiquitin-tagged MyD88 to ATG5, forming a MyD88-eIF3k-ATG5 complex that is transported to the autophagosome for degradation, thereby terminating innate immune signaling.","method":"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, overexpression and knockdown experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple co-IP and functional assays in a single lab study using a teleost fish model","pmids":["35176284"],"is_preprint":false},{"year":2023,"finding":"Acute depletion of eIF3K promotes global translation, cell proliferation, tumor growth, and stress resistance by de-repressing the synthesis of ribosomal protein RPS15A. eIF3K and eIF3L form a mRNA-specific module that controls RPS15A translation by binding to the 5'-UTR of RPS15A mRNA; disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA negated the anabolic effects of eIF3K depletion. Ectopic expression of RPS15A mimicked the anabolic effects of eIF3K depletion. eIF3K and eIF3L are selectively downregulated in response to ER and oxidative stress, suggesting this module acts as a rheostat of ribosome content.","method":"Multiomic profiling (proteomics, translatome), acute depletion of eIF3 subunits, ectopic RPS15A expression, 5'-UTR binding disruption experiments, mathematical modeling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (multiomic profiling, functional rescue, 5'-UTR binding disruption, mathematical modeling) establishing a mechanistic pathway in a single rigorous study","pmids":["37155573"],"is_preprint":false},{"year":2025,"finding":"Homozygous variants in EIF3K (missense p.Asp43Gly and intronic c.355-13A>G) are associated with a neurodevelopmental syndrome. The intronic variant causes aberrant splicing of EIF3K pre-mRNA (insertion of 12 intronic base pairs, skipping of 2 exons) and significantly reduced EIF3K protein levels in patient skin fibroblasts, establishing that loss of EIF3K function underlies the phenotype.","method":"Whole exome/genome sequencing, RT-PCR splicing analysis, Western blot of patient fibroblasts, familial segregation analysis","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional validation of splice variant by RT-PCR and Western blot in patient cells, single study","pmids":["40219605"],"is_preprint":false}],"current_model":"EIF3K is the smallest, non-essential subunit of the eukaryotic translation initiation factor 3 (eIF3) complex, harboring a HAM domain and a WH domain (crystal structure resolved); it associates with the 40S ribosomal subunit and directly contacts eIF3c, eIF3g, and eIF3j, but unlike core eIF3 subunits it acts as a mRNA-selective translational repressor—specifically suppressing RPS15A synthesis via binding to its 5'-UTR to restrain ribosome biogenesis—such that its loss paradoxically promotes global translation and stress resistance; outside the ribosomal context, eIF3K binds cyclin D3, PML nuclear bodies, the 5-HT7 receptor, and dynein intermediate chain, and serves as an autophagic receptor bridging K27-ubiquitinated MyD88 to ATG5 for degradation, thereby suppressing NF-κB innate immune signaling."},"narrative":{"mechanistic_narrative":"EIF3K is the smallest subunit of the mammalian eIF3 translation initiation complex, integrating into the holocomplex through direct binary contacts with eIF3c, eIF3g, and eIF3j and co-sedimenting with eIF3 on 40S ribosomal subunits [PMID:14519125]. Its crystal structure resolves two domains—a HEAT-analogous (HAM) domain and a winged-helix-like (WH) domain—that present discrete protein- and putative RNA-binding surfaces [PMID:15180986]. Functionally, EIF3K is not a core processivity factor but an mRNA-selective regulator: together with eIF3L it forms a module that binds the 5'-UTR of RPS15A mRNA to repress its translation, so that acute EIF3K depletion de-represses RPS15A synthesis and thereby promotes global translation, proliferation, tumor growth, and stress resistance [PMID:37155573]. Consistent with this restraining role, loss of the EIF3K ortholog in C. elegans extends lifespan via DAF-16/FOXO and confers ER-stress resistance independent of the canonical UPR branches and of DAF-16, without altering bulk protein synthesis [PMID:27690135]. Beyond the ribosome, EIF3K engages partners across compartments—cyclin D3 [PMID:15327989], the 5-HT7 receptor [PMID:16935469], PML nuclear bodies via a dedicated isoform [PMID:24036361], and cytoplasmic dynein intermediate chain at actin-dependent cortical sites of cell-cell contact [PMID:12006665]—and acts as an autophagic adaptor bridging K27-ubiquitinated MyD88 to ATG5 to suppress NF-κB innate immune signaling [PMID:35176284]. Homozygous loss-of-function EIF3K variants underlie a neurodevelopmental syndrome [PMID:40219605].","teleology":[{"year":2002,"claim":"Before its assignment to eIF3, the protein (PLAC-24) was first characterized as a direct dynein-associated factor, establishing an extra-ribosomal cytoskeletal/junctional context for EIF3K.","evidence":"Protein interaction screen and immunocytochemistry with cytoskeletal disruption and beta-catenin overexpression in epithelial cells","pmids":["12006665"],"confidence":"Medium","gaps":["Functional consequence of dynein binding for translation or transport unresolved","Relationship between cortical recruitment and eIF3 holocomplex membership unclear"]},{"year":2003,"claim":"Identifying EIF3K as the twelfth eIF3 subunit with defined binary contacts placed it structurally within the initiation machinery and established its core interaction partners.","evidence":"Co-IP, affinity purification, sucrose gradient cosedimentation, baculovirus reconstitution, and GST pull-down in mammalian/insect systems","pmids":["14519125"],"confidence":"High","gaps":["Whether EIF3K is required for eIF3 activity not tested","Functional role distinct from scaffolding not addressed"]},{"year":2004,"claim":"The crystal structure defined EIF3K's two-domain architecture and mapped candidate binding surfaces, providing the structural basis for its protein and RNA interactions.","evidence":"X-ray crystallography with structural comparison and sequence conservation analysis","pmids":["15180986"],"confidence":"High","gaps":["RNA-binding activity inferred from structure but not demonstrated biochemically","Specific partners contacting each surface not identified structurally"]},{"year":2004,"claim":"Linking EIF3K to cyclin D3 connected it to cell-cycle-coupled control of translational output.","evidence":"Yeast two-hybrid, in vitro binding, co-IP, and confocal colocalization in human cells","pmids":["15327989"],"confidence":"Medium","gaps":["Whether cyclin D3 acts through EIF3K to upregulate translation not directly shown","Nuclear vs cytoplasmic function of the interaction unresolved"]},{"year":2006,"claim":"Demonstrating EIF3K binding to the 5-HT7 receptor and driving its plasma-membrane relocalization extended its extra-ribosomal roles to receptor expression and trafficking.","evidence":"Yeast two-hybrid, co-IP, deletion mapping, and immunofluorescence in COS-7 cells","pmids":["16935469"],"confidence":"Medium","gaps":["Mechanism by which EIF3K increases receptor levels (translation vs stability) not distinguished","Physiological relevance in neurons not tested"]},{"year":2013,"claim":"Identifying an EIF3K isoform that targets PML nuclear bodies linked the protein to a nuclear tumor-suppressor compartment.","evidence":"Yeast two-hybrid with PML-I bait, in vitro pull-down, co-IP, and co-immunofluorescence in human cells","pmids":["24036361"],"confidence":"Medium","gaps":["Function of EIF3K at PML bodies unknown","Whether isoform-specific localization affects translation unexamined"]},{"year":2016,"claim":"Genetic loss of the EIF3K ortholog extending lifespan and ER-stress resistance without altering bulk translation revealed a dedicated regulatory, rather than essential, role for the accessory subunit.","evidence":"Loss-of-function genetics, lifespan and stress assays, and epistasis with DAF-16/UPR mutants in C. elegans","pmids":["27690135"],"confidence":"High","gaps":["Molecular target mediating lifespan/stress effects not identified in this study","DAF-16-dependent lifespan vs DAF-16-independent stress resistance not mechanistically reconciled"]},{"year":2022,"claim":"Defining EIF3K as an autophagic adaptor bridging K27-ubiquitinated MyD88 to ATG5 established a translation-independent role in terminating NF-κB innate immune signaling.","evidence":"Co-IP, ubiquitination assays, autophagy flux assays, and gain/loss-of-function in teleost fish","pmids":["35176284"],"confidence":"Medium","gaps":["Conservation of the MyD88-EIF3K-ATG5 axis in mammals not established","Domain of EIF3K mediating ubiquitin/ATG5 bridging not mapped"]},{"year":2023,"claim":"Showing that the EIF3K/eIF3L module represses RPS15A translation via its 5'-UTR provided the central mechanism: EIF3K is an mRNA-selective brake on ribosome biogenesis whose loss drives anabolic, pro-growth output.","evidence":"Multiomic profiling, acute subunit depletion, ectopic RPS15A rescue, 5'-UTR binding disruption, and mathematical modeling","pmids":["37155573"],"confidence":"High","gaps":["Direct RNA contact by EIF3K vs eIF3L not separated","Signal coupling stress to EIF3K/eIF3L downregulation undefined"]},{"year":2025,"claim":"Identifying homozygous loss-of-function EIF3K variants in a neurodevelopmental syndrome established the gene's physiological requirement in humans.","evidence":"Exome/genome sequencing, RT-PCR splicing analysis, Western blot of patient fibroblasts, and familial segregation","pmids":["40219605"],"confidence":"Medium","gaps":["Cellular pathway linking EIF3K loss to neurodevelopmental phenotype not defined","Whether RPS15A de-repression contributes to disease unexplored"]},{"year":null,"claim":"How EIF3K's many extra-ribosomal interactions (dynein, cyclin D3, 5-HT7, PML, MyD88-ATG5) integrate with its core role as an mRNA-selective translational repressor remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking ribosomal and non-ribosomal functions","Tissue- and isoform-specific deployment of EIF3K functions uncharacterized","Mammalian validation of the autophagy/NF-κB role absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[8,1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]}],"complexes":["eIF3"],"partners":["EIF3C","EIF3G","EIF3J","EIF3L","CCND3","HTR7","PML","MYD88"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBQ5","full_name":"Eukaryotic translation initiation factor 3 subunit K","aliases":["Eukaryotic translation initiation factor 3 subunit 12","Muscle-specific gene M9 protein","PLAC-24","eIF-3 p25","eIF-3 p28"],"length_aa":218,"mass_kda":25.1,"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)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UBQ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EIF3K","classification":"Not Classified","n_dependent_lines":144,"n_total_lines":1208,"dependency_fraction":0.11920529801324503},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000178982","cell_line_id":"CID000974","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"EIF3B","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":10.0},{"gene":"EIF3M","stoichiometry":10.0},{"gene":"EIF3L","stoichiometry":10.0},{"gene":"EIF3E","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":4.0},{"gene":"EIF3I","stoichiometry":4.0},{"gene":"EIF3H","stoichiometry":4.0},{"gene":"RACK1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000974","total_profiled":1310},"omim":[{"mim_id":"609596","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 3, SUBUNIT K; EIF3K","url":"https://www.omim.org/entry/609596"},{"mim_id":"123834","title":"CYCLIN D3; CCND3","url":"https://www.omim.org/entry/123834"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EIF3K"},"hgnc":{"alias_symbol":["PRO1474","HSPC029","PTD001","PLAC-24","M9","ARG134"],"prev_symbol":["EIF3S12"]},"alphafold":{"accession":"Q9UBQ5","domains":[{"cath_id":"1.25.40.250","chopping":"1-126","consensus_level":"medium","plddt":89.8128,"start":1,"end":126}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBQ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBQ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBQ5-F1-predicted_aligned_error_v6.png","plddt_mean":87.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EIF3K","jax_strain_url":"https://www.jax.org/strain/search?query=EIF3K"},"sequence":{"accession":"Q9UBQ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBQ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBQ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBQ5"}},"corpus_meta":[{"pmid":"9105034","id":"PMC_9105034","title":"A 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Structural comparison and sequence conservation analysis identified three putative protein-binding surfaces and potential RNA binding activity.\",\n      \"method\": \"X-ray crystallography with structural comparison and sequence conservation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination with functional domain mapping and surface analysis in a single rigorous study\",\n      \"pmids\": [\"15180986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"eIF3K (28 kDa) was identified as the twelfth subunit of mammalian eIF3 complex. It co-immunoprecipitates with the eIF3 complex, co-purifies with other eIF3 subunits upon affinity purification, colocalizes with eIF3 on 40S ribosomal subunits, and forms a stable complex with core eIF3 subunits when co-expressed in baculovirus-infected insect cells. Direct binary interactions were established with eIF3c, eIF3g, and eIF3j by GST pull-down assays.\",\n      \"method\": \"Co-immunoprecipitation, affinity purification, sucrose gradient sedimentation, baculovirus co-expression, GST pull-down assay\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, affinity purification, ribosome cosedimentation, baculovirus reconstitution, GST pulldown) in a single focused study\",\n      \"pmids\": [\"14519125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"eIF3K (p28 subunit) interacts with cyclin D3. The interaction was identified by yeast two-hybrid screen of a human fetal liver cDNA library, confirmed by in vitro binding assay, co-immunoprecipitation in vivo, and co-localization by confocal microscopy. Cyclin D3 interacts with eIF3K through its C-terminal domain. eIF3K localizes to both nucleus and cytoplasm and co-localizes with cyclin D3. Overexpression of cyclin D3 upregulates cellular translation activity without changing mRNA levels.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, confocal immunofluorescence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, in vitro binding, co-IP, colocalization) in a single lab study\",\n      \"pmids\": [\"15327989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"eIF3K (PLAC-24) interacts with all three isoforms of the 5-HT7 receptor. Interaction was identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation in transfected COS-7 cells. The interaction is not restricted to the receptor C-terminus. Both the HAM and WH domains of eIF3K interact with the 5-HT7(a) receptor. Overexpression of eIF3K causes a ~3-fold increase in 5-HT7(a) receptor expression levels. Co-expression with the receptor causes eIF3K to relocate from nucleus/perinuclear sites to the plasma membrane, suggesting a role in receptor transport and stabilization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, deletion mutagenesis, immunofluorescence co-localization\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal approaches (Y2H + co-IP + domain mapping) in a single lab study\",\n      \"pmids\": [\"16935469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PLAC-24 (eIF3K) binds directly to cytoplasmic dynein intermediate chain (DIC) and is not a dynactin subunit; the binding is independent of dynein-dynactin association. eIF3K shows a punctate perinuclear distribution in isolated cells but is specifically recruited to cortical sites of cell-cell contact in epithelial cells, where it co-localizes with adherens junction components. Cortical localization requires intact actin filaments but not microtubules (shown by latrunculin vs. nocodazole treatment). Overexpression of beta-catenin abolishes eIF3K localization to cell-cell contacts.\",\n      \"method\": \"Protein interaction screen, immunocytochemistry, cytoskeletal disruption assays (latrunculin, nocodazole), beta-catenin overexpression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding established by screen with functional localization studies using pharmacological perturbations and overexpression, single lab\",\n      \"pmids\": [\"12006665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"eIF3K interacts with the PML tumor suppressor protein. Interaction was identified by yeast two-hybrid screen using PML isoform I (PML-I) peptide sequences as bait, and confirmed by in vitro pull-down and in vivo co-immunoprecipitation and co-immunofluorescence in human cells. A novel eIF3K isoform (eIF3K-2) was identified that specifically co-localizes to PML nuclear bodies, particularly those enriched in PML-I, while eIF3K isoform 1 associates poorly with PML NBs. This identifies eIF3K as the first known eIF3 subunit to interact directly with PML.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, co-immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, pulldown, co-IP, co-IF) in a single lab study\",\n      \"pmids\": [\"24036361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function mutations in C. elegans eif-3.K (ortholog of EIF3K) extend lifespan by ~40% and confer enhanced resistance to ER stress without affecting bulk protein synthesis or growth rates. Lifespan extension requires the DAF-16 (FOXO) transcription factor. Enhanced ER stress resistance is independent of IRE-1-XBP-1, ATF-6, and PEK-1 pathways and also independent of DAF-16, indicating eIF3K and eIF3L accessory subunits have a distinct regulatory role in ER stress and aging responses.\",\n      \"method\": \"Loss-of-function genetics, lifespan assays, epistasis analysis with DAF-16, IRE-1, XBP-1, ATF-6, PEK-1 mutants, protein synthesis measurements\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with multiple epistasis experiments, orthogonal phenotypic readouts, and mechanistic pathway placement in a rigorous study\",\n      \"pmids\": [\"27690135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In teleost fish, eIF3K acts as a suppressor of the NF-κB pathway. Mechanistically, eIF3K expression (induced by Vibrio harveyi) enhances E3 ligase Nrdp1-mediated K27-linked ubiquitination of MyD88. eIF3K then bridges ubiquitin-tagged MyD88 to ATG5, forming a MyD88-eIF3k-ATG5 complex that is transported to the autophagosome for degradation, thereby terminating innate immune signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, overexpression and knockdown experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple co-IP and functional assays in a single lab study using a teleost fish model\",\n      \"pmids\": [\"35176284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Acute depletion of eIF3K promotes global translation, cell proliferation, tumor growth, and stress resistance by de-repressing the synthesis of ribosomal protein RPS15A. eIF3K and eIF3L form a mRNA-specific module that controls RPS15A translation by binding to the 5'-UTR of RPS15A mRNA; disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA negated the anabolic effects of eIF3K depletion. Ectopic expression of RPS15A mimicked the anabolic effects of eIF3K depletion. eIF3K and eIF3L are selectively downregulated in response to ER and oxidative stress, suggesting this module acts as a rheostat of ribosome content.\",\n      \"method\": \"Multiomic profiling (proteomics, translatome), acute depletion of eIF3 subunits, ectopic RPS15A expression, 5'-UTR binding disruption experiments, mathematical modeling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (multiomic profiling, functional rescue, 5'-UTR binding disruption, mathematical modeling) establishing a mechanistic pathway in a single rigorous study\",\n      \"pmids\": [\"37155573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homozygous variants in EIF3K (missense p.Asp43Gly and intronic c.355-13A>G) are associated with a neurodevelopmental syndrome. The intronic variant causes aberrant splicing of EIF3K pre-mRNA (insertion of 12 intronic base pairs, skipping of 2 exons) and significantly reduced EIF3K protein levels in patient skin fibroblasts, establishing that loss of EIF3K function underlies the phenotype.\",\n      \"method\": \"Whole exome/genome sequencing, RT-PCR splicing analysis, Western blot of patient fibroblasts, familial segregation analysis\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional validation of splice variant by RT-PCR and Western blot in patient cells, single study\",\n      \"pmids\": [\"40219605\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EIF3K is the smallest, non-essential subunit of the eukaryotic translation initiation factor 3 (eIF3) complex, harboring a HAM domain and a WH domain (crystal structure resolved); it associates with the 40S ribosomal subunit and directly contacts eIF3c, eIF3g, and eIF3j, but unlike core eIF3 subunits it acts as a mRNA-selective translational repressor—specifically suppressing RPS15A synthesis via binding to its 5'-UTR to restrain ribosome biogenesis—such that its loss paradoxically promotes global translation and stress resistance; outside the ribosomal context, eIF3K binds cyclin D3, PML nuclear bodies, the 5-HT7 receptor, and dynein intermediate chain, and serves as an autophagic receptor bridging K27-ubiquitinated MyD88 to ATG5 for degradation, thereby suppressing NF-κB innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF3K is the smallest subunit of the mammalian eIF3 translation initiation complex, integrating into the holocomplex through direct binary contacts with eIF3c, eIF3g, and eIF3j and co-sedimenting with eIF3 on 40S ribosomal subunits [#1]. Its crystal structure resolves two domains—a HEAT-analogous (HAM) domain and a winged-helix-like (WH) domain—that present discrete protein- and putative RNA-binding surfaces [#0]. Functionally, EIF3K is not a core processivity factor but an mRNA-selective regulator: together with eIF3L it forms a module that binds the 5'-UTR of RPS15A mRNA to repress its translation, so that acute EIF3K depletion de-represses RPS15A synthesis and thereby promotes global translation, proliferation, tumor growth, and stress resistance [#8]. Consistent with this restraining role, loss of the EIF3K ortholog in C. elegans extends lifespan via DAF-16/FOXO and confers ER-stress resistance independent of the canonical UPR branches and of DAF-16, without altering bulk protein synthesis [#6]. Beyond the ribosome, EIF3K engages partners across compartments—cyclin D3 [#2], the 5-HT7 receptor [#3], PML nuclear bodies via a dedicated isoform [#5], and cytoplasmic dynein intermediate chain at actin-dependent cortical sites of cell-cell contact [#4]—and acts as an autophagic adaptor bridging K27-ubiquitinated MyD88 to ATG5 to suppress NF-\\u03baB innate immune signaling [#7]. Homozygous loss-of-function EIF3K variants underlie a neurodevelopmental syndrome [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Before its assignment to eIF3, the protein (PLAC-24) was first characterized as a direct dynein-associated factor, establishing an extra-ribosomal cytoskeletal/junctional context for EIF3K.\",\n      \"evidence\": \"Protein interaction screen and immunocytochemistry with cytoskeletal disruption and beta-catenin overexpression in epithelial cells\",\n      \"pmids\": [\"12006665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of dynein binding for translation or transport unresolved\", \"Relationship between cortical recruitment and eIF3 holocomplex membership unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying EIF3K as the twelfth eIF3 subunit with defined binary contacts placed it structurally within the initiation machinery and established its core interaction partners.\",\n      \"evidence\": \"Co-IP, affinity purification, sucrose gradient cosedimentation, baculovirus reconstitution, and GST pull-down in mammalian/insect systems\",\n      \"pmids\": [\"14519125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EIF3K is required for eIF3 activity not tested\", \"Functional role distinct from scaffolding not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The crystal structure defined EIF3K's two-domain architecture and mapped candidate binding surfaces, providing the structural basis for its protein and RNA interactions.\",\n      \"evidence\": \"X-ray crystallography with structural comparison and sequence conservation analysis\",\n      \"pmids\": [\"15180986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding activity inferred from structure but not demonstrated biochemically\", \"Specific partners contacting each surface not identified structurally\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking EIF3K to cyclin D3 connected it to cell-cycle-coupled control of translational output.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, and confocal colocalization in human cells\",\n      \"pmids\": [\"15327989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cyclin D3 acts through EIF3K to upregulate translation not directly shown\", \"Nuclear vs cytoplasmic function of the interaction unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating EIF3K binding to the 5-HT7 receptor and driving its plasma-membrane relocalization extended its extra-ribosomal roles to receptor expression and trafficking.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, deletion mapping, and immunofluorescence in COS-7 cells\",\n      \"pmids\": [\"16935469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EIF3K increases receptor levels (translation vs stability) not distinguished\", \"Physiological relevance in neurons not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying an EIF3K isoform that targets PML nuclear bodies linked the protein to a nuclear tumor-suppressor compartment.\",\n      \"evidence\": \"Yeast two-hybrid with PML-I bait, in vitro pull-down, co-IP, and co-immunofluorescence in human cells\",\n      \"pmids\": [\"24036361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of EIF3K at PML bodies unknown\", \"Whether isoform-specific localization affects translation unexamined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic loss of the EIF3K ortholog extending lifespan and ER-stress resistance without altering bulk translation revealed a dedicated regulatory, rather than essential, role for the accessory subunit.\",\n      \"evidence\": \"Loss-of-function genetics, lifespan and stress assays, and epistasis with DAF-16/UPR mutants in C. elegans\",\n      \"pmids\": [\"27690135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target mediating lifespan/stress effects not identified in this study\", \"DAF-16-dependent lifespan vs DAF-16-independent stress resistance not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining EIF3K as an autophagic adaptor bridging K27-ubiquitinated MyD88 to ATG5 established a translation-independent role in terminating NF-\\u03baB innate immune signaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, autophagy flux assays, and gain/loss-of-function in teleost fish\",\n      \"pmids\": [\"35176284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of the MyD88-EIF3K-ATG5 axis in mammals not established\", \"Domain of EIF3K mediating ubiquitin/ATG5 bridging not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that the EIF3K/eIF3L module represses RPS15A translation via its 5'-UTR provided the central mechanism: EIF3K is an mRNA-selective brake on ribosome biogenesis whose loss drives anabolic, pro-growth output.\",\n      \"evidence\": \"Multiomic profiling, acute subunit depletion, ectopic RPS15A rescue, 5'-UTR binding disruption, and mathematical modeling\",\n      \"pmids\": [\"37155573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA contact by EIF3K vs eIF3L not separated\", \"Signal coupling stress to EIF3K/eIF3L downregulation undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying homozygous loss-of-function EIF3K variants in a neurodevelopmental syndrome established the gene's physiological requirement in humans.\",\n      \"evidence\": \"Exome/genome sequencing, RT-PCR splicing analysis, Western blot of patient fibroblasts, and familial segregation\",\n      \"pmids\": [\"40219605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular pathway linking EIF3K loss to neurodevelopmental phenotype not defined\", \"Whether RPS15A de-repression contributes to disease unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EIF3K's many extra-ribosomal interactions (dynein, cyclin D3, 5-HT7, PML, MyD88-ATG5) integrate with its core role as an mRNA-selective translational repressor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking ribosomal and non-ribosomal functions\", \"Tissue- and isoform-specific deployment of EIF3K functions uncharacterized\", \"Mammalian validation of the autophagy/NF-\\u03baB role absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [8, 1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72613\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"eIF3\"],\n    \"partners\": [\"EIF3C\", \"EIF3G\", \"EIF3J\", \"EIF3L\", \"CCND3\", \"HTR7\", \"PML\", \"MYD88\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}