{"gene":"EXOSC5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2010,"finding":"Human Rrp46 (hRrp46/EXOSC5) forms homodimers both as a recombinant protein and in a cellular environment (in addition to its association with the exosome complex), but lacks detectable nuclease activity despite binding DNA. Crystal structure of rice Rrp46 (oRrp46) at 2.0 Å resolution revealed that dimeric oRrp46 has both phosphorolytic RNase and hydrolytic DNase activities; site-directed mutagenesis (E160Q abolished DNase; K75E/Q76E abolished RNase) confirmed critical catalytic/substrate-binding residues.","method":"Crystal structure determination (X-ray crystallography at 2.0 Å), site-directed mutagenesis, in vitro nuclease assays, Co-IP/homodimerization assay in cellular extracts","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vitro enzymatic assays in one study; multiple orthogonal methods establishing structure-function relationships","pmids":["20660080"],"is_preprint":false},{"year":2020,"finding":"EXOSC5 is a structural subunit of the RNA exosome complex; pathogenic missense variants (p.Thr114Ile, p.Leu206His, p.Met148Thr) modeled in budding yeast and mammalian cells cause defects in RNA exosome function and altered interactions with other RNA exosome subunits. Loss of exosc5 in zebrafish produces developmental abnormalities (shortened/curved bodies, reduced head/eye size, edema), establishing a required role in development.","method":"Yeast and mammalian cell modeling of patient variants, RNA exosome functional assays, zebrafish loss-of-function (morpholino/genetic), interaction assays with exosome subunits","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary approaches (yeast modeling, mammalian cells, zebrafish KO) from a single lab; functional and interaction readouts","pmids":["32504085"],"is_preprint":false},{"year":2022,"finding":"EXOSC5 knockdown in gastric cancer cells reduces cyclin D1 expression and increases p21 and p27 levels, causing G1/S cell cycle arrest, via modulation of AKT and STAT3 signaling pathways.","method":"siRNA knockdown, Western blot, CCK-8/colony formation assays, flow cytometry, in vivo xenograft","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily knockdown with pathway readout by Western blot; no direct mechanistic reconstitution","pmids":["35371329"],"is_preprint":false},{"year":2022,"finding":"EXOSC5 knockdown in hepatocellular carcinoma cell lines reduces cell proliferation, and this effect is associated with reduced STAT3 activation, placing EXOSC5 upstream of STAT3 in promoting HCC cell growth.","method":"siRNA knockdown, Western blot, cell proliferation assays","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (knockdown + pathway Western blot), no mechanistic reconstitution","pmids":["36293016"],"is_preprint":false},{"year":2024,"finding":"EXOSC5 knockdown in endometrial cancer cells reduces NTN4 (netrin-4) expression; NTN4 acts as a secreted ligand that binds integrin β1 and activates the FAK/SRC axis to elevate c-MYC activity, thereby maintaining cancer stem cell self-renewal. EXOSC5 thus promotes EC cancer stem cell activity upstream of the NTN4/integrin β1/FAK/SRC/c-MYC pathway.","method":"siRNA knockdown, exogenous NTN4 treatment, Western blot, tumor sphere assays, in vivo tumorigenicity assay","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by knockdown and rescue with recombinant protein, no direct binding/reconstitution of EXOSC5 in the pathway","pmids":["38164180"],"is_preprint":false}],"current_model":"EXOSC5 (hRrp46p) is a structural subunit of the RNA exosome complex that forms homodimers independently of the complex and lacks intrinsic nuclease activity in humans; pathogenic variants disrupt RNA exosome function and inter-subunit interactions, causing neurodevelopmental disease, while in cancer contexts EXOSC5 has been placed upstream of STAT3 and NTN4/integrin β1 signaling to promote proliferation and stemness, though the direct molecular mechanism linking its exosome function to these downstream pathways remains unresolved."},"narrative":{"mechanistic_narrative":"EXOSC5 (hRrp46) is a structural subunit of the RNA exosome complex required for normal RNA processing and development [PMID:32504085]. The human protein forms homodimers both as a recombinant protein and in cellular extracts and binds DNA, but lacks detectable intrinsic nuclease activity, in contrast to the rice ortholog oRrp46 whose dimeric form possesses both phosphorolytic RNase and hydrolytic DNase activities dependent on identified catalytic and substrate-binding residues [PMID:20660080]. Pathogenic missense variants modeled in yeast and mammalian cells disrupt RNA exosome function and alter interactions with other exosome subunits, and loss of exosc5 in zebrafish produces developmental abnormalities including shortened/curved bodies and reduced head and eye size, establishing a required developmental role [PMID:32504085]. The direct molecular link between EXOSC5's exosome function and the downstream proliferative and stemness phenotypes reported in cancer contexts has not been characterized in the available corpus.","teleology":[{"year":2010,"claim":"It was unknown whether human Rrp46 carried intrinsic catalytic activity or behaved purely as a structural subunit; comparison of the human protein with the rice ortholog established that human EXOSC5 dimerizes and binds DNA but lacks nuclease activity, whereas the catalytic machinery is preserved and structurally defined in the plant ortholog.","evidence":"X-ray crystal structure of rice Rrp46 at 2.0 Å, site-directed mutagenesis of catalytic residues, in vitro nuclease assays, and homodimerization Co-IP in human cell extracts","pmids":["20660080"],"confidence":"High","gaps":["No structure of the human EXOSC5 protein itself","Why human EXOSC5 lacks the nuclease activity retained in the rice ortholog is not resolved","Functional consequence of EXOSC5 homodimerization independent of the exosome is undefined"]},{"year":2020,"claim":"It was unknown whether EXOSC5 variants cause human disease and how they affect the exosome; modeling of patient missense variants and zebrafish loss-of-function established EXOSC5 as a structural exosome subunit whose disruption impairs exosome function, alters inter-subunit interactions, and is required for normal development.","evidence":"Yeast and mammalian cell modeling of patient variants, RNA exosome functional and interaction assays, and zebrafish loss-of-function","pmids":["32504085"],"confidence":"Medium","gaps":["Specific RNA substrates mis-processed upon EXOSC5 disruption not defined","Tissue-specific basis of the neurodevelopmental phenotype unresolved","Quantitative effect of each variant on exosome assembly not separated from activity defects"]},{"year":2022,"claim":"It was unknown whether EXOSC5 influences tumor cell proliferation; knockdown in gastric and hepatocellular carcinoma cells linked EXOSC5 to cell cycle progression and STAT3/AKT signaling, placing it upstream of proliferative pathways in cancer.","evidence":"siRNA knockdown with Western blot, proliferation/colony formation assays, flow cytometry cell cycle analysis, and xenografts in gastric and HCC cells","pmids":["35371329","36293016"],"confidence":"Low","gaps":["No mechanistic reconstitution connecting exosome function to STAT3/AKT","Single-lab knockdown studies without rescue or direct molecular interaction data","Whether the effect depends on exosome RNA processing is untested"]},{"year":2024,"claim":"It was unknown how EXOSC5 might support cancer stem cell behavior; knockdown in endometrial cancer cells reduced NTN4 expression and placed EXOSC5 upstream of an NTN4/integrin β1/FAK/SRC/c-MYC self-renewal axis.","evidence":"siRNA knockdown, exogenous NTN4 rescue, Western blot, tumor sphere assays, and in vivo tumorigenicity assays","pmids":["38164180"],"confidence":"Low","gaps":["No direct binding or reconstitution of EXOSC5 within the NTN4 pathway","Mechanism by which an exosome subunit controls NTN4 transcript or protein levels unknown","Single-lab pathway-placement study"]},{"year":null,"claim":"The direct molecular mechanism connecting EXOSC5's RNA exosome function to the downstream STAT3 and NTN4/integrin β1 signaling outputs observed in cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No RNA substrate identified that bridges exosome activity to these signaling pathways","No reconstitution or direct interaction data linking EXOSC5 to the cancer pathways","Whether oncogenic effects require an intact exosome complex is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1]}],"complexes":["RNA exosome"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQT4","full_name":"Exosome complex component RRP46","aliases":["Chronic myelogenous leukemia tumor antigen 28","Exosome component 5","Ribosomal RNA-processing protein 46","p12B"],"length_aa":235,"mass_kda":25.2,"function":"Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes (PubMed:11782436, PubMed:21269460). In vitro, EXOSC5 does not bind or digest single-stranded RNA and binds to double-stranded DNA without detectable DNase activity (PubMed:20660080)","subcellular_location":"Nucleus, nucleolus; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NQT4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOSC5","classification":"Common Essential","n_dependent_lines":1120,"n_total_lines":1208,"dependency_fraction":0.9271523178807947},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RBM7","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EXOSC5","total_profiled":1310},"omim":[{"mim_id":"619576","title":"CEREBELLAR ATAXIA, BRAIN ABNORMALITIES, AND CARDIAC CONDUCTION DEFECTS; CABAC","url":"https://www.omim.org/entry/619576"},{"mim_id":"606492","title":"EXOSOME COMPONENT 5; EXOSC5","url":"https://www.omim.org/entry/606492"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EXOSC5"},"hgnc":{"alias_symbol":["hRrp46p","Rrp46p","RRP46","RRP41B","MGC12901","p12B"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQT4","domains":[{"cath_id":"3.30.230.70","chopping":"32-234","consensus_level":"medium","plddt":92.0218,"start":32,"end":234}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQT4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQT4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQT4-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOSC5","jax_strain_url":"https://www.jax.org/strain/search?query=EXOSC5"},"sequence":{"accession":"Q9NQT4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQT4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQT4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQT4"}},"corpus_meta":[{"pmid":"32504085","id":"PMC_32504085","title":"Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32504085","citation_count":29,"is_preprint":false},{"pmid":"19861556","id":"PMC_19861556","title":"Transcript-based cloning of RRP46, a regulator of rRNA processing and R gene-independent cell death in barley-powdery mildew interactions.","date":"2009","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/19861556","citation_count":22,"is_preprint":false},{"pmid":"20660080","id":"PMC_20660080","title":"Structural and biochemical characterization of CRN-5 and Rrp46: an exosome component participating in apoptotic DNA degradation.","date":"2010","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20660080","citation_count":12,"is_preprint":false},{"pmid":"34089229","id":"PMC_34089229","title":"Risk of sudden cardiac death in EXOSC5-related disease.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34089229","citation_count":12,"is_preprint":false},{"pmid":"38164180","id":"PMC_38164180","title":"EXOSC5 maintains cancer stem cell activity in endometrial cancer by regulating the NTN4/integrin β1 signalling axis.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38164180","citation_count":11,"is_preprint":false},{"pmid":"35371329","id":"PMC_35371329","title":"EXOSC5 promotes proliferation of gastric cancer through regulating AKT/STAT3 signaling pathways.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35371329","citation_count":10,"is_preprint":false},{"pmid":"36293016","id":"PMC_36293016","title":"Integrated Bioinformatic Investigation of EXOSCs in Hepatocellular Carcinoma Followed by the Preliminary Validation of EXOSC5 in Cell Proliferation.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36293016","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6032,"output_tokens":1405,"usd":0.019585,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8121,"output_tokens":2073,"usd":0.046215,"stage2_stop_reason":"end_turn"},"total_usd":0.0658,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Human Rrp46 (hRrp46/EXOSC5) forms homodimers both as a recombinant protein and in a cellular environment (in addition to its association with the exosome complex), but lacks detectable nuclease activity despite binding DNA. Crystal structure of rice Rrp46 (oRrp46) at 2.0 Å resolution revealed that dimeric oRrp46 has both phosphorolytic RNase and hydrolytic DNase activities; site-directed mutagenesis (E160Q abolished DNase; K75E/Q76E abolished RNase) confirmed critical catalytic/substrate-binding residues.\",\n      \"method\": \"Crystal structure determination (X-ray crystallography at 2.0 Å), site-directed mutagenesis, in vitro nuclease assays, Co-IP/homodimerization assay in cellular extracts\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vitro enzymatic assays in one study; multiple orthogonal methods establishing structure-function relationships\",\n      \"pmids\": [\"20660080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EXOSC5 is a structural subunit of the RNA exosome complex; pathogenic missense variants (p.Thr114Ile, p.Leu206His, p.Met148Thr) modeled in budding yeast and mammalian cells cause defects in RNA exosome function and altered interactions with other RNA exosome subunits. Loss of exosc5 in zebrafish produces developmental abnormalities (shortened/curved bodies, reduced head/eye size, edema), establishing a required role in development.\",\n      \"method\": \"Yeast and mammalian cell modeling of patient variants, RNA exosome functional assays, zebrafish loss-of-function (morpholino/genetic), interaction assays with exosome subunits\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary approaches (yeast modeling, mammalian cells, zebrafish KO) from a single lab; functional and interaction readouts\",\n      \"pmids\": [\"32504085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EXOSC5 knockdown in gastric cancer cells reduces cyclin D1 expression and increases p21 and p27 levels, causing G1/S cell cycle arrest, via modulation of AKT and STAT3 signaling pathways.\",\n      \"method\": \"siRNA knockdown, Western blot, CCK-8/colony formation assays, flow cytometry, in vivo xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily knockdown with pathway readout by Western blot; no direct mechanistic reconstitution\",\n      \"pmids\": [\"35371329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EXOSC5 knockdown in hepatocellular carcinoma cell lines reduces cell proliferation, and this effect is associated with reduced STAT3 activation, placing EXOSC5 upstream of STAT3 in promoting HCC cell growth.\",\n      \"method\": \"siRNA knockdown, Western blot, cell proliferation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (knockdown + pathway Western blot), no mechanistic reconstitution\",\n      \"pmids\": [\"36293016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EXOSC5 knockdown in endometrial cancer cells reduces NTN4 (netrin-4) expression; NTN4 acts as a secreted ligand that binds integrin β1 and activates the FAK/SRC axis to elevate c-MYC activity, thereby maintaining cancer stem cell self-renewal. EXOSC5 thus promotes EC cancer stem cell activity upstream of the NTN4/integrin β1/FAK/SRC/c-MYC pathway.\",\n      \"method\": \"siRNA knockdown, exogenous NTN4 treatment, Western blot, tumor sphere assays, in vivo tumorigenicity assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by knockdown and rescue with recombinant protein, no direct binding/reconstitution of EXOSC5 in the pathway\",\n      \"pmids\": [\"38164180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOSC5 (hRrp46p) is a structural subunit of the RNA exosome complex that forms homodimers independently of the complex and lacks intrinsic nuclease activity in humans; pathogenic variants disrupt RNA exosome function and inter-subunit interactions, causing neurodevelopmental disease, while in cancer contexts EXOSC5 has been placed upstream of STAT3 and NTN4/integrin β1 signaling to promote proliferation and stemness, though the direct molecular mechanism linking its exosome function to these downstream pathways remains unresolved.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOSC5 (hRrp46) is a structural subunit of the RNA exosome complex required for normal RNA processing and development [#1]. The human protein forms homodimers both as a recombinant protein and in cellular extracts and binds DNA, but lacks detectable intrinsic nuclease activity, in contrast to the rice ortholog oRrp46 whose dimeric form possesses both phosphorolytic RNase and hydrolytic DNase activities dependent on identified catalytic and substrate-binding residues [#0]. Pathogenic missense variants modeled in yeast and mammalian cells disrupt RNA exosome function and alter interactions with other exosome subunits, and loss of exosc5 in zebrafish produces developmental abnormalities including shortened/curved bodies and reduced head and eye size, establishing a required developmental role [#1]. The direct molecular link between EXOSC5's exosome function and the downstream proliferative and stemness phenotypes reported in cancer contexts has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"It was unknown whether human Rrp46 carried intrinsic catalytic activity or behaved purely as a structural subunit; comparison of the human protein with the rice ortholog established that human EXOSC5 dimerizes and binds DNA but lacks nuclease activity, whereas the catalytic machinery is preserved and structurally defined in the plant ortholog.\",\n      \"evidence\": \"X-ray crystal structure of rice Rrp46 at 2.0 \\u00c5, site-directed mutagenesis of catalytic residues, in vitro nuclease assays, and homodimerization Co-IP in human cell extracts\",\n      \"pmids\": [\"20660080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the human EXOSC5 protein itself\",\n        \"Why human EXOSC5 lacks the nuclease activity retained in the rice ortholog is not resolved\",\n        \"Functional consequence of EXOSC5 homodimerization independent of the exosome is undefined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"It was unknown whether EXOSC5 variants cause human disease and how they affect the exosome; modeling of patient missense variants and zebrafish loss-of-function established EXOSC5 as a structural exosome subunit whose disruption impairs exosome function, alters inter-subunit interactions, and is required for normal development.\",\n      \"evidence\": \"Yeast and mammalian cell modeling of patient variants, RNA exosome functional and interaction assays, and zebrafish loss-of-function\",\n      \"pmids\": [\"32504085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific RNA substrates mis-processed upon EXOSC5 disruption not defined\",\n        \"Tissue-specific basis of the neurodevelopmental phenotype unresolved\",\n        \"Quantitative effect of each variant on exosome assembly not separated from activity defects\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"It was unknown whether EXOSC5 influences tumor cell proliferation; knockdown in gastric and hepatocellular carcinoma cells linked EXOSC5 to cell cycle progression and STAT3/AKT signaling, placing it upstream of proliferative pathways in cancer.\",\n      \"evidence\": \"siRNA knockdown with Western blot, proliferation/colony formation assays, flow cytometry cell cycle analysis, and xenografts in gastric and HCC cells\",\n      \"pmids\": [\"35371329\", \"36293016\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mechanistic reconstitution connecting exosome function to STAT3/AKT\",\n        \"Single-lab knockdown studies without rescue or direct molecular interaction data\",\n        \"Whether the effect depends on exosome RNA processing is untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"It was unknown how EXOSC5 might support cancer stem cell behavior; knockdown in endometrial cancer cells reduced NTN4 expression and placed EXOSC5 upstream of an NTN4/integrin \\u03b21/FAK/SRC/c-MYC self-renewal axis.\",\n      \"evidence\": \"siRNA knockdown, exogenous NTN4 rescue, Western blot, tumor sphere assays, and in vivo tumorigenicity assays\",\n      \"pmids\": [\"38164180\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct binding or reconstitution of EXOSC5 within the NTN4 pathway\",\n        \"Mechanism by which an exosome subunit controls NTN4 transcript or protein levels unknown\",\n        \"Single-lab pathway-placement study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular mechanism connecting EXOSC5's RNA exosome function to the downstream STAT3 and NTN4/integrin \\u03b21 signaling outputs observed in cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No RNA substrate identified that bridges exosome activity to these signaling pathways\",\n        \"No reconstitution or direct interaction data linking EXOSC5 to the cancer pathways\",\n        \"Whether oncogenic effects require an intact exosome complex is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"RNA exosome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}