{"gene":"INTS10","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2020,"finding":"INTS10, INTS13 (Asunder), and INTS14 form a separable, functional module of the Integrator complex. The INTS13-INTS14 sub-complex adopts a strongly entwined structure with a unique chain interlink and structural homology to the Ku70-Ku80 DNA repair complex. The module binds DNA and RNA with preference for RNA hairpins, plays an accessory role in snRNA 3'-end maturation, and has a stronger influence on transcription termination after pausing. INTS13 directly binds Integrator's cleavage module via a conserved C-terminal motif.","method":"Biochemical reconstitution, X-ray crystallography, RNA/DNA binding assays, cross-linking mass spectrometry, in vivo functional assays (snRNA processing, transcription termination)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + reconstitution + functional assays in single study with multiple orthogonal methods","pmids":["32647223"],"is_preprint":false},{"year":2021,"finding":"INTS10, INTS13, and INTS14 form a biochemically separable subcomplex of Integrator. Cryo-EM structure of the INTS4/9/11 catalytic core at 3.5 Å reveals the spatial organization of catalytic nuclease INTS11 bound to its catalytically impaired homolog INTS9 via multiple interdependent interfaces, with INTS4 (a helical repeat protein) stabilizing the nuclease domains; all three form a composite electropositive groove suggesting RNA binding.","method":"Cryo-EM structure determination (3.5 Å), biochemical subcomplex characterization","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with biochemical validation of INTS10/13/14 module","pmids":["33548203"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the complete Integrator-PP2A complex reveal that the INTS10-INTS13-INTS14-INTS15 module adopts a scorpion-tail shape in a pre-termination complex and that its 'sting' may open the DSIF DNA clamp to facilitate Pol II termination. Three functional states were resolved: pre-termination, post-termination, and a free inactive closed conformation.","method":"Cryo-EM structure determination of multiple functional states of the complete Integrator-PP2A complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — multiple cryo-EM structures with mechanistic model for INTS10-containing module in termination","pmids":["38570683"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of human INTS10/13/14/15 and INTS5/8/10/15 sub-complexes were determined. INTS10 participates in two distinct sub-complexes within Integrator. An integrative model of fully assembled Integrator bound to the paused elongation complex was built, and INTS13 was identified as a platform for recruitment of transcription factors (e.g., ZNF655) to modulate Integrator association at specific loci.","method":"Cryo-EM structure determination of sub-complexes, in silico protein-protein interaction screen, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of INTS10-containing modules with functional interaction mapping","pmids":["38823386"],"is_preprint":false},{"year":2016,"finding":"INTS10 suppresses HBV replication via IRF3 in liver cells. INTS10 protein levels are significantly decreased in persistently HBV-infected subjects compared to spontaneously recovered subjects and negatively correlate with HBV load.","method":"In vitro HBV replication assay in liver cells with INTS10 manipulation, eQTL analysis, clinical sample correlation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro loss-of-function assay in liver cells with mechanistic link to IRF3, single lab","pmids":["27244555"],"is_preprint":false},{"year":2024,"finding":"Depletion of the INTS10 subunit of Integrator disrupts neural fate specification: INTS10 knockdown upends neural traits and redirects cells towards mesenchymal identity. The INTS10-containing enhancer module stabilizes SOX2 binding at chromatin upon exit from pluripotency and promotes epigenetic changes at neural enhancers.","method":"INTS10 siRNA/shRNA depletion, ChIP-seq, ATAC-seq, transcriptomic profiling during neural differentiation","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular phenotype (cell fate) and chromatin-level mechanistic readout, single lab","pmids":["39592860"],"is_preprint":false},{"year":2026,"finding":"Coxsackievirus B3 protease 3C (3Cpro) cleaves INTS10 at residue Q221. Depletion of INTS10 enhances CVB3 replication and blocks snRNA (U1, U2) processing. Overexpression of U1 snRNA inhibits CVB3 infection while knockdown promotes it, indicating that 3Cpro-mediated cleavage of INTS10 disrupts U snRNA processing to subvert host antiviral defenses.","method":"Protease cleavage assay, site-directed mutagenesis (Q221 cleavage site), INTS10 depletion/overexpression, snRNA manipulation, viral replication assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro cleavage assay with mutagenesis plus functional snRNA rescue experiments, single lab","pmids":["41596640"],"is_preprint":false},{"year":2023,"finding":"Compound heterozygous mutations in RNU4ATAC (encoding U4atac snRNA) cause aberrant splicing of minor introns in INTS10 (and INTS7), leading to reduced INTS10 protein levels and altered assembly of Integrator subunits in patient-derived lymphoblastoid cells.","method":"RT-PCR of minor intron splicing, western blot of protein levels, Integrator co-immunoprecipitation/assembly assay in patient cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — patient cell experiments with multiple readouts linking U4atac mutations to INTS10 processing and Integrator assembly","pmids":["36537210"],"is_preprint":false}],"current_model":"INTS10 is a structural and functional subunit of the metazoan Integrator complex that, together with INTS13 and INTS14 (and INTS15), forms a nucleic-acid-binding 'enhancer module' with a scorpion-tail architecture that contacts the DSIF DNA clamp to facilitate RNA Pol II termination, stabilizes transcription factor (e.g., SOX2) binding at neural enhancers to direct cell fate, and suppresses HBV replication via IRF3; its activity is targeted by viral proteases (CVB3 3Cpro cleaves it at Q221 to disrupt snRNA processing) and its expression depends on correct minor intron splicing."},"narrative":{"teleology":[{"year":2016,"claim":"Before a structural or mechanistic role for INTS10 within Integrator was defined, its antiviral function was identified: INTS10 suppresses HBV replication through IRF3 in liver cells, establishing a link between this Integrator subunit and innate immune signaling.","evidence":"HBV replication assays with INTS10 manipulation in liver cells, eQTL analysis, and clinical sample correlation","pmids":["27244555"],"confidence":"Medium","gaps":["Mechanism by which INTS10 activates or cooperates with IRF3 is undefined","Whether this antiviral function requires the intact Integrator complex or is autonomous","Single-lab finding without independent replication"]},{"year":2020,"claim":"The first biochemical and structural demonstration that INTS10, INTS13, and INTS14 form a separable functional module within Integrator answered how the complex is organized modularly: the module binds nucleic acids (preferring RNA hairpins), contributes to snRNA 3′-end processing, and has a stronger role in transcription termination than in cleavage per se.","evidence":"X-ray crystallography of INTS13–INTS14 dimer, reconstitution of the trimeric module, RNA/DNA binding assays, cross-linking mass spectrometry, and in vivo snRNA processing and termination assays","pmids":["32647223"],"confidence":"High","gaps":["INTS10's direct contacts within the module were not resolved at atomic level","How the module docks onto the Pol II elongation complex was unknown","Whether additional subunits (e.g., INTS15) complete the module"]},{"year":2021,"claim":"Cryo-EM of the INTS4/9/11 catalytic core confirmed that INTS10/13/14 is biochemically separable from the cleavage module, establishing the principle that Integrator is composed of distinct, modular enzymatic and regulatory assemblies.","evidence":"3.5 Å cryo-EM structure of catalytic core and biochemical fractionation of subcomplexes","pmids":["33548203"],"confidence":"High","gaps":["How the INTS10-containing module communicates with the catalytic module during termination","No structure of the INTS10 module in isolation at high resolution"]},{"year":2023,"claim":"Patient-derived cells carrying U4atac snRNA mutations revealed that INTS10 expression depends on correct minor intron splicing, providing a genetic explanation for how minor spliceosome dysfunction can propagate into Integrator assembly defects.","evidence":"RT-PCR of minor intron retention in INTS10 transcripts, western blot for reduced protein, and co-IP showing altered Integrator assembly in RNU4ATAC-mutant lymphoblastoid cells","pmids":["36537210"],"confidence":"Medium","gaps":["Whether reduced INTS10 alone accounts for the Integrator assembly defect or whether concurrent INTS7 reduction contributes","Functional consequences for snRNA processing and termination in these patient cells were not tested"]},{"year":2024,"claim":"Cryo-EM structures of the complete Integrator–PP2A complex in three functional states revealed that the INTS10/13/14/15 module adopts a scorpion-tail architecture whose 'sting' opens the DSIF DNA clamp, providing a direct mechanistic model for how this module promotes Pol II termination.","evidence":"Cryo-EM of pre-termination, post-termination, and free inactive states of Integrator–PP2A","pmids":["38570683"],"confidence":"High","gaps":["Mutational validation of the scorpion-tail sting contact with DSIF","Whether the conformational switch between states is regulated by post-translational modifications"]},{"year":2024,"claim":"Structures of INTS10-containing sub-complexes (INTS10/13/14/15 and INTS5/8/10/15) showed INTS10 bridges two distinct modules, and INTS13 was identified as a platform recruiting transcription factors such as ZNF655, revealing how Integrator achieves locus-specific targeting.","evidence":"Cryo-EM of sub-complexes, in silico PPI screen, co-immunoprecipitation","pmids":["38823386"],"confidence":"High","gaps":["Functional consequence of disrupting the INTS5/8/10/15 interface specifically","How ZNF655 recruitment translates into gene-specific transcriptional outcomes"]},{"year":2024,"claim":"Depletion of INTS10 redirected differentiating cells from neural to mesenchymal fate, demonstrating that the enhancer module stabilizes SOX2 at neural enhancers during pluripotency exit, thereby linking Integrator's termination function to cell fate decisions.","evidence":"siRNA/shRNA knockdown of INTS10 during neural differentiation, ChIP-seq for SOX2, ATAC-seq, and transcriptomic profiling","pmids":["39592860"],"confidence":"Medium","gaps":["Whether INTS10's role in neural specification is independent of its termination function","Whether other enhancer-module subunits phenocopy the fate switch upon individual depletion"]},{"year":2026,"claim":"Identification of CVB3 3Cpro cleavage of INTS10 at Q221 established that viruses directly target the Integrator enhancer module to disable U snRNA processing, connecting INTS10's structural role to host–pathogen defense.","evidence":"In vitro protease cleavage assay, Q221 site-directed mutagenesis, INTS10 depletion/overexpression, snRNA manipulation, and viral replication assays","pmids":["41596640"],"confidence":"Medium","gaps":["Whether cleavage at Q221 disrupts the INTS10/13/14/15 module architecture specifically or Integrator assembly globally","In vivo validation in animal models of CVB3 infection"]},{"year":null,"claim":"The direct structural contacts of INTS10 within the scorpion-tail module and at the DSIF interface lack mutational validation, and the relationship between INTS10's roles in termination, enhancer regulation, and innate antiviral defense remains unintegrated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of INTS10 alone or with defined interaction surfaces mutated","Whether INTS10's anti-HBV/IRF3 function operates through Integrator or independently","How the dual module membership of INTS10 (INTS10/13/14/15 and INTS5/8/10/15) is coordinated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":["Integrator complex","INTS10/INTS13/INTS14/INTS15 module","INTS5/INTS8/INTS10/INTS15 module"],"partners":["INTS13","INTS14","INTS15","INTS5","INTS8","SOX2","IRF3"],"other_free_text":[]},"mechanistic_narrative":"INTS10 is a structural subunit of the metazoan Integrator complex that participates in RNA polymerase II transcription termination, snRNA 3′-end processing, and enhancer-mediated gene regulation. Together with INTS13, INTS14, and INTS15, INTS10 forms a separable nucleic-acid-binding module that adopts a scorpion-tail architecture and contacts the DSIF DNA clamp to facilitate Pol II termination at paused genes; INTS10 also bridges a second sub-complex (INTS5/8/10/15), positioning it at the interface of distinct Integrator functional modules [PMID:32647223, PMID:38570683, PMID:38823386]. This enhancer module stabilizes SOX2 binding at neural enhancers during exit from pluripotency, directing cells toward neural rather than mesenchymal fate, and INTS10 loss disrupts this specification [PMID:39592860]. INTS10 is targeted by Coxsackievirus B3 protease 3Cpro, which cleaves it at Q221 to impair U snRNA processing and promote viral replication, while in hepatocytes INTS10 suppresses HBV replication via IRF3 [PMID:41596640, PMID:27244555]."},"prefetch_data":{"uniprot":{"accession":"Q9NVR2","full_name":"Integrator complex subunit 10","aliases":[],"length_aa":710,"mass_kda":82.2,"function":"Component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes (PubMed:38570683, PubMed:38823386). The integrator complex provides a quality checkpoint during transcription elongation by driving premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: the complex terminates transcription by (1) catalyzing dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A/RPB1 and SUPT5H/SPT5, (2) degrading the exiting nascent RNA transcript via endonuclease activity and (3) promoting the release of Pol II from bound DNA (PubMed:38570683). The integrator complex is also involved in terminating the synthesis of non-coding Pol II transcripts, such as enhancer RNAs (eRNAs), small nuclear RNAs (snRNAs), telomerase RNAs and long non-coding RNAs (lncRNAs) (PubMed:16239144, PubMed:32647223). Within the integrator complex, INTS10 is part of the integrator tail module that acts as a platform for the recruitment of transcription factors at promoters (PubMed:38823386). May be not involved in the recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex (PubMed:23904267)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NVR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INTS10","classification":"Not Classified","n_dependent_lines":503,"n_total_lines":1208,"dependency_fraction":0.4163907284768212},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SUPT5H","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/INTS10","total_profiled":1310},"omim":[{"mim_id":"621239","title":"INTEGRATOR COMPLEX SUBUNIT 15; INTS15","url":"https://www.omim.org/entry/621239"},{"mim_id":"620878","title":"INTEGRATOR COMPLEX SUBUNIT 14; INTS14","url":"https://www.omim.org/entry/620878"},{"mim_id":"615079","title":"INTEGRATOR COMPLEX SUBUNIT 13; INTS13","url":"https://www.omim.org/entry/615079"},{"mim_id":"611353","title":"INTEGRATOR COMPLEX SUBUNIT 10; INTS10","url":"https://www.omim.org/entry/611353"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INTS10"},"hgnc":{"alias_symbol":["FLJ10569","INT10"],"prev_symbol":["C8orf35"]},"alphafold":{"accession":"Q9NVR2","domains":[{"cath_id":"-","chopping":"612-710","consensus_level":"medium","plddt":83.6762,"start":612,"end":710}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVR2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVR2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVR2-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTS10","jax_strain_url":"https://www.jax.org/strain/search?query=INTS10"},"sequence":{"accession":"Q9NVR2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVR2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVR2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVR2"}},"corpus_meta":[{"pmid":"22076464","id":"PMC_22076464","title":"Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.","date":"2011","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/22076464","citation_count":94,"is_preprint":false},{"pmid":"25555482","id":"PMC_25555482","title":"Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.","date":"2014","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25555482","citation_count":72,"is_preprint":false},{"pmid":"27244555","id":"PMC_27244555","title":"Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27244555","citation_count":60,"is_preprint":false},{"pmid":"33548203","id":"PMC_33548203","title":"Structure of the catalytic core of the Integrator complex.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33548203","citation_count":54,"is_preprint":false},{"pmid":"32647223","id":"PMC_32647223","title":"INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32647223","citation_count":52,"is_preprint":false},{"pmid":"38570683","id":"PMC_38570683","title":"Structural basis of Integrator-dependent RNA polymerase II termination.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/38570683","citation_count":49,"is_preprint":false},{"pmid":"39719507","id":"PMC_39719507","title":"In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds.","date":"2024","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39719507","citation_count":33,"is_preprint":false},{"pmid":"38823386","id":"PMC_38823386","title":"Structural basis of the Integrator complex assembly and association with transcription factors.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38823386","citation_count":25,"is_preprint":false},{"pmid":"28027311","id":"PMC_28027311","title":"Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28027311","citation_count":22,"is_preprint":false},{"pmid":"16507104","id":"PMC_16507104","title":"A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; 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The INTS13-INTS14 sub-complex adopts a strongly entwined structure with a unique chain interlink and structural homology to the Ku70-Ku80 DNA repair complex. The module binds DNA and RNA with preference for RNA hairpins, plays an accessory role in snRNA 3'-end maturation, and has a stronger influence on transcription termination after pausing. INTS13 directly binds Integrator's cleavage module via a conserved C-terminal motif.\",\n      \"method\": \"Biochemical reconstitution, X-ray crystallography, RNA/DNA binding assays, cross-linking mass spectrometry, in vivo functional assays (snRNA processing, transcription termination)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + reconstitution + functional assays in single study with multiple orthogonal methods\",\n      \"pmids\": [\"32647223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INTS10, INTS13, and INTS14 form a biochemically separable subcomplex of Integrator. Cryo-EM structure of the INTS4/9/11 catalytic core at 3.5 Å reveals the spatial organization of catalytic nuclease INTS11 bound to its catalytically impaired homolog INTS9 via multiple interdependent interfaces, with INTS4 (a helical repeat protein) stabilizing the nuclease domains; all three form a composite electropositive groove suggesting RNA binding.\",\n      \"method\": \"Cryo-EM structure determination (3.5 Å), biochemical subcomplex characterization\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with biochemical validation of INTS10/13/14 module\",\n      \"pmids\": [\"33548203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the complete Integrator-PP2A complex reveal that the INTS10-INTS13-INTS14-INTS15 module adopts a scorpion-tail shape in a pre-termination complex and that its 'sting' may open the DSIF DNA clamp to facilitate Pol II termination. Three functional states were resolved: pre-termination, post-termination, and a free inactive closed conformation.\",\n      \"method\": \"Cryo-EM structure determination of multiple functional states of the complete Integrator-PP2A complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple cryo-EM structures with mechanistic model for INTS10-containing module in termination\",\n      \"pmids\": [\"38570683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of human INTS10/13/14/15 and INTS5/8/10/15 sub-complexes were determined. INTS10 participates in two distinct sub-complexes within Integrator. An integrative model of fully assembled Integrator bound to the paused elongation complex was built, and INTS13 was identified as a platform for recruitment of transcription factors (e.g., ZNF655) to modulate Integrator association at specific loci.\",\n      \"method\": \"Cryo-EM structure determination of sub-complexes, in silico protein-protein interaction screen, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of INTS10-containing modules with functional interaction mapping\",\n      \"pmids\": [\"38823386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"INTS10 suppresses HBV replication via IRF3 in liver cells. INTS10 protein levels are significantly decreased in persistently HBV-infected subjects compared to spontaneously recovered subjects and negatively correlate with HBV load.\",\n      \"method\": \"In vitro HBV replication assay in liver cells with INTS10 manipulation, eQTL analysis, clinical sample correlation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro loss-of-function assay in liver cells with mechanistic link to IRF3, single lab\",\n      \"pmids\": [\"27244555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of the INTS10 subunit of Integrator disrupts neural fate specification: INTS10 knockdown upends neural traits and redirects cells towards mesenchymal identity. The INTS10-containing enhancer module stabilizes SOX2 binding at chromatin upon exit from pluripotency and promotes epigenetic changes at neural enhancers.\",\n      \"method\": \"INTS10 siRNA/shRNA depletion, ChIP-seq, ATAC-seq, transcriptomic profiling during neural differentiation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype (cell fate) and chromatin-level mechanistic readout, single lab\",\n      \"pmids\": [\"39592860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Coxsackievirus B3 protease 3C (3Cpro) cleaves INTS10 at residue Q221. Depletion of INTS10 enhances CVB3 replication and blocks snRNA (U1, U2) processing. Overexpression of U1 snRNA inhibits CVB3 infection while knockdown promotes it, indicating that 3Cpro-mediated cleavage of INTS10 disrupts U snRNA processing to subvert host antiviral defenses.\",\n      \"method\": \"Protease cleavage assay, site-directed mutagenesis (Q221 cleavage site), INTS10 depletion/overexpression, snRNA manipulation, viral replication assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro cleavage assay with mutagenesis plus functional snRNA rescue experiments, single lab\",\n      \"pmids\": [\"41596640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Compound heterozygous mutations in RNU4ATAC (encoding U4atac snRNA) cause aberrant splicing of minor introns in INTS10 (and INTS7), leading to reduced INTS10 protein levels and altered assembly of Integrator subunits in patient-derived lymphoblastoid cells.\",\n      \"method\": \"RT-PCR of minor intron splicing, western blot of protein levels, Integrator co-immunoprecipitation/assembly assay in patient cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient cell experiments with multiple readouts linking U4atac mutations to INTS10 processing and Integrator assembly\",\n      \"pmids\": [\"36537210\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTS10 is a structural and functional subunit of the metazoan Integrator complex that, together with INTS13 and INTS14 (and INTS15), forms a nucleic-acid-binding 'enhancer module' with a scorpion-tail architecture that contacts the DSIF DNA clamp to facilitate RNA Pol II termination, stabilizes transcription factor (e.g., SOX2) binding at neural enhancers to direct cell fate, and suppresses HBV replication via IRF3; its activity is targeted by viral proteases (CVB3 3Cpro cleaves it at Q221 to disrupt snRNA processing) and its expression depends on correct minor intron splicing.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INTS10 is a structural subunit of the metazoan Integrator complex that participates in RNA polymerase II transcription termination, snRNA 3′-end processing, and enhancer-mediated gene regulation. Together with INTS13, INTS14, and INTS15, INTS10 forms a separable nucleic-acid-binding module that adopts a scorpion-tail architecture and contacts the DSIF DNA clamp to facilitate Pol II termination at paused genes; INTS10 also bridges a second sub-complex (INTS5/8/10/15), positioning it at the interface of distinct Integrator functional modules [PMID:32647223, PMID:38570683, PMID:38823386]. This enhancer module stabilizes SOX2 binding at neural enhancers during exit from pluripotency, directing cells toward neural rather than mesenchymal fate, and INTS10 loss disrupts this specification [PMID:39592860]. INTS10 is targeted by Coxsackievirus B3 protease 3Cpro, which cleaves it at Q221 to impair U snRNA processing and promote viral replication, while in hepatocytes INTS10 suppresses HBV replication via IRF3 [PMID:41596640, PMID:27244555].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Before a structural or mechanistic role for INTS10 within Integrator was defined, its antiviral function was identified: INTS10 suppresses HBV replication through IRF3 in liver cells, establishing a link between this Integrator subunit and innate immune signaling.\",\n      \"evidence\": \"HBV replication assays with INTS10 manipulation in liver cells, eQTL analysis, and clinical sample correlation\",\n      \"pmids\": [\"27244555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which INTS10 activates or cooperates with IRF3 is undefined\",\n        \"Whether this antiviral function requires the intact Integrator complex or is autonomous\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The first biochemical and structural demonstration that INTS10, INTS13, and INTS14 form a separable functional module within Integrator answered how the complex is organized modularly: the module binds nucleic acids (preferring RNA hairpins), contributes to snRNA 3′-end processing, and has a stronger role in transcription termination than in cleavage per se.\",\n      \"evidence\": \"X-ray crystallography of INTS13–INTS14 dimer, reconstitution of the trimeric module, RNA/DNA binding assays, cross-linking mass spectrometry, and in vivo snRNA processing and termination assays\",\n      \"pmids\": [\"32647223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"INTS10's direct contacts within the module were not resolved at atomic level\",\n        \"How the module docks onto the Pol II elongation complex was unknown\",\n        \"Whether additional subunits (e.g., INTS15) complete the module\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM of the INTS4/9/11 catalytic core confirmed that INTS10/13/14 is biochemically separable from the cleavage module, establishing the principle that Integrator is composed of distinct, modular enzymatic and regulatory assemblies.\",\n      \"evidence\": \"3.5 Å cryo-EM structure of catalytic core and biochemical fractionation of subcomplexes\",\n      \"pmids\": [\"33548203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the INTS10-containing module communicates with the catalytic module during termination\",\n        \"No structure of the INTS10 module in isolation at high resolution\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Patient-derived cells carrying U4atac snRNA mutations revealed that INTS10 expression depends on correct minor intron splicing, providing a genetic explanation for how minor spliceosome dysfunction can propagate into Integrator assembly defects.\",\n      \"evidence\": \"RT-PCR of minor intron retention in INTS10 transcripts, western blot for reduced protein, and co-IP showing altered Integrator assembly in RNU4ATAC-mutant lymphoblastoid cells\",\n      \"pmids\": [\"36537210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether reduced INTS10 alone accounts for the Integrator assembly defect or whether concurrent INTS7 reduction contributes\",\n        \"Functional consequences for snRNA processing and termination in these patient cells were not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of the complete Integrator–PP2A complex in three functional states revealed that the INTS10/13/14/15 module adopts a scorpion-tail architecture whose 'sting' opens the DSIF DNA clamp, providing a direct mechanistic model for how this module promotes Pol II termination.\",\n      \"evidence\": \"Cryo-EM of pre-termination, post-termination, and free inactive states of Integrator–PP2A\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mutational validation of the scorpion-tail sting contact with DSIF\",\n        \"Whether the conformational switch between states is regulated by post-translational modifications\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Structures of INTS10-containing sub-complexes (INTS10/13/14/15 and INTS5/8/10/15) showed INTS10 bridges two distinct modules, and INTS13 was identified as a platform recruiting transcription factors such as ZNF655, revealing how Integrator achieves locus-specific targeting.\",\n      \"evidence\": \"Cryo-EM of sub-complexes, in silico PPI screen, co-immunoprecipitation\",\n      \"pmids\": [\"38823386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of disrupting the INTS5/8/10/15 interface specifically\",\n        \"How ZNF655 recruitment translates into gene-specific transcriptional outcomes\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Depletion of INTS10 redirected differentiating cells from neural to mesenchymal fate, demonstrating that the enhancer module stabilizes SOX2 at neural enhancers during pluripotency exit, thereby linking Integrator's termination function to cell fate decisions.\",\n      \"evidence\": \"siRNA/shRNA knockdown of INTS10 during neural differentiation, ChIP-seq for SOX2, ATAC-seq, and transcriptomic profiling\",\n      \"pmids\": [\"39592860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether INTS10's role in neural specification is independent of its termination function\",\n        \"Whether other enhancer-module subunits phenocopy the fate switch upon individual depletion\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of CVB3 3Cpro cleavage of INTS10 at Q221 established that viruses directly target the Integrator enhancer module to disable U snRNA processing, connecting INTS10's structural role to host–pathogen defense.\",\n      \"evidence\": \"In vitro protease cleavage assay, Q221 site-directed mutagenesis, INTS10 depletion/overexpression, snRNA manipulation, and viral replication assays\",\n      \"pmids\": [\"41596640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether cleavage at Q221 disrupts the INTS10/13/14/15 module architecture specifically or Integrator assembly globally\",\n        \"In vivo validation in animal models of CVB3 infection\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct structural contacts of INTS10 within the scorpion-tail module and at the DSIF interface lack mutational validation, and the relationship between INTS10's roles in termination, enhancer regulation, and innate antiviral defense remains unintegrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of INTS10 alone or with defined interaction surfaces mutated\",\n        \"Whether INTS10's anti-HBV/IRF3 function operates through Integrator or independently\",\n        \"How the dual module membership of INTS10 (INTS10/13/14/15 and INTS5/8/10/15) is coordinated in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953854\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"Integrator complex\",\n      \"INTS10/INTS13/INTS14/INTS15 module\",\n      \"INTS5/INTS8/INTS10/INTS15 module\"\n    ],\n    \"partners\": [\n      \"INTS13\",\n      \"INTS14\",\n      \"INTS15\",\n      \"INTS5\",\n      \"INTS8\",\n      \"SOX2\",\n      \"IRF3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_ids. I used \"GO:0008953854\" which is wrong — that's mixing GO and Reactome. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"INTS10 is a structural subunit of the metazoan Integrator complex that participates in RNA polymerase II transcription termination, snRNA 3′-end processing, and enhancer-mediated gene regulation. Together with INTS13, INTS14, and INTS15, INTS10 forms a separable nucleic-acid-binding module that adopts a scorpion-tail architecture and contacts the DSIF DNA clamp to facilitate Pol II termination at paused genes; INTS10 also bridges a second sub-complex (INTS5/8/10/15), positioning it at the interface of distinct Integrator functional modules [PMID:32647223, PMID:38570683, PMID:38823386]. This enhancer module stabilizes SOX2 binding at neural enhancers during exit from pluripotency, directing cells toward neural rather than mesenchymal fate, and INTS10 loss disrupts this specification [PMID:39592860]. INTS10 is targeted by Coxsackievirus B3 protease 3Cpro, which cleaves it at Q221 to impair U snRNA processing and promote viral replication, while in hepatocytes INTS10 suppresses HBV replication via IRF3 [PMID:41596640, PMID:27244555].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Before a structural or mechanistic role for INTS10 within Integrator was defined, its antiviral function was identified: INTS10 suppresses HBV replication through IRF3 in liver cells, establishing a link between this Integrator subunit and innate immune signaling.\",\n      \"evidence\": \"HBV replication assays with INTS10 manipulation in liver cells, eQTL analysis, and clinical sample correlation\",\n      \"pmids\": [\"27244555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which INTS10 activates or cooperates with IRF3 is undefined\",\n        \"Whether this antiviral function requires the intact Integrator complex or is autonomous\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The first biochemical and structural demonstration that INTS10, INTS13, and INTS14 form a separable functional module within Integrator answered how the complex is organized modularly: the module binds nucleic acids (preferring RNA hairpins), contributes to snRNA 3′-end processing, and has a stronger role in transcription termination than in cleavage per se.\",\n      \"evidence\": \"X-ray crystallography of INTS13–INTS14 dimer, reconstitution of the trimeric module, RNA/DNA binding assays, cross-linking mass spectrometry, and in vivo snRNA processing and termination assays\",\n      \"pmids\": [\"32647223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"INTS10's direct contacts within the module were not resolved at atomic level\",\n        \"How the module docks onto the Pol II elongation complex was unknown\",\n        \"Whether additional subunits (e.g., INTS15) complete the module\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM of the INTS4/9/11 catalytic core confirmed that INTS10/13/14 is biochemically separable from the cleavage module, establishing the principle that Integrator is composed of distinct, modular enzymatic and regulatory assemblies.\",\n      \"evidence\": \"3.5 Å cryo-EM structure of catalytic core and biochemical fractionation of subcomplexes\",\n      \"pmids\": [\"33548203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the INTS10-containing module communicates with the catalytic module during termination\",\n        \"No structure of the INTS10 module in isolation at high resolution\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Patient-derived cells carrying U4atac snRNA mutations revealed that INTS10 expression depends on correct minor intron splicing, providing a genetic explanation for how minor spliceosome dysfunction can propagate into Integrator assembly defects.\",\n      \"evidence\": \"RT-PCR of minor intron retention in INTS10 transcripts, western blot for reduced protein, and co-IP showing altered Integrator assembly in RNU4ATAC-mutant lymphoblastoid cells\",\n      \"pmids\": [\"36537210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether reduced INTS10 alone accounts for the Integrator assembly defect or whether concurrent INTS7 reduction contributes\",\n        \"Functional consequences for snRNA processing and termination in these patient cells were not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of the complete Integrator–PP2A complex in three functional states revealed that the INTS10/13/14/15 module adopts a scorpion-tail architecture whose 'sting' opens the DSIF DNA clamp, providing a direct mechanistic model for how this module promotes Pol II termination.\",\n      \"evidence\": \"Cryo-EM of pre-termination, post-termination, and free inactive states of Integrator–PP2A\",\n      \"pmids\": [\"38570683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mutational validation of the scorpion-tail sting contact with DSIF\",\n        \"Whether the conformational switch between states is regulated by post-translational modifications\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Structures of INTS10-containing sub-complexes (INTS10/13/14/15 and INTS5/8/10/15) showed INTS10 bridges two distinct modules, and INTS13 was identified as a platform recruiting transcription factors such as ZNF655, revealing how Integrator achieves locus-specific targeting.\",\n      \"evidence\": \"Cryo-EM of sub-complexes, in silico PPI screen, co-immunoprecipitation\",\n      \"pmids\": [\"38823386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of disrupting the INTS5/8/10/15 interface specifically\",\n        \"How ZNF655 recruitment translates into gene-specific transcriptional outcomes\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Depletion of INTS10 redirected differentiating cells from neural to mesenchymal fate, demonstrating that the enhancer module stabilizes SOX2 at neural enhancers during pluripotency exit, thereby linking Integrator's termination function to cell fate decisions.\",\n      \"evidence\": \"siRNA/shRNA knockdown of INTS10 during neural differentiation, ChIP-seq for SOX2, ATAC-seq, and transcriptomic profiling\",\n      \"pmids\": [\"39592860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether INTS10's role in neural specification is independent of its termination function\",\n        \"Whether other enhancer-module subunits phenocopy the fate switch upon individual depletion\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of CVB3 3Cpro cleavage of INTS10 at Q221 established that viruses directly target the Integrator enhancer module to disable U snRNA processing, connecting INTS10's structural role to host–pathogen defense.\",\n      \"evidence\": \"In vitro protease cleavage assay, Q221 site-directed mutagenesis, INTS10 depletion/overexpression, snRNA manipulation, and viral replication assays\",\n      \"pmids\": [\"41596640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether cleavage at Q221 disrupts the INTS10/13/14/15 module architecture specifically or Integrator assembly globally\",\n        \"In vivo validation in animal models of CVB3 infection\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct structural contacts of INTS10 within the scorpion-tail module and at the DSIF interface lack mutational validation, and the relationship between INTS10's roles in termination, enhancer regulation, and innate antiviral defense remains unintegrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of INTS10 alone or with defined interaction surfaces mutated\",\n        \"Whether INTS10's anti-HBV/IRF3 function operates through Integrator or independently\",\n        \"How the dual module membership of INTS10 (INTS10/13/14/15 and INTS5/8/10/15) is coordinated in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"Integrator complex\",\n      \"INTS10/INTS13/INTS14/INTS15 module\",\n      \"INTS5/INTS8/INTS10/INTS15 module\"\n    ],\n    \"partners\": [\n      \"INTS13\",\n      \"INTS14\",\n      \"INTS15\",\n      \"INTS5\",\n      \"INTS8\",\n      \"SOX2\",\n      \"IRF3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}