Affinage

INTS10

Integrator complex subunit 10 · UniProt Q9NVR2

Length
710 aa
Mass
82.2 kDa
Annotated
2026-06-10
22 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTS10 is a core subunit of the metazoan Integrator complex that, together with INTS13 and INTS14 (and INTS15), forms a separable, structurally defined auxiliary module distinct from the catalytic INTS4/9/11 core (PMID:32647223, PMID:33548203). The INTS10-INTS13-INTS14 module binds DNA and RNA with a preference for RNA hairpins and connects to Integrator's cleavage module through a conserved C-terminal motif in INTS13, positioning it to bridge target transcripts to the catalytic core; functionally this module plays an accessory role in snRNA maturation but exerts a stronger influence on transcription termination after Pol II pausing (PMID:32647223). Cryo-EM of the complete Integrator-PP2A assembly shows INTS10-INTS13-INTS14-INTS15 forming a scorpion-tail-shaped module whose 'sting' can open the DSIF DNA clamp in the pre-termination complex, providing a structural basis for its role in promoter-proximal termination (PMID:38570683). Within this module INTS13 acts as a recruitment platform for sequence-specific transcription factors including ZNF655 and ZBTB26, which target Integrator to specific promoters and enhancers and modulate transcriptional attenuation and activation (PMID:38823386, PMID:42219880). Beyond transcription regulation, INTS10 governs cell-fate decisions, stabilizing SOX2 binding at neural enhancers upon exit from pluripotency such that its depletion shifts cells toward mesenchymal identity (PMID:39592860), and it acts as an antiviral factor: it suppresses HBV replication via IRF3 (PMID:27244555) and its 3'-end snRNA-processing function is subverted by enteroviral 3C protease, which cleaves INTS10 at Q221 to impair U1/U2 snRNA biogenesis (PMID:41596640).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2020 High

    Established that INTS10 is not merely a peripheral Integrator subunit but the anchor of a distinct, biochemically separable module with intrinsic nucleic-acid-binding activity that physically bridges the catalytic cleavage module to target transcripts.

    Evidence Biochemical reconstitution, X-ray crystallography of INTS13-INTS14, cross-linking MS, and RNA/DNA binding plus functional snRNA and termination assays

    PMID:32647223

    Open questions at the time
    • Did not resolve full-length INTS10 structure within assembled Integrator
    • Mechanism by which RNA-hairpin preference selects substrates not defined
  2. 2021 High

    Defined the INTS10/13/14 module as architecturally separate from the catalytic INTS4/9/11 ternary core, clarifying division of labor within Integrator.

    Evidence Biochemical fractionation and 3.5 Å cryo-EM of the INTS4/9/11 catalytic core

    PMID:33548203

    Open questions at the time
    • Structure of the INTS10-containing module itself not resolved here
    • Physical coupling geometry between module and catalytic core unresolved
  3. 2024 High

    Placed INTS10 within the complete Integrator-PP2A holoenzyme and provided a mechanical model for how the module drives Pol II termination by opening the DSIF clamp.

    Evidence Cryo-EM structures of the Integrator-PP2A complex in multiple functional states

    PMID:38570683

    Open questions at the time
    • Direct demonstration that the 'sting' opens DSIF in cells not shown
    • Dynamics of the conformational transition not captured
  4. 2024 High

    Showed INTS10 (via INTS13) serves as a transcription-factor docking platform, explaining how Integrator is targeted to specific genomic loci for attenuation.

    Evidence Cryo-EM of INTS10/13/14/15 and INTS5/8/10/15 sub-complexes plus in silico TF screen and biochemical validation of ZNF655-INTS13 binding

    PMID:38823386

    Open questions at the time
    • Generality of TF recruitment beyond ZNF655 not established here
    • Direct contribution of INTS10 versus INTS13 to TF binding not separated
  5. 2016 Medium

    First functional role for INTS10 outside transcription machinery: an antiviral factor restricting HBV through the IRF3 pathway, with clinical correlation to viral persistence.

    Evidence Cell-based HBV replication assays, eQTL analysis, and clinical plasma INTS10 measurements

    PMID:27244555

    Open questions at the time
    • Molecular link between INTS10 and IRF3 not mechanistically resolved
    • Single lab; whether antiviral activity requires Integrator assembly unknown
  6. 2023 Medium

    Demonstrated that INTS10 protein abundance depends on minor-spliceosome processing of its own minor intron, linking RNU4ATAC dysfunction to Integrator assembly defects.

    Evidence RT-PCR splicing and western blot in RNU4ATAC compound-heterozygous patient lymphoblastoid cells

    PMID:36537210

    Open questions at the time
    • Direct causal contribution of INTS10 loss to patient phenotype not isolated
    • Single patient-cell study
  7. 2024 Medium

    Connected INTS10 to cell-fate determination, showing it stabilizes SOX2 at neural enhancers to enforce neural over mesenchymal identity during exit from pluripotency.

    Evidence INTS10 depletion, ChIP and SOX2 chromatin-binding assays, and cell-fate marker analysis

    PMID:39592860

    Open questions at the time
    • Mechanism of SOX2 stabilization by the module not defined
    • Single lab
  8. 2026 Medium

    Identified INTS10 as a direct target of viral subversion, with CVB3 3C protease cleaving it at Q221 to disable host U snRNA biogenesis and promote viral replication.

    Evidence 3Cpro cleavage assay with Q221 mutagenesis, INTS10 knockdown/overexpression with viral readouts, and U1/U2 snRNA manipulation

    PMID:41596640

    Open questions at the time
    • Whether cleavage disrupts module assembly versus catalytic coupling not resolved
    • Single lab
  9. 2026 Medium

    Extended INTS10's regulatory repertoire to transcriptional activation by showing ZBTB26 recruits Integrator via INTS10/INTS13 to sustain active states at promoters and enhancers.

    Evidence Co-IP, ChIP-seq, and ZBTB26 knockdown with transcriptional and occupancy readouts

    PMID:42219880

    Open questions at the time
    • Relative contribution of INTS10 versus INTS13 to ZBTB26 binding not separated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the INTS10 module's nucleic-acid preferences and TF-docking activity are integrated to choose between termination, snRNA processing, and enhancer activation at individual loci remains unresolved.
  • No unified model linking RNA-hairpin recognition to locus selection
  • Determinants partitioning attenuation versus activation outcomes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0003677 DNA binding 1 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 2
Partners
INTS13INTS14INTS15SOX2ZBTB26ZNF655
Complex memberships
INTS10-INTS13-INTS14(-INTS15) auxiliary moduleIntegrator complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 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 INTS10-INTS13-INTS14 module displays affinity for DNA and RNA, preferring RNA hairpins. INTS13 directly binds Integrator's cleavage module via a conserved C-terminal motif, suggesting the module bridges cleavage module and target transcripts. The module plays an accessory role in snRNA maturation but has a stronger influence on transcription termination after pausing. Biochemical reconstitution, X-ray crystallography, mass spectrometry cross-linking, RNA/DNA binding assays, functional snRNA processing and transcription termination assays Nature communications High 32647223
2021 The INTS10/13/14 sub-complex is one of the biochemically characterized modules of the Integrator complex, distinct from the catalytic core INTS4/9/11 ternary complex. Cryo-EM structure of the catalytic core reveals how INTS11 nuclease is stabilized by INTS9 and INTS4, forming a composite electropositive groove for putative RNA binding. Biochemical fractionation, cryo-EM (3.5 Å resolution structure of INTS4/9/11) Molecular cell High 33548203
2024 Cryo-EM structures of complete Integrator-PP2A complex reveal that INTS10-INTS13-INTS14-INTS15 form a scorpion-tail-shaped module. In the pre-termination complex, this module's 'sting' may open the DSIF DNA clamp to facilitate Pol II termination. This provides structural evidence for the module's role in the termination mechanism. Cryo-EM (multiple functional state structures of Integrator-PP2A complex) Nature High 38570683
2024 Cryo-EM structures of human Integrator sub-complexes INTS10/13/14/15 and INTS5/8/10/15 were determined. INTS13 within the fully assembled Integrator was identified as a direct binding platform for transcription factor ZNF655, which modulates Integrator stability at specific genomic loci and regulates transcription attenuation. Cryo-EM structure determination, in silico protein-protein interaction screen of >1,500 TFs, biochemical validation of ZNF655-INTS13 interaction Molecular cell High 38823386
2016 INTS10 suppresses HBV replication via IRF3 in liver cells. Clinical plasma INTS10 levels are significantly decreased in persistent HBV-infected individuals compared to spontaneously recovered subjects and negatively correlate with HBV load. Cell-based HBV replication assays in liver cells, expression quantitative trait locus analysis, clinical plasma sample measurements Nature communications Medium 27244555
2024 Depletion of Integrator's INTS10 subunit disrupts neural cell identity, causing cells to shift towards mesenchymal identity. INTS10 is part of an enhancer module of Integrator that stabilizes SOX2 binding at chromatin upon exit from pluripotency, promoting epigenetic changes and transcription factor binding at neural enhancers. INTS10 knockdown/depletion, chromatin immunoprecipitation, cell fate assays (neural vs. mesenchymal identity markers), SOX2 chromatin binding assays Nature cell biology Medium 39592860
2023 RNU4ATAC mutations in patient-derived cells cause splicing defects of INTS7 and INTS10 minor introns, leading to reduced levels of INTS7 and INTS10 proteins, and subsequent alterations in the assembly of Integrator subunits, demonstrating that INTS10 protein homeostasis depends on proper minor spliceosome function. Analysis of lymphoblastoid cells from RNU4ATAC compound heterozygous patients; RT-PCR splicing assays, western blot protein quantification, Integrator assembly analysis Nucleic acids research Medium 36537210
2026 INTS10 is a substrate of Coxsackievirus B3 (CVB3) 3C protease (3Cpro), which cleaves INTS10 at residue Q221. This cleavage disrupts U snRNA (U1 and U2) processing. Knockdown of INTS10 enhances CVB3 replication; overexpression of U1 snRNA inhibits CVB3 infection while knockdown promotes it, indicating that 3Cpro-mediated INTS10 cleavage subverts host defenses by impairing snRNA biogenesis. Protease cleavage assay with CVB3 3Cpro, site-directed mutagenesis identifying Q221 cleavage site, INTS10 knockdown/overexpression with viral replication readout, U1/U2 snRNA overexpression/knockdown assays International journal of molecular sciences Medium 41596640
2026 ZBTB26 interacts with the Integrator auxiliary module via INTS10 and INTS13, binds specific DNA motifs, and co-occupies select promoters and enhancers with Integrator. ZBTB26 is required for recruitment of Integrator to target loci, and the ZBTB26-Integrator axis sustains active transcriptional states at specific promoters and enhancers, extending Integrator's function to transcriptional activation. Co-immunoprecipitation, ChIP-seq, ZBTB26 knockdown with transcriptional readouts, genome-wide occupancy analysis FASEB journal Medium 42219880

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia. Leukemia 94 22076464
2014 Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans. Biological psychiatry 72 25555482
2016 Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese. Nature communications 60 27244555
2021 Structure of the catalytic core of the Integrator complex. Molecular cell 55 33548203
2024 Structural basis of Integrator-dependent RNA polymerase II termination. Nature 53 38570683
2020 INTS10-INTS13-INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module. Nature communications 52 32647223
2024 In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds. Nature neuroscience 35 39719507
2024 Structural basis of the Integrator complex assembly and association with transcription factors. Molecular cell 27 38823386
2016 Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution. PLoS genetics 22 28027311
2020 Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population. Human genetics 19 32902719
2006 A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans. BMC medical genetics 19 16507104
2021 Dupilumab for STAT3-Hyper-IgE Syndrome With Refractory Intestinal Complication. Pediatrics 11 34417287
2013 Targeted exome capture and sequencing identifies novel PRPF31 mutations in autosomal dominant retinitis pigmentosa in Chinese families. BMJ open 11 24202059
2023 Mutations in the non-coding RNU4ATAC gene affect the homeostasis and function of the Integrator complex. Nucleic acids research 9 36537210
2024 The enhancer module of Integrator controls cell identity and early neural fate commitment. Nature cell biology 7 39592860
2021 Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma. Molecular carcinogenesis 5 34133796
2017 Genetic profile and biological implication of PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) in human cancers: an analysis using The Cancer Genome Atlas. Oncotarget 5 28978030
2023 Case report: Complete pathological admission in N3 unresectable locally advanced lung adenocarcinoma with a novel INTS10-ALK and EML4-ALK fusion after neoadjuvant crizotinib. Frontiers in oncology 1 37064118
2026 Coxsackievirus B3 Cleaves INTS10 Through 3C Protease to Facilitate Its Replication. International journal of molecular sciences 0 41596640
2026 A ZBTB26-Integrator Axis Mediates Targeted Transcriptional Activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 42219880
2025 Genome-Wide Association Studies of Growth and Carcass Traits in Charolais Cattle Based on High-Coverage Whole-Genome Resequencing. International journal of molecular sciences 0 41373569
2025 Expression and significance of INTS10 and IRF3 in chronic hepatitis B patients. Frontiers in microbiology 0 41383743

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