INTS10

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).

1. 2016 Medium

   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

   PMID:27244555

   Open questions at the time

   • 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
2. 2020 High

   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

   PMID:32647223

   Open questions at the time

   • 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
3. 2021 High

   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

   PMID:33548203

   Open questions at the time

   • How the INTS10-containing module communicates with the catalytic module during termination
   • No structure of the INTS10 module in isolation at high resolution
4. 2023 Medium

   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

   PMID:36537210

   Open questions at the time

   • 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
5. 2024 High

   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

   PMID:38570683

   Open questions at the time

   • Mutational validation of the scorpion-tail sting contact with DSIF
   • Whether the conformational switch between states is regulated by post-translational modifications
6. 2024 High

   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

   PMID:38823386

   Open questions at the time

   • Functional consequence of disrupting the INTS5/8/10/15 interface specifically
   • How ZNF655 recruitment translates into gene-specific transcriptional outcomes
7. 2024 Medium

   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

   PMID:39592860

   Open questions at the time

   • 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
8. 2026 Medium

   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

   PMID:41596640

   Open questions at the time

   • 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

• 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.
• 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