Affinage

INTS4

Integrator complex subunit 4 · UniProt Q96HW7

Length
963 aa
Mass
108.2 kDa
Annotated
2026-06-10
10 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTS4 is a helical-repeat scaffold subunit of the Integrator complex that, together with INTS9 and INTS11, forms the heterotrimeric cleavage module responsible for the complex's endonucleolytic activity in small nuclear RNA (snRNA) 3'-end processing (PMID:29471365, PMID:22250197). INTS4 binds specifically to the pre-assembled INTS9/11 heterodimer—not either subunit alone—using both N-terminal HEAT repeats and a β-sheet-rich C-terminal region, and cryo-EM shows it stabilizes the INTS9/INTS11 nuclease domains through multiple interdependent interfaces while contributing to a composite electropositive groove that forms the catalytic core's RNA-binding path (PMID:29471365, PMID:33548203). Maturation of the cleavage module is templated: BRAT1 and WDR73 keep INTS9/11 inactive and block premature INTS4 association, BRAT1 mediates nuclear import of INTS9/11, INTS4 joins in the nucleus, and incorporation of inositol hexakisphosphate (IP6) into an electropositive pocket at the three-subunit interface locks the mature conformation required for both snRNA 3'-end processing and mRNA transcription attenuation (PMID:36180473, PMID:39032489). Loss of INTS4 abrogates snRNA maturation and disrupts Cajal body homeostasis, causing mislocalization of coilin, SMN, and Sm proteins (PMID:22250197).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2012 High

    Established that INTS4 is functionally essential for snRNA maturation, answering whether this subunit contributes to Integrator output at the cellular level.

    Evidence siRNA knockdown of INTS4 in human cells with immunofluorescence and northern blotting

    PMID:22250197

    Open questions at the time
    • Did not define INTS4's biochemical role within the complex
    • Did not identify direct binding partners of INTS4
  2. 2018 High

    Defined INTS4 as a dedicated scaffold of a heterotrimeric cleavage module, showing it binds the INTS9/11 heterodimer but neither subunit alone and mapping the required domains.

    Evidence Reciprocal Co-IP with domain-deletion analysis and snRNA processing/Cajal body readouts in human cells

    PMID:29471365

    Open questions at the time
    • No structural basis for the INTS4/9/11 interaction
    • Did not address how the module is assembled in vivo
  3. 2021 High

    Provided the structural mechanism by which INTS4 organizes the catalytic core, showing it stabilizes the INTS9/INTS11 nuclease domains and helps form a composite RNA-binding groove.

    Evidence 3.5 Å cryo-EM structure with biochemical reconstitution of the INTS4/9/11 subcomplex

    PMID:33548203

    Open questions at the time
    • RNA-binding path inferred from electrostatics, not RNA-bound structure
    • Did not reveal cofactor requirements
  4. 2022 High

    Identified IP6 as an essential structural cofactor locking the mature cleavage module, linking a small-molecule ligand to both snRNA processing and transcription attenuation.

    Evidence 2.74 Å cryo-EM of Drosophila ICM plus mutagenesis, IP6-binding assays, and functional assays, confirmed in human ICM

    PMID:36180473

    Open questions at the time
    • IP6 site is 55 Å from the active site; the allosteric coupling mechanism is not detailed
    • Did not establish the assembly order of IP6 incorporation
  5. 2022 Medium

    Distinguished cleavage-module assembly from broader complex assembly, showing the INTS4/9/11 interaction is independent of INTS11 SUMOylation.

    Evidence Co-IP with a SUMOylation-deficient INTS11 mutant comparing interactions across subunits

    PMID:36454007

    Open questions at the time
    • Subsidiary result of an INTS11-focused study
    • Single lab; functional consequence for INTS4 not directly assayed
  6. 2024 High

    Revealed a chaperoned biogenesis pathway, showing BRAT1/WDR73 keep INTS9/11 inactive and block premature INTS4 binding, with INTS4 joining in the nucleus and IP6-dependent BRAT1 release completing maturation.

    Evidence Co-IP, assembly/maturation and nuclear import assays with IP6-dependence experiments

    PMID:39032489

    Open questions at the time
    • Precise trigger for INTS4 recruitment in the nucleus not fully resolved
    • How disease mutations in BRAT1/WDR73 perturb the pathway not detailed
  7. 2025 Medium

    Demonstrated temporal and tissue-specific requirements for INTS4 in a whole organism, separating developmental essentiality from germline snRNA processing.

    Evidence Auxin-inducible degron depletion of C. elegans INTS-4 with snRNA processing and developmental/lifespan phenotyping

    PMID:40071568

    Open questions at the time
    • Single lab in C. elegans; mammalian stage-specificity not addressed
    • Molecular basis for stage-dependent dispensability unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IP6 binding at a site 55 Å from the active site allosterically licenses catalysis, and how RNA substrate is engaged by the electropositive groove, remain unresolved.
  • No RNA-bound structure of the cleavage module
  • Allosteric pathway from the IP6 pocket to the active site uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 3 GO:0005198 structural molecule activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
BRAT1INTS11INTS9WDR73
Complex memberships
Integrator cleavage module (INTS4/9/11)Integrator complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 INTS4 is a specific and conserved interaction partner of INTS9 and INTS11 that binds only the INTS9/11 heterodimer, not either subunit individually. INTS4 possesses N-terminal HEAT repeats (similar to Symplekin) and a β-sheet-rich C-terminal region, both of which are required for binding INTS9/11. INTS4/9/11 form a heterotrimeric 'cleavage module' responsible for the endonucleolytic activity of the Integrator complex. Co-immunoprecipitation, domain-deletion analysis, functional assays for UsnRNA 3'-end processing, Cajal body integrity, and histone locus body formation; depletion of INTS4 abrogated snRNA processing Nucleic acids research High 29471365
2021 Cryo-EM structure of the INTS4/9/11 ternary complex at 3.5 Å resolution shows that INTS4, a helical-repeat protein, stabilizes the nuclease domains of INTS11 and INTS9 via several interdependent interfaces. All three subunits form a composite electropositive groove that constitutes a putative RNA-binding path within the catalytic core. Cryo-electron microscopy at 3.5 Å resolution; biochemical reconstitution of INTS4/9/11 subcomplex Molecular cell High 33548203
2012 Depletion of INTS4 abrogates snRNA 3'-end processing, causes accumulation of the Cajal body marker coilin in nucleoli, disrupts normal Cajal body composition (loss of SMN, Sm proteins, and snRNAs from foci), and induces cytoplasmic granule formation of SMN and Sm proteins, demonstrating that INTS4 is essential for snRNA maturation and Cajal body homeostasis. siRNA-mediated knockdown of INTS4 in human cells, immunofluorescence microscopy, northern blotting for snRNA processing Journal of cell science High 22250197
2022 Cryo-EM structure of the Drosophila INTS4/9/11 (ICM) at 2.74 Å resolution reveals stable association of an inositol hexakisphosphate (IP6) molecule in a highly electropositive pocket at the interface of all three ICM subunits, 55 Å from the INTS11 active site. IP6 binding was confirmed in human ICM. Mutations in the IP6-binding site or disruption of IP6 biosynthesis significantly reduced Integrator function in snRNA 3'-end processing and mRNA transcription attenuation. Cryo-EM structure determination (2.74 Å), site-directed mutagenesis of IP6-binding residues, IP6-binding assays, snRNA processing assays, mRNA transcription attenuation assays Nature communications High 36180473
2024 BRAT1 and WDR73 are biogenesis factors for the INTS4/9/11 cleavage module: they keep INTS9/11 inactive by blocking the endonuclease active site and prevent premature INTS4 association during maturation. BRAT1 also facilitates nuclear import of INTS9/11, after which INTS4 joins in the nucleus. Final BRAT1 release requires locking of the mature cleavage module conformation by IP6. Co-immunoprecipitation, assembly/maturation assays, nuclear import assays, IP6-dependence experiments; mutations in BRAT1, WDR73, and INTS11 linked to Integrator assembly defects Molecular cell High 39032489
2022 An INTS11 SUMOylation-deficient mutant retains interaction with INTS4 and INTS9 but loses interaction with other Integrator subunits, indicating that the INTS4/9/11 cleavage module interaction is independent of INTS11 SUMOylation whereas broader complex assembly is not. Co-immunoprecipitation with SUMOylation-deficient INTS11 mutant (Lys381/462/475Arg), comparison of interactions with INTS4, INTS9, and other subunits Nucleic acids research Medium 36454007
2025 In C. elegans, auxin-inducible degradation of INTS-4 (the INTS4 ortholog) demonstrates that Integrator activity is critical for development at the L1 larval stage but becomes dispensable after L2/L3; germline-specific INTS-4 degradation causes accumulation of misprocessed snRNA transcripts without impairing development or lifespan. Auxin-inducible degron (AID) system for temporal depletion of C. elegans INTS-4; snRNA processing assays, developmental and lifespan phenotyping Biology open Medium 40071568

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Integrator subunit 4 is a 'Symplekin-like' scaffold that associates with INTS9/11 to form the Integrator cleavage module. Nucleic acids research 67 29471365
2021 Structure of the catalytic core of the Integrator complex. Molecular cell 55 33548203
2012 The integrator complex is required for integrity of Cajal bodies. Journal of cell science 37 22250197
2006 Characterization of KIAA0513, a novel signaling molecule that interacts with modulators of neuroplasticity, apoptosis, and the cytoskeleton. Brain research 23 17010949
2022 Inositol hexakisphosphate is required for Integrator function. Nature communications 17 36180473
2022 SUMO conjugation regulates the activity of the Integrator complex. Nucleic acids research 10 36454007
2024 Assembly mechanism of Integrator's RNA cleavage module. Molecular cell 9 39032489
2023 Coevolution combined with molecular dynamics simulations provides structural and mechanistic insights into the interactions between the integrator complex subunits. Computational and structural biotechnology journal 3 38074468
2025 Differential effect of ubiquitous and germline depletion of Integrator complex function on C. elegans physiology. Biology open 2 40071568
2026 Blood-Based Immunoglobulin-Bound Neoantigen Signatures Associated with MEN Type 1-Related Duodenopancreatic Neuroendocrine Tumor Progression. Journal of the American College of Surgeons 0 41562477

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