Affinage

CNOT10

CCR4-NOT transcription complex subunit 10 · UniProt Q9H9A5

Length
744 aa
Mass
82.3 kDa
Annotated
2026-06-09
15 papers in source corpus 8 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

CNOT10 is a conserved subunit of the CCR4-NOT deadenylase complex that anchors mRNA turnover and post-transcriptional gene regulation (PMID:23232451, PMID:36586408). Together with CNOT11, it forms a structurally defined N-terminal module in which two helical domains of the scaffold CNOT1 sandwich CNOT10 and CNOT11, while a conserved CNOT11 'antenna' domain protrudes to recruit the partner GGNBP2; CNOT11 bridges CNOT10 to CNOT1 and is required for CNOT10 association with the complex (PMID:23232451, PMID:36586408). This module operates as a protein-protein interaction platform that determines complex composition and integrity: in trypanosomes TbCNOT10 is essential for viability, stabilizes the TbCAF1-TbNOT1 association, and is required for global mRNA turnover, with depletion stabilizing most mRNAs (PMID:23221646). In human cells CNOT10 directs specific decay programs, mediating tubulin mRNA autoregulation and basal tubulin mRNA stability (PMID:41426964), acting in the early phase of ARE-containing mRNA reduction as a TTP/ZFP36-proximal factor without contributing to steady-state decay (PMID:42049461), and shaping ES-cell transcript programs within the RNF219 regulatory axis (PMID:33104214). Beyond canonical deadenylation, CNOT10—together with CNOT11 and GGNBP2—regulates innate sensing of unedited cellular dsRNA upstream of cytoplasmic MDA5 (PMID:39576872).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2012 High

    Established that CNOT10 is not a peripheral associate but part of a defined N-terminal module of CCR4-NOT, answering how it docks onto the complex.

    Evidence Co-immunoprecipitation, affinity purification, and interaction mapping in human cells

    PMID:23232451

    Open questions at the time
    • Functional consequence of the module for deadenylation not addressed in this study
    • Structural basis of the CNOT1-CNOT10-CNOT11 interface not yet resolved at this stage
  2. 2012 High

    Showed in trypanosomes that CNOT10 is essential and required for complex integrity and global mRNA turnover, but the parallel human experiment revealed species-specific differences in how it controls catalytic-subunit association.

    Evidence RNAi/siRNA depletion, Co-IP, yeast two-hybrid, and mRNA stability assays in trypanosomes and human HEK cells

    PMID:23221646

    Open questions at the time
    • Why human CNOT10 depletion does not detach CAF1 while trypanosome depletion does is unexplained
    • Specific mRNA targets in human cells not defined here
  3. 2020 Medium

    Placed CNOT10 in a defined regulatory axis with RNF219 controlling 2-cell-specific and neuronal transcripts, moving from generic deadenylase subunit to a transcript-program regulator in stem cells.

    Evidence siRNA knockdown, RNA-seq, and in vitro deadenylation assay in mouse ES cells

    PMID:33104214

    Open questions at the time
    • Pathway placement inferred from gene-set overlap rather than direct mechanism
    • Direct interaction between CNOT10 and RNF219 not demonstrated
  4. 2022 High

    Resolved the high-resolution architecture of the CNOT1-CNOT10-CNOT11 module and identified the CNOT11 antenna as a recruitment surface for GGNBP2, establishing the module as a protein-protein interaction platform.

    Evidence Cryo-EM/X-ray structural determination with biochemical interaction validation

    PMID:36586408

    Open questions at the time
    • Functional output of GGNBP2 recruitment to mRNA decay not established here
    • Whether other partners use the same antenna surface is unknown
  5. 2024 Medium

    Demonstrated a non-deadenylase-centric role: CNOT10/CNOT11 with GGNBP2 control innate sensing of unedited cellular dsRNA, positioned downstream of transcription but upstream of MDA5.

    Evidence Genome-wide CRISPR knockout screen with genetic epistasis and IFN-induction assays

    PMID:39576872

    Open questions at the time
    • Molecular step by which CNOT10 influences dsRNA sensing not defined
    • Whether this requires the deadenylase activity of CCR4-NOT is unresolved
  6. 2025 Medium

    Confirmed CNOT10 as a central effector of CCR4-NOT-mediated tubulin mRNA autoregulation, linking it to a specific decay program responsive to soluble tubulin.

    Evidence siRNA knockdown with Roadblock-qPCR kinetic measurement of mRNA decay in human cells

    PMID:41426964

    Open questions at the time
    • Mechanism coupling soluble tubulin sensing to CNOT10 not detailed
    • Whether tubulin mRNA is a direct substrate of the module unaddressed
  7. 2025 Low

    Implicated CNOT10 in the interferon-responsive microglia state via a non-canonical role independent of its deadenylase function, extending its reach into innate-immune cell-state control.

    Evidence Genome-wide CRISPRi screen with IFIT1 reporter in iPSC-derived microglia (preprint)

    PMID:bio_10.1101_2025.06.05.658176

    Open questions at the time
    • Preprint screen hit with limited mechanistic follow-up; molecular basis of the non-canonical role not detailed
    • Independence from CCR4-NOT function asserted but not biochemically demonstrated
  8. 2026 Medium

    Defined CNOT10 as a TTP-proximal factor acting in the early transcriptional phase of ARE-mRNA reduction, distinguishing its contribution from steady-state decay.

    Evidence Proximity labeling, tetracycline-responsive luciferase reporter assay, and siRNA knockdown in human cells

    PMID:42049461

    Open questions at the time
    • Direct physical interaction between CNOT10 and TTP not biochemically confirmed
    • Mechanism distinguishing early-phase from steady-state action unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CNOT10 switches between canonical CCR4-NOT deadenylation and its non-canonical roles in dsRNA sensing and microglial interferon responses remains unresolved.
  • No mechanism links module assembly to selection between deadenylase-dependent and -independent functions
  • Direct substrate or RNA-binding contribution of CNOT10 itself not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Pathway
R-HSA-8953854 Metabolism of RNA 3
Partners
CAF1CNOT1CNOT11GGNBP2
Complex memberships
CCR4-NOT

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 CNOT10 and CNOT11 (C2ORF29) form a distinct module of the human CCR4-NOT complex that interacts with the N-terminal region of CNOT1. CNOT11 interacts with the first amino acids of CNOT1 and with CNOT10, and is required for the association of CNOT10 with the CCR4-NOT complex. Co-immunoprecipitation, affinity purification, interaction mapping RNA biology High 23232451
2012 In trypanosomes, TbCNOT10 is essential for growth and stabilizes the interaction between the deadenylase TbCAF1 and the NOT complex scaffold TbNOT1; depletion of TbCNOT10 causes decreased TbNOT1 levels, detachment of TbCAF1 from the complex, and pronounced stabilization of most trypanosome mRNAs. RNAi depletion, co-immunoprecipitation, yeast two-hybrid, mRNA stability assays Nucleic acids research High 23221646
2012 Depletion of CNOT10 from human embryonic kidney cells did NOT affect the association of CAF1 with the NOT complex (negative finding contrasting with the trypanosome result). siRNA knockdown, co-immunoprecipitation Nucleic acids research Medium 23221646
2022 High-resolution structural analysis revealed that the human N-terminal module of CCR4-NOT is composed of CNOT1, CNOT10, and CNOT11, where two helical domains of CNOT1 sandwich CNOT10 and CNOT11, and the most conserved domain of CNOT11 protrudes as a solvent-exposed 'antenna'. The module functions as a protein-protein interaction platform, with GGNBP2 identified as a conserved interacting partner of the CNOT11 antenna domain via structural and biochemical analyses. Cryo-EM/X-ray crystallography structural determination, biochemical interaction assays Cell reports High 36586408
2020 RNF219 interacts with the CCR4-NOT deadenylase complex; CNOT10 depletion in mouse embryonic stem cells upregulates a subset of genes (2-cell-specific and neuronal genes) that overlap with those downregulated by RNF219 knockdown, placing CNOT10 in the same regulatory axis for these transcripts during ES cell biology. siRNA knockdown, RNA-seq, in vitro deadenylation assay Journal of molecular cell biology Medium 33104214
2025 siRNA knockdown of CNOT10 (and CNOT11) impairs tubulin autoregulation and basal tubulin mRNA stability, identifying CNOT10 as a central effector of CCR4-NOT-mediated tubulin mRNA degradation in response to elevated soluble tubulin levels. siRNA knockdown, Roadblock-qPCR kinetic measurements of mRNA decay microPublication biology Medium 41426964
2026 CNOT10, identified as a TTP-proximal factor by proximity labeling, together with tryptophan residues in the TTP N-terminus, is involved in the reduction of ARE-containing mRNA levels during the early (transcriptional) phase of gene expression but is NOT involved in steady-state mRNA decay. Proximity labeling (BioID/APEX), cell-based luciferase reporter assay with tetracycline-responsive promoter, siRNA knockdown RNA (New York, N.Y.) Medium 42049461
2024 GGNBP2, CNOT10, and CNOT11 interact and collectively regulate sensing of unedited cellular dsRNA by MDA5; loss of CNOT10/CNOT11 (identified in a genome-wide CRISPR screen) modifies the response to unedited dsRNA downstream of transcription but upstream of cytoplasmic MDA5 sensing. Genome-wide CRISPR knockout screen, genetic epistasis, functional assays for IFN induction Science immunology Medium 39576872
2025 CRISPRi knockdown screen in human iPSC-derived microglia identified CNOT10 as a regulator of the Interferon-Responsive Microglia (IRM) state, with a non-canonical role in IRM activation independent of its traditional CCR4-NOT deadenylase function. Genome-wide CRISPRi screen, IFIT1 reporter readout in iPSC-derived microglia bioRxivpreprint Low bio_10.1101_2025.06.05.658176

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 C2ORF29/CNOT11 and CNOT10 form a new module of the CCR4-NOT complex. RNA biology 61 23232451
2012 Trypanosome CNOT10 is essential for the integrity of the NOT deadenylase complex and for degradation of many mRNAs. Nucleic acids research 27 23221646
2022 The human CNOT1-CNOT10-CNOT11 complex forms a structural platform for protein-protein interactions. Cell reports 21 36586408
2020 Identification of Target Genes in Hypertension and Left Ventricular Remodeling. Medicine 15 32664164
2020 RNF219 interacts with CCR4-NOT in regulating stem cell differentiation. Journal of molecular cell biology 15 33104214
2018 Copy number variation and regions of homozygosity analysis in patients with MÜLLERIAN aplasia. Molecular cytogenetics 14 29434669
2023 Epigenome-wide association study in Chinese monozygotic twins identifies DNA methylation loci associated with blood pressure. Clinical epigenetics 13 36869404
2016 A balanced chromosomal translocation involving chromosomes 3 and 16 in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome reveals new candidate genes at 3p22.3 and 16p13.3. Molecular cytogenetics 10 27478502
2024 GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing. Science immunology 5 39576872
2024 Sex-biased genetic regulation of inflammatory proteins in the Dutch population. BMC genomics 4 38326779
2023 Differential transcript usage across mammalian oocytes at the germinal vesicle and metaphase II stages. Theriogenology 1 37995439
2026 CNOT10 is involved in TTP-mediated AU-rich element containing mRNA metabolism, independent of mRNA decay regulation. bioRxiv : the preprint server for biology 0 41542502
2026 A natural product-hybridization approach toward anticancer drug discovery: synthesis and antitumor evaluation of CTBC6, designed from sulforaphane and magnolol. Bioorganic chemistry 0 41774989
2026 CNOT10 is involved in TTP-mediated AU-rich element containing mRNA metabolism, independent of mRNA decay regulation. RNA (New York, N.Y.) 0 42049461
2025 The CCR4-NOT deadenylase complex mediates tubulin autoregulation via specific adapters CNOT10 and CNOT11. microPublication biology 0 41426964

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