Affinage

CNOT4

CCR4-NOT transcription complex subunit 4 · UniProt O95628

Length
575 aa
Mass
63.5 kDa
Annotated
2026-04-28
38 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNOT4/Not4 is a RING-domain E3 ubiquitin ligase subunit of the CCR4-NOT complex that integrates ubiquitin-dependent protein quality control with mRNA decay and translational surveillance. Its N-terminal C4C4 RING finger domain selectively engages UbcH5B and ubiquitinates diverse substrates—including the ribosomal protein Rps7A on translating ribosomes, the proteasomal ATPase Rpt5 during proteasome assembly, the ribosome quality-control sensor ZNF598 during mitochondrial stress, ABCE1 to initiate mitophagy, cyclin C and the transcription factor Yap1 during oxidative stress, and PAF1 in the nucleus—thereby coordinating co-translational quality control, proteasome biogenesis, stress-responsive transcription factor turnover, and mitophagy initiation (PMID:11087754, PMID:15062086, PMID:22243599, PMID:30530678, PMID:38388640, PMID:29861391, PMID:22421358, PMID:25933433). In metazoans, CNOT4 associates with the CCR4-NOT complex through a CAF40-binding motif rather than the direct NOT1 contacts used by yeast Not4, and this interaction is required for mRNA destabilization; CNOT4 also functions as an mRNA adaptor directing transcripts to the CNOT7 deadenylase, and its depletion paradoxically accelerates global mRNA decay in a codon-optimality-dependent manner (PMID:30692204, PMID:34026442, PMID:41161383). Conditional knockout of Cnot4 in mouse male germ cells causes defective DNA damage repair and loss of X-Y chromosomal crossover, resulting in male infertility (PMID:34026442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing that NOT4 is a core subunit of a discrete nuclear complex that globally represses TATA-dependent Pol II transcription resolved the organizational framework within which NOT4 functions.

    Evidence Two-hybrid interaction mapping, allele-specific suppression, and biochemical co-fractionation in yeast

    PMID:7926748

    Open questions at the time
    • Catalytic activity of Not4 within the complex unknown
    • Mechanism of transcriptional repression unresolved
  2. 1999 High

    Mapping NOT4's interaction to the C-terminal region of NOT1 and demonstrating its partial functional independence from the CCR4/CAF1 deadenylase module established that the complex has modular architecture with distinct sub-functions.

    Evidence Co-immunoprecipitation, biochemical fractionation, and genetic epistasis in yeast

    PMID:10490603

    Open questions at the time
    • Nature of Not4's independent function unknown
    • Whether Not4 has enzymatic activity undetermined
  3. 2000 High

    Solving the solution structure of the CNOT4 C4C4 RING finger revealed a cross-brace zinc-coordination fold, establishing CNOT4 as a potential E3 ubiquitin ligase by structural analogy to known RING E3s.

    Evidence Heteronuclear NMR with ¹¹³Cd-substitution on recombinant human CNOT4 RING domain

    PMID:11087754

    Open questions at the time
    • E3 ligase activity not yet demonstrated biochemically
    • E2 partner unknown
  4. 2004 High

    Demonstrating that the CNOT4 RING domain specifically interacts with the E2 enzyme UbcH5B and modeling the E2-E3 interface established the molecular basis for CNOT4's ubiquitin ligase activity and its E2 selectivity.

    Evidence NMR chemical shift perturbation, HADDOCK docking, and biochemical mutagenesis

    PMID:15062086

    Open questions at the time
    • No physiological substrate identified
    • In vivo ubiquitination activity not shown
  5. 2010 Medium

    Identifying Cdc17 (DNA polymerase-α catalytic subunit) as a target of Not4/Ubc4-dependent turnover linked the E3 ligase to DNA replication fork homeostasis, providing the first genetic evidence for a physiological substrate.

    Evidence Genetic epistasis, deletion/overexpression, and growth assays in yeast

    PMID:20660159

    Open questions at the time
    • Direct ubiquitination of Cdc17 by Not4 not demonstrated in vitro
    • Ubiquitination sites on Cdc17 unmapped
  6. 2011 High

    Showing that Not4 deletion destabilizes proteasome regulatory particle assemblies and impairs Ecm29 chaperone function revealed a direct role for the E3 ligase in proteasome integrity, expanding its function beyond transcription.

    Evidence Proteasome purification, co-immunoprecipitation, and in vivo ubiquitination assays in yeast

    PMID:21321079

    Open questions at the time
    • Specific proteasomal substrate of Not4 ubiquitination not identified
    • Mechanism of Ecm29 stabilization unclear
  7. 2012 High

    Identifying Rps7A, cyclin C, and Yap1 as direct Not4 ubiquitination substrates in parallel studies established the enzyme's multi-substrate repertoire spanning ribosome quality control, stress-responsive transcription factor turnover, and cell cycle regulation.

    Evidence In vitro ubiquitination assays, polysome fractionation, subcellular localization, and genetic deletion in yeast

    PMID:22243599 PMID:22421358 PMID:22707721

    Open questions at the time
    • Whether Rps7A ubiquitination is regulatory or degradative unclear
    • Signals recruiting Not4 to specific substrates unknown
  8. 2015 High

    Demonstrating that Not4 associates with polysomes and represses translation of stalling-prone transcripts linked its ubiquitin ligase activity to co-translational quality control, while identification of PAF1 as a human CNOT4 substrate extended substrate repertoire to a Pol II-associated factor.

    Evidence Polysome fractionation, ribosome profiling, protein aggregation assays in yeast; co-immunoprecipitation and ubiquitination assays in human cells

    PMID:25933433 PMID:25971775

    Open questions at the time
    • Precise ribosomal events triggering Not4 recruitment undefined
    • Whether PAF1 degradation requires CCR4-NOT complex context unknown
  9. 2017 High

    Showing that CNOT4 monoubiquitinates influenza A virus nucleoprotein at RNA-binding groove lysines to promote viral RNA replication demonstrated a non-degradative ubiquitination function exploited by a pathogen.

    Evidence In vitro ubiquitination, mass spectrometry, site-directed mutagenesis, and siRNA knockdown in human cells

    PMID:28536288

    Open questions at the time
    • How CNOT4 recognizes NP unclear
    • Whether other viral proteins are substrates untested
  10. 2018 High

    Three studies collectively established that Not4 ubiquitinates Rpt5 as a proteasome assembly checkpoint, ubiquitinates ABCE1 at stalled ribosomes to initiate mitophagy, and cooperates between its RING and RRM-C domains for proteasome and transcriptional regulation—revealing how substrate-specific ubiquitination events link translational surveillance to organelle quality control.

    Evidence In vitro ubiquitination with structural analysis for Rpt5; co-IP and Drosophila genetics for ABCE1; domain mutagenesis with transcriptomics and ChIP for RING/RRM-C cooperation

    PMID:29802328 PMID:29861391 PMID:30530678

    Open questions at the time
    • Structural basis of Not4-Rpt5 interaction not resolved at atomic level
    • Whether ABCE1 ubiquitination is conserved in mammals not shown
    • How RING and RRM-C domains coordinate mechanistically unresolved
  11. 2019 High

    Crystal structures of metazoan NOT4's CAF40-binding motif bound to CAF40 revealed how NOT4 associates with the CCR4-NOT complex in metazoans—via a mechanism distinct from yeast—and showed this interaction is functionally required for mRNA decay.

    Evidence Crystal structure, NMR, structure-guided mutagenesis, and tethered mRNA decay reporter in Drosophila/human cells

    PMID:30692204

    Open questions at the time
    • Whether CAF40-binding motif is required for all CNOT4 E3 substrates unknown
    • Full-length CNOT4 structure in complex context unavailable
  12. 2021 High

    Multiple studies established that Not4 modulates translation elongation in a codon-dependent manner via Rps7A ubiquitination, functions as an mRNA adaptor directing transcripts to CNOT7 for deadenylation required for male fertility, and promotes UFD substrate degradation at a post-ubiquitylation step—broadening the functional scope to translational fidelity, germ cell development, and proteasomal delivery.

    Evidence Ribosome profiling in yeast; conditional knockout mouse with RNA-seq; UFD substrate assays in yeast

    PMID:33727038 PMID:34026442 PMID:34469733

    Open questions at the time
    • Structural basis of CNOT4-CNOT7 mRNA handoff unknown
    • Whether mRNA adaptor and E3 functions are concurrent or mutually exclusive unclear
  13. 2023 Medium

    Studies on MMF1 mRNA co-translational docking and on mRNA solubility regulation revealed that Not4 promotes ribosome pausing to enable nascent-chain-mediated mitochondrial targeting and inversely regulates mRNA solubility relative to Not1, linking translational pausing to organelle-specific mRNA fate decisions.

    Evidence Polysome fractionation and ubiquitination assays for MMF1; ribosome profiling of soluble/insoluble fractions

    PMID:36803582 PMID:37094076

    Open questions at the time
    • Generality of Not4-promoted pausing for other mito-targeted mRNAs untested
    • Mechanism by which Not4 depletion alters mRNA solubility unclear
  14. 2024 High

    Identification of ZNF598 as a CNOT4-dependent K63-ubiquitination substrate during mitochondrial stress established a direct connection between CNOT4 and ribosome-associated quality control (RQC) signaling, while TRIM21-mediated K48/K6-linked ubiquitination of CNOT4 at K239 revealed how CNOT4 itself is regulated.

    Evidence Ubiquitination assays, co-IP, siRNA, and Drosophila genetics for ZNF598; co-IP, mutagenesis, and knockdown in HCC cells for TRIM21-CNOT4

    PMID:38388640 PMID:39019859

    Open questions at the time
    • Whether CNOT4-ZNF598 axis operates independently of CCR4-NOT complex untested
    • Physiological contexts beyond HCC for TRIM21-mediated CNOT4 turnover unknown
  15. 2025 Medium

    Acute CNOT4 depletion in human cells paradoxically accelerated global mRNA decay in a codon-optimality-dependent manner without disrupting CCR4-NOT complex integrity, challenging simple models in which CNOT4 promotes deadenylation and decay.

    Evidence Auxin-induced degron depletion, BioID proximity labeling, and transcriptome-wide mRNA stability measurement

    PMID:41161383

    Open questions at the time
    • Mechanism by which CNOT4 loss accelerates decay unresolved
    • Whether this reflects de-repression of alternative decay pathways unknown
    • Reconciliation with yeast data showing Not4 promotes decay needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how CNOT4 selects among its many substrates in different cellular contexts, whether its E3 ligase and mRNA adaptor functions operate simultaneously or are mutually exclusive, and the structural basis of full-length CNOT4 within the CCR4-NOT complex.
  • No structure of full-length CNOT4 in the context of the assembled CCR4-NOT complex
  • Substrate selection mechanism unresolved
  • Relative contributions of E3 ligase vs. mRNA adaptor functions in mammalian physiology unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-8953854 Metabolism of RNA 4 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 2
Partners
ABCE1CAF40NOT1PAF1RPS7ARPT5UBCH5BZNF598
Complex memberships
CCR4-NOT

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 NOT1, NOT2, NOT3, and NOT4 form a discrete ~500 kDa nuclear complex that acts as a global negative regulator of RNA polymerase II transcription, preferentially repressing TC TATA-element-dependent transcription; NOT4 interacts with NOT1 and NOT3 in two-hybrid assays, and overexpression of NOT3 or NOT4 suppresses not1 and not2 mutations, placing NOT4 within the complex by genetic epistasis. Two-hybrid interaction, allele-specific suppression, biochemical co-fractionation Genes & development High 7926748
1999 Within the CCR4-NOT complex, NOT4 interacts with the C-terminal region (residues 1490–2108) of NOT1, is physically and functionally more peripheral than CCR4 and CAF1, and has partially separate functions from the CCR4/CAF1 sub-module; genetic analysis shows ccr4 or caf1 deletion suppresses phenotypes caused by not mutations including NOT4. Co-immunoprecipitation, biochemical fractionation, genetic epistasis/deletion analysis Molecular and cellular biology High 10490603
2000 Human CNOT4 contains a C4C4-type RING finger (residues 1–78) that coordinates two zinc ions in a cross-brace manner via cysteine residues; its 3D solution structure was determined, revealing an alpha-helix and three long loops with overall folding similar to C3HC4 RING fingers but with distinct secondary structural elements in non-conserved regions. Heteronuclear NMR with 113Cd-substitution, structure determination The Journal of biological chemistry High 11087754
2004 The N-terminal RING finger domain of CNOT4 acts as an E3 ubiquitin ligase that specifically interacts with the ubiquitin-conjugating enzyme UbcH5B; NMR chemical shift perturbation mapped residues on UbcH5B responsible for CNOT4 RING binding, and HADDOCK docking generated structural models of the E2/E3 complex revealing differences from the c-Cbl/UbcH7 complex that explain E2/E3 specificity. NMR chemical shift perturbation, HADDOCK docking, biochemical mutagenesis Structure High 15062086
2005 The two zinc-binding sites in the C4C4 RING domain of CNOT4 show differential Zn2+/Cd2+ metal exchange rates explained by differences in site accessibility and electrostatic interactions; backbone dynamics by NMR showed CNOT4 RING domain is more rigid than the p44 RING domain, reflecting distinct protein-protein interaction modes. NMR backbone dynamics, metal exchange experiments Journal of molecular biology High 15890366
2010 Not4 (together with Ubc4) is required for ubiquitin-mediated destabilization of Cdc17, the catalytic subunit of DNA polymerase-α in yeast; disruption of Cdc17 turnover via not4 mutation causes hydroxyurea sensitivity and synthetic dosage lethality upon Cdc17 overexpression, establishing Not4 as part of a pathway regulating pol-α levels at the replication fork. Genetic epistasis, deletion/overexpression analysis, growth assays Molecular biology of the cell Medium 20660159
2011 Not4 E3 ligase is required for proteasome integrity in yeast: deletion of Not4 leads to salt-resistant RP-CP complexes, instability of all other RP forms, accumulation of polyubiquitinated proteins, and reduced free ubiquitin. Not4 associates with RP species in purified proteasome holoenzyme and interacts with the proteasome chaperone Ecm29; in the absence of Not4, Ecm29 is ubiquitinated and degraded and interacts poorly with the proteasome. Proteasome purification, co-immunoprecipitation, in vivo ubiquitination assay, genetic deletion Molecular and cellular biology High 21321079
2012 Not4p is the E3 ubiquitin ligase mediating H2O2-induced cyclin C destruction in yeast; Not4p polyubiquitylates cyclin C in vitro via Lys48-linked ubiquitin chains, targeting it for 26S proteasome degradation; cyclin C must translocate from nucleus to cytoplasm (requiring the cell-wall-integrity MAPK module and phospholipase C) before Not4p-dependent degradation, and cytoplasm-restricted cyclin C remains subject to Not4p-mediated destruction. In vitro ubiquitination assay, genetic deletion, subcellular localization imaging, proteasome inhibition Journal of cell science High 22421358
2012 Not4 E3 ligase ubiquitinates the ribosomal protein Rps7A (but not its paralogue Rps7B) in vivo and in vitro; ubiquitinated Rps7A is found exclusively in 80S and polysome fractions, not free 40S fractions; deletion of Not4 causes accumulation of aggregated proteins including ribosomal proteins and ribosome-associated chaperones, and reduces polysome levels; Not5 presence in polysomes depends on Not4. In vitro and in vivo ubiquitination assays, polysome fractionation, genetic deletion Molecular microbiology High 22243599
2012 Nuclear Not4 E3 ligase promotes degradation of the transcription factor Yap1 in an oxidant-stimulated fashion; Not4 physically binds Yap1 in an oxidant-dependent manner; Yap1 degradation requires its ability to bind DNA, a domain in its N-terminal region, and is proteasome-dependent; this pathway is conserved in Candida albicans Cap1. Co-immunoprecipitation, ubiquitin mutant screening, proteasome inhibition, genetic deletion The Journal of biological chemistry Medium 22707721
2014 Not4 plays a role in protein quality control independently of the Ccr4 deadenylase module of the CCR4-NOT complex; Not4's function in clearing aberrant proteins is mediated at least in part via the proteasome, distinct from the mRNA deadenylation function of Ccr4/Caf1. Genetic epistasis, deletion analysis, protein aggregation assays PloS one Medium 24465968
2015 Not4 associates with polysomes in yeast and contributes to translational repression of transcripts causing transient ribosome stalling; absence of Not4 enhanced expression of arrested nascent polypeptides, caused constitutive protein folding stress and aggregation, and impaired global translational repression upon nutrient withdrawal, phenotypes similar to those from impaired mRNA decapping. Polysome fractionation, ribosome profiling, protein aggregation assays, genetic deletion The EMBO journal High 25971775
2015 Human CNOT4 controls degradation of PAF1 (RNA Pol II-associated factor 1) by promoting its polyubiquitination and subsequent 26S proteasome-dependent degradation; this degradation requires nuclear localization of PAF1 but not its chromatin binding; CNOT4 specifically targets PAF1 but not other PAF complex components. Co-immunoprecipitation, ubiquitination assay, proteasome inhibition, NLS-mutant analysis PloS one Medium 25933433
2017 Human CNOT4 acts as an E3 ubiquitin ligase for influenza A virus nucleoprotein (NP), monoubiquitinating NP at multiple lysine residues including K184, K227, and K273 in the RNA-binding groove; CNOT4 interacts with NP in cells; in vitro ubiquitination confirmed CNOT4 directly ubiquitinates NP; ubiquitination promotes viral RNA replication without affecting NP stability; CNOT4 and USP11 antagonistically regulate NP ubiquitination. Co-immunoprecipitation, in vitro ubiquitination assay, mass spectrometry, site-directed mutagenesis, siRNA knockdown/overexpression mBio High 28536288
2018 Not4 ubiquitin ligase mediates ubiquitination of ABCE1 in response to mitochondrial damage; this occurs at ribosomes stalled during translation of mitochondrial outer membrane-localized mRNAs (e.g., C-I30); CNOT4 is recruited together with co-translational quality control factors Pelo and ABCE1 to the ribosome/mRNA-RNP complex; ABCE1 ubiquitination generates poly-ubiquitin signals that recruit autophagy receptors to initiate mitophagy. Co-immunoprecipitation, ubiquitination assay, Drosophila genetic model, cell biology Cell metabolism High 29861391
2018 Not4 selectively ubiquitinates Rpt5 (a proteasomal ATPase) during Rpt ring assembly; Not4 competes with chaperones Nas2 and Hsm3 for access to Rpt5 ubiquitination sites; Rpt5 ubiquitination does not destabilize the ring but blocks incorporation of Rpn1 and Ubp6, thereby acting as an assembly checkpoint ensuring accuracy of proteasome holoenzyme maturation. In vitro ubiquitination assay, structural analysis using known co-crystal structures, genetic epistasis, biochemical purification Proceedings of the National Academy of Sciences of the United States of America High 30530678
2018 The Not4 RRM-C domain (RNA recognition motif and C3H1 domain) and RING domain cooperatively regulate proteasome assembly and Pol II-dependent gene expression; the RING domain is required for Ccr4-Not association with RNA Pol II; individual RING or RRM-C mutants fail to replicate not4Δ proteasome defects, but combined mutation does; Not4 RRM-C affects a specific subset of Pol II-regulated genes. Transcriptome analysis, Pol II ChIP, genetic mutant analysis, co-immunoprecipitation Scientific reports Medium 29802328
2019 Metazoan NOT4 associates with the CCR4-NOT complex through a conserved CAF40-binding motif (CBM) in its C-terminal region; crystal structures of the CBM-CAF40 complex reveal a binding surface mutually exclusive with Roquin/Bag of marbles binding; CAF40 depletion or structure-guided mutagenesis of the NOT4-CAF40 interface impairs NOT4-dependent decay of tethered reporter mRNAs, demonstrating this interaction is functionally required for mRNA decay. Crystal structure, NMR, mutagenesis, mRNA decay reporter assay, CAF40 depletion Genes & development High 30692204
2021 Not4 and Not5 modulate translation elongation dynamics in a codon-dependent manner, changing ribosome A-site dwelling occupancy; Not4-mediated Rps7A ubiquitination and a moonlighting function of Rli1 enable translation of polyarginine stretches; Not5 resides in condensate puncta that co-purify with ribosomes and Rli1 but exclude eIF5A; codon-specific effects in not5Δ cells inversely correlate with eIF5A depletion effects. Ribosome profiling, polysome co-purification, genetic deletion, overexpression analysis Cell reports High 34469733
2021 Mouse CNOT4 functions as a mRNA adaptor for the CCR4-NOT complex by targeting mRNAs to CNOT7 for deadenylation of poly(A) tails; conditional knockout of Cnot4 in male germ cells causes defective DNA damage repair and homologous crossover between X and Y chromosomes; CNOT4-dependent mRNA removal during zygotene-to-pachytene transition is required for male fertility. Conditional knockout mouse, RNA-seq, mRNA poly(A) analysis, immunofluorescence Advanced science High 34026442
2021 Not4 is required for UPS-dependent degradation of ubiquitin fusion degradation (UFD) pathway substrates at a post-ubiquitylation step; Not4 binds cellular ubiquitin conjugates and promotes ubiquitin-dependent proteasomal degradation independently from other Ccr4-Not subunits. Genetic deletion, substrate degradation assay, co-immunoprecipitation with ubiquitin conjugates Biochimica et biophysica acta. Molecular cell research Medium 33727038
2023 Not4 promotes ribosome pausing during MMF1 mRNA translation, leading to co-translational docking of MMF1 mRNA to mitochondria via the nascent Mmf1 chain's mitochondrial targeting sequence, the Egd1 chaperone, Om14 outer membrane protein, and the co-translational import machinery; Not4 also ubiquitinates Egd1; together with Caf130, Cis1, autophagy, and no-go-decay, this constitutes a mechanism (Mito-ENCay) that limits MMF1 overexpression. Genetic deletion, polysome fractionation, ubiquitination assay, co-immunoprecipitation Nucleic acids research Medium 37094076
2023 Not1 and Not4 inversely regulate mRNA solubility in yeast: Not4 depletion solubilizes mRNAs with lower non-optimal codon content, while Not1 depletion solubilizes mitochondrial mRNAs; insoluble mRNAs are enriched for ribosomes dwelling at non-optimal codons and show higher proportion of co-translational degradation; Not1 promoter association may set mRNA solubility. Ribosome profiling of soluble/insoluble fractions, genetic depletion, mRNA decay analysis Genome biology Medium 36803582
2023 CNOT4 facilitates ubiquitination and 26S proteasome-dependent degradation of PAF1 in non-small cell lung cancer cells; co-immunoprecipitation confirmed CNOT4-PAF1 interaction; CNOT4 overexpression inhibited tumor proliferation, migration, and stemness in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, xenograft model Molecular carcinogenesis Medium 37493105
2024 CNOT4 promotes K63-linked ubiquitination of ZNF598 (a key ribosome-associated quality control sensor) in a CNOT4-dependent manner; this ubiquitination is upregulated upon mitochondrial stress; ZNF598 ubiquitination promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. Ubiquitination assay, co-immunoprecipitation, siRNA knockdown, Drosophila genetic models Nature communications High 38388640
2024 TNKS1BP1 interacts with TRIM21 to mediate ubiquitination of CNOT4 at K239 via K48- and K6-linked ubiquitin chains, leading to CNOT4 degradation; CNOT4 degradation inhibits the JAK2/STAT3 pathway in hepatocellular carcinoma, promoting tumor progression and immune evasion. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, knockdown studies Cell death & disease Medium 39019859
2025 CNOT4 depletion in human cells does not affect CCR4-NOT complex integrity but unexpectedly accelerates global mRNA decay, opposite to the effect of CNOT1 depletion; BioID proximity labeling confirmed CNOT4 association with the CCR4-NOT complex in cells despite not co-purifying by standard biochemical methods; changes in mRNA stability correlated with codon optimality of transcripts. Auxin-induced degron depletion, BioID proximity labeling, transcriptome-wide mRNA stability analysis The Journal of biological chemistry Medium 41161383
2025 In Drosophila, Cnot4 ubiquitin ligase mediates ubiquitination of secretory granules to mark them for crinophagic lysosomal degradation; loss of Cnot4 impairs glue granule fusion with lysosomes, while Cnot4 overexpression induces premature crinophagy; Cnot4 acts antagonistically to the deubiquitinase Usp7 in this process. Genetic loss-of-function, overexpression, live imaging, ubiquitination assay in Drosophila salivary glands bioRxivpreprint Medium bio_10.1101_2025.09.24.678350

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 NOT1(CDC39), NOT2(CDC36), NOT3, and NOT4 encode a global-negative regulator of transcription that differentially affects TATA-element utilization. Genes & development 183 7926748
1999 The CCR4 and CAF1 proteins of the CCR4-NOT complex are physically and functionally separated from NOT2, NOT4, and NOT5. Molecular and cellular biology 137 10490603
2004 Structural model of the UbcH5B/CNOT4 complex revealed by combining NMR, mutagenesis, and docking approaches. Structure (London, England : 1993) 111 15062086
2012 Presence of Not5 and ubiquitinated Rps7A in polysome fractions depends upon the Not4 E3 ligase. Molecular microbiology 79 22243599
2000 The structure of the C4C4 ring finger of human NOT4 reveals features distinct from those of C3HC4 RING fingers. The Journal of biological chemistry 77 11087754
2018 Ubiquitination of ABCE1 by NOT4 in Response to Mitochondrial Damage Links Co-translational Quality Control to PINK1-Directed Mitophagy. Cell metabolism 73 29861391
2011 Not4 E3 ligase contributes to proteasome assembly and functional integrity in part through Ecm29. Molecular and cellular biology 68 21321079
2012 Oxidative-stress-induced nuclear to cytoplasmic relocalization is required for Not4-dependent cyclin C destruction. Journal of cell science 53 22421358
2017 CNOT4-Mediated Ubiquitination of Influenza A Virus Nucleoprotein Promotes Viral RNA Replication. mBio 46 28536288
2015 Not4-dependent translational repression is important for cellular protein homeostasis in yeast. The EMBO journal 45 25971775
2012 Proteolytic degradation of the Yap1 transcription factor is regulated by subcellular localization and the E3 ubiquitin ligase Not4. The Journal of biological chemistry 42 22707721
2014 The Not4 E3 ligase and CCR4 deadenylase play distinct roles in protein quality control. PloS one 39 24465968
2019 A conserved CAF40-binding motif in metazoan NOT4 mediates association with the CCR4-NOT complex. Genes & development 35 30692204
2021 Not4 and Not5 modulate translation elongation by Rps7A ubiquitination, Rli1 moonlighting, and condensates that exclude eIF5A. Cell reports 32 34469733
2021 The CNOT4 Subunit of the CCR4-NOT Complex is Involved in mRNA Degradation, Efficient DNA Damage Repair, and XY Chromosome Crossover during Male Germ Cell Meiosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 31 34026442
2004 Deletion of the NOT4 gene impairs hyphal development and pathogenicity in Candida albicans. Microbiology (Reading, England) 31 14702416
2014 The role of the E3 ligase Not4 in cotranslational quality control. Frontiers in genetics 28 24904641
2010 Ubc4 and Not4 regulate steady-state levels of DNA polymerase-α to promote efficient and accurate DNA replication. Molecular biology of the cell 23 20660159
2005 Dynamics and metal exchange properties of C4C4 RING domains from CNOT4 and the p44 subunit of TFIIH. Journal of molecular biology 22 15890366
2013 The Not4 RING E3 Ligase: A Relevant Player in Cotranslational Quality Control. ISRN molecular biology 16 27335678
2015 Protein Degradation of RNA Polymerase II-Association Factor 1(PAF1) Is Controlled by CNOT4 and 26S Proteasome. PloS one 14 25933433
2024 Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis. Nature communications 13 38388640
2018 Ubiquitin-dependent switch during assembly of the proteasomal ATPases mediated by Not4 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 13 30530678
2024 TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion. Cell death & disease 12 39019859
2023 Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events. Genome biology 12 36803582
2018 The conserved RNA recognition motif and C3H1 domain of the Not4 ubiquitin ligase regulate in vivo ligase function. Scientific reports 11 29802328
2021 Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer. Cancer science 10 34626022
2023 CNOT4 suppresses nonsmall cell lung cancer progression by promoting the degradation of PAF1. Molecular carcinogenesis 6 37493105
2020 CNOT4 enhances the efficacy of anti-PD-1 immunotherapy in a model of non-small cell lung cancer. FEBS open bio 6 33034149
2023 Not4-dependent targeting of MMF1 mRNA to mitochondria limits its expression via ribosome pausing, Egd1 ubiquitination, Caf130, no-go-decay and autophagy. Nucleic acids research 4 37094076
2023 [Hydnocarpin inhibits malignant progression of triple negative breast cancer via CNOT4-mediated ubiquitination and degradation of YAP]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 4 37802875
2021 CNOT4 suppresses non-small cell lung cancer progression and is required for effector cytolytic T lymphocytes cell responses to lung cancer cells. Molecular immunology 4 33592572
2021 Ccr4-Not complex subunits Ccr4, Caf1, and Not4 are novel proteolysis factors promoting the degradation of ubiquitin-dependent substrates by the 26S proteasome. Biochimica et biophysica acta. Molecular cell research 4 33727038
2025 Cnot4 heterozygosity attenuates high fat diet-induced obesity in mice and impairs PPARγ-mediated adipocyte differentiation. PloS one 3 40424271
2025 Auxin-induced depletion of human CCR4-NOT subunits reveals opposing functions of CNOT1 and CNOT4 in mRNA metabolism. The Journal of biological chemistry 2 41161383
2023 Depletion of CNOT4 modulates the DNA damage responses following ionizing radiation (IR). Journal of cancer research and therapeutics 1 38554309
2024 Ubiquitination-deficit of Cnot4 impairs the capacity of proliferation and differentiation in mouse embryonic stem cells. Biochemical and biophysical research communications 0 39798536
2021 The C-terminal region of yeast ubiquitin-protein ligase Not4 mediates its cellular localization and stress response. FEMS microbiology letters 0 34338747