Affinage

EXOSC4

Exosome complex component RRP41 · UniProt Q9NPD3

Length
245 aa
Mass
26.4 kDa
Annotated
2026-06-09
71 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EXOSC4 (human Rrp41p) is a structural RNase PH-like subunit of the conserved RNA exosome, the principal 3'→5' RNA-degradation and surveillance machine of the cell (PMID:11110791, PMID:17174896). It assembles with five other RNase PH-like subunits into the hexameric ring that forms the core of the exosome, and biochemical and structural work places EXOSC4 within the central channel through which RNA substrates are threaded to reach the catalytic Rrp44/Dis3 exoribonuclease (PMID:12419256, PMID:17174896, PMID:19879841). Although the yeast ortholog retains a phosphorolytic active site that is dispensable for core exosome activity in vivo (PMID:17173052), the EXOSC4-containing ring is functionally essential: channel-blocking mutations restrict RNA passage to Rrp44 and stabilize both nuclear and cytoplasmic substrates, and the channel routes distinct substrate classes by threading versus direct access (PMID:19879841, PMID:23404585, PMID:28355211). Through this activity EXOSC4 supports 3' processing of 5.8S rRNA, 3'→5' mRNA turnover including AU-rich element- and PTC-containing transcripts, nonsense-mediated decay, and nuclear surveillance of read-through transcripts, minor (U12-type) intron-containing pre-mRNAs, and unstable noncoding RNAs (PMID:9482746, PMID:12086625, PMID:14527413, PMID:17545563, PMID:23000172, PMID:24848017). EXOSC4 is required to maintain a stable exosome complex—its depletion co-depletes other subunits—and it is an initiating subunit in the hierarchical assembly of the mammalian exosome, with unincorporated orphan EXOSC4 cleared by the ubiquitin-proteasome system [PMID:17545563, PMID:bio_10.1101_2025.03.14.643291]. A pathogenic missense variant (p.Leu187Pro) causes a neurodevelopmental disorder by lowering EXOSC4 levels, impairing its incorporation into the exosome, and blocking pre-rRNA (7S) processing with consequent translational defects (PMID:39009343). EXOSC4 is amplified in multiple cancers, where its depletion impairs proliferation and invasion in part through destabilization of specific transcripts such as SESN2 and repression of BIK (PMID:24763612, PMID:35008922).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 High

    Established the founding identity of the protein: a yeast exosome subunit with intrinsic phosphorolytic exoribonuclease activity required for rRNA maturation, defining the exosome as an RNA-degradation machine.

    Evidence Complex purification, in vitro exoribonuclease assay, and genetic depletion with rRNA processing readout in yeast

    PMID:9390555

    Open questions at the time
    • Whether the in vitro phosphorolytic activity is the functionally relevant catalytic source was not resolved
    • Human ortholog not yet characterized
  2. 1998 High

    Extended Rrp41 function beyond rRNA to cytoplasmic mRNA decay, placing it in a 3'→5' degradation pathway modulated by Ski cofactors.

    Evidence Genetic loss-of-function, mRNA half-life measurements, and epistasis with ski mutants in yeast

    PMID:9482746

    Open questions at the time
    • Direct substrate contacts not mapped
    • Mechanism of Ski-complex coupling unresolved
  3. 2000 High

    Demonstrated that the human ortholog (EXOSC4) is a bona fide exosome subunit conserved enough to replace its yeast counterpart, with the human complex retaining exoribonuclease activity.

    Evidence cDNA cloning, fractionation, co-IP with patient sera, in vitro activity, and yeast complementation

    PMID:11110791

    Open questions at the time
    • Stoichiometry and ring architecture not yet defined
    • Functional substrate repertoire in human cells unaddressed
  4. 2002 Medium

    Defined how EXOSC4 fits into the complex architecturally by mapping its direct interactions in assembly of the six-membered RNase PH-like ring.

    Evidence Mammalian two-hybrid and co-immunoprecipitation

    PMID:12419256

    Open questions at the time
    • Assembly order/hierarchy not determined
    • Two-hybrid interactions not confirmed structurally
  5. 2002 High

    Placed Rrp41 in nuclear RNA surveillance and 3'-end processing by showing it degrades read-through transcripts from defective 3' cleavage.

    Evidence Conditional GAL::RRP41 depletion, Northern blotting, epistasis with rrp6 and rna14/rna15

    PMID:12086625

    Open questions at the time
    • Direct vs indirect substrate recognition not distinguished
  6. 2003 Medium

    Connected EXOSC4 to specific mammalian decay branches—NMD and AU-rich element-mediated decay—via physical association with pathway factors.

    Evidence Co-immunopurification with Upf1/2/3X and decapping/exonuclease factors plus siRNA decay-rate readouts

    PMID:12788944 PMID:14527413

    Open questions at the time
    • Direct vs complex-mediated interactions unresolved
    • Recruitment mechanism to NMD targets unknown
  7. 2006 High

    Provided the structural and biochemical foundation: reconstitution and crystallography of the human 9-subunit ring (including EXOSC4) revealed processive phosphorolytic activity and conserved decay surfaces.

    Evidence Recombinant reconstitution, in vitro exoribonuclease assays, X-ray crystallography at 3.35 Å

    PMID:17174896

    Open questions at the time
    • RNA path through the ring not yet visualized with substrate
    • Catalytic contribution of individual ring subunits unresolved
  8. 2006 High

    Reframed EXOSC4's catalytic role as primarily structural by showing its conserved active site is dispensable for exosome activity in yeast, in contrast to Dis3.

    Evidence Active-site mutagenesis with in vitro and in vivo functional readouts

    PMID:17173052

    Open questions at the time
    • Whether residual phosphorolytic activity matters in other species/contexts unresolved
  9. 2006 Medium

    Characterized EXOSC4's RNA-binding preference and its role in targeted decay pathways, including AU-rich element binding and ZAP-directed viral mRNA degradation.

    Evidence In vitro RNA-binding assays with AREs; co-sedimentation, co-IP, pull-down, and siRNA with viral mRNA stability readout

    PMID:16912217 PMID:17185417

    Open questions at the time
    • EXOSC4 does not contact ZAP directly—recruitment is via hRrp46p
    • Functional weight of ARE binding within the assembled ring unclear
  10. 2007 Medium

    Showed EXOSC4 is required for exosome complex stability and identified how Rrp44 docks onto the Rrp41 subunit to gate substrate access.

    Evidence siRNA co-depletion with gradient sedimentation and mRNA stability assays; EM reconstruction of Rrp44-bound exosome

    PMID:17545563 PMID:17942686

    Open questions at the time
    • Quantitative contribution of EXOSC4 loss to each subunit's stability not dissected
    • EM resolution limits atomic interpretation
  11. 2009 High

    Established the central mechanistic principle that RNA threads through the EXOSC4-containing ring channel to reach Rrp44, enabling processive degradation without helicases.

    Evidence X-ray crystallography (3.0 Å Rrp44-Rrp41-Rrp45) and biochemical threading assays with channel-blocking mutations

    PMID:19879841

    Open questions at the time
    • Substrate-specific routing rules not yet defined
  12. 2007 Medium

    Identified a regulatory feedback loop in which Rrp41 mRNA itself is a specific Dcp2 decapping substrate recognized through a 5' stem-loop structure.

    Evidence In vitro decapping and RNA-binding assays, reporter transfection, Dcp2 knockdown stability readout, and stem-loop mutagenesis

    PMID:18039849 PMID:19233875

    Open questions at the time
    • Physiological consequence of Rrp41 mRNA autoregulation not established
  13. 2012 High

    Mapped EXOSC4's direct transcriptome-wide RNA contacts in vivo, defining its substrate landscape including CUTs/SUTs, pre-tRNAs, snoRNAs, and unspliced pre-mRNAs.

    Evidence In vivo UV crosslinking and cDNA analysis (CRAC) of Rrp41 in yeast

    PMID:23000172

    Open questions at the time
    • Crosslink sites do not distinguish channel-threaded vs ring-surface contacts
  14. 2013 High

    Demonstrated that the EXOSC4/Rrp41 channel governs both exonucleolytic and endonucleolytic Dis3 activities and is essential in vivo, via channel-blocking mutants causing substrate accumulation and synthetic lethality with rrp6Δ.

    Evidence Channel-blocking mutagenesis, genetic epistasis, RNA accumulation assays, and reconstitution with thermophile exosomes

    PMID:23404585

    Open questions at the time
    • Direct relevance of channel routing to specific human substrates not tested here
  15. 2014 Medium

    Expanded EXOSC4's surveillance scope and linked it to disease-relevant phenotypes: degradation of minor U12-type intron-containing transcripts and a role in cancer cell proliferation and invasion.

    Evidence siRNA knockdown with RNA-seq and decay kinetics; knockdown with proliferation, invasion, and xenograft readouts

    PMID:24763612 PMID:24848017

    Open questions at the time
    • Cancer phenotype mechanism not yet tied to specific transcripts
    • Direct vs general exosome-loss effects not separated
  16. 2017 Medium

    Refined the channeling model by showing EXOSC4 channel access is differentially required for cytoplasmic versus nuclear substrates, implying distinct RNA routing between exosome populations.

    Evidence CRAC with channel-blocking Rrp41 mutants in yeast

    PMID:28355211

    Open questions at the time
    • Structural basis of nuclear vs cytoplasmic routing preference unresolved
  17. 2020 Medium

    Linked EXOSC4 to higher-order RNA regulation by showing its loss destabilizes the exosome, attenuates P-body formation, and impairs stress resistance, and confirmed predominant nuclear/nucleolar localization of the Rrp41 subunit.

    Evidence siRNA knockdown with P-body imaging and Western blotting; confocal microscopy of tagged Rrp41/Rrp43 in yeast

    PMID:32518284 PMID:32554806

    Open questions at the time
    • Mechanistic link between exosome integrity and P-body assembly not defined
    • Human localization not directly addressed in these studies
  18. 2022 Medium

    Identified specific downstream effectors of EXOSC4 in cancer, showing it destabilizes SESN2 mRNA and represses BIK to support tumor cell viability.

    Evidence siRNA knockdown, mRNA stability assays, and rescue knockdown of BIK/SESN2

    PMID:35008922

    Open questions at the time
    • Direct EXOSC4-target contact not demonstrated
    • Generality across cancer types untested
  19. 2024 High

    Established EXOSC4 as a Mendelian disease gene, mechanistically linking a missense variant to reduced protein stability, impaired exosome incorporation, blocked pre-rRNA processing, and translational defects.

    Evidence Exome sequencing with yeast modeling (Rrp41-L187P), co-purification, polysome profiling, and RNA accumulation assays

    PMID:39009343

    Open questions at the time
    • Patient tissue/cellular phenotype not directly examined
    • Genotype-phenotype range across variants not defined
  20. 2025 Medium

    Defined the assembly logic in which EXOSC4 initiates hierarchical mammalian exosome assembly and orphan unincorporated EXOSC4 is cleared by the proteasome, and showed humanized yeast distinguishes stability-defective from function-defective patient variants.

    Evidence Inducible CRISPR depletion in mES cells with proteasome inhibition; humanized yeast complementation with variant growth/protein-level assays

    PMID:39982806 PMID:bio_10.1101_2025.03.14.643291

    Open questions at the time
    • Assembly intermediates not structurally resolved
    • Preprint status for the assembly-hierarchy work

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EXOSC4 is recruited to specific substrate classes—including any chromatin-guided targeting of noncoding RNA surveillance—and the structural basis distinguishing nuclear from cytoplasmic substrate routing remain open.
  • EXOSC4-H3K9me3/H3K14ac chromatin recruitment not functionally validated (preprint, mass spec only)
  • No human structure of EXOSC4 with bound substrate in nuclear vs cytoplasmic contexts
  • Direct vs complex-mediated nature of most substrate interactions unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0140098 catalytic activity, acting on RNA 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
DCP2DIS3EXOSC2EXOSC4EXOSC7EXOSC9PM/SCL-75
Complex memberships
RNA exosomeRNase PH-like hexameric exosome ring

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Rrp41p (yeast ortholog of EXOSC4) is a component of the yeast exosome complex and exhibits phosphorolytic 3'→5' exoribonuclease activity in vitro; it is homologous to bacterial RNase PH and is required for 3' processing of 5.8S rRNA. Protein complex purification, in vitro exoribonuclease assay with recombinant protein, genetic depletion with rRNA processing phenotype readout Cell High 9390555
1998 SKI6/RRP41 (yeast ortholog of EXOSC4) is required for 3'→5' degradation of mRNA in yeast; both Ski6p/Rrp41p and Rrp4p are components of the exosome complex that carries out the 3'→5' mRNA decay pathway, and this pathway is modulated by Ski2p, Ski3p, and Ski8p. Genetic loss-of-function (ski6/rrp41 mutants), mRNA half-life measurements, epistasis with ski2/ski3/ski8 mutants The EMBO journal High 9482746
2000 Human Rrp41p (EXOSC4) is a component of the human exosome complex, localizes to the nucleus and nucleolus but is also present in the cytoplasm, co-fractionates with other human exosome subunits in a large complex, is co-immunoprecipitated by anti-PM/Scl patient sera, and the immunoprecipitated complex has 3'→5' exoribonuclease activity. Expression of hRrp41p in yeast complements lethality caused by depletion of yeast Rrp41p. cDNA cloning, recombinant protein expression, Western blotting, size exclusion chromatography, co-immunoprecipitation, in vitro exoribonuclease assay, yeast complementation The Journal of biological chemistry High 11110791
2002 Protein-protein interaction mapping shows that EXOSC4 (hRrp41p) participates in assembly of the six human RNase PH-like exosome subunits into a hexameric ring structure; mammalian two-hybrid assays identified direct protein-protein interactions between individual RNase PH-like subunits, and co-immunoprecipitation suggested at least two copies of hRrp41p associate with a single exosome. Mammalian two-hybrid system, co-immunoprecipitation Journal of molecular biology Medium 12419256
2002 Depletion of the core exosome component Rrp41p (yeast ortholog of EXOSC4) stabilizes long read-through transcripts generated from pre-mRNAs with defective 3' cleavage, and exosome processing of these read-through transcripts can generate functional, translatable mRNAs when uncoupled polyadenylation is permitted; this places Rrp41p in nuclear RNA surveillance and mRNA 3'-end processing. Genetic depletion of Rrp41p (GAL::RRP41), Northern blotting, epistasis with rrp6 and rna14/rna15 mutations Molecular cell High 12086625
2003 In mammalian nonsense-mediated mRNA decay (NMD), the exosome component Rrp41 co-immunopurifies with NMD factors Upf1, Upf2, and Upf3X as well as with decapping enzymes and other exonucleases, placing EXOSC4 (hRrp41) in the NMD pathway degradation complex. Co-immunopurification of NMD factors with exosome components, siRNA knockdown of exosome components with mRNA abundance and decay rate measurements Molecular cell Medium 14527413
2003 The N-terminal extension of PM/Scl-75 (hRrp75) mediates its association with the exosome complex through protein-protein interactions with hRrp46p and hRrp41p (EXOSC4), one of which was confirmed by mammalian two-hybrid assay; this interaction is required for stable exosome incorporation of PM/Scl-75. Deletion mutagenesis, co-immunoprecipitation, mammalian two-hybrid assay The Journal of biological chemistry Medium 12788944
2006 Reconstituted human 9-subunit exosome containing hRrp41 (EXOSC4)/hRrp45 exhibits processive phosphorolytic 3'→5' exoribonuclease activity on AU-rich, poly(A), and generic RNA substrates; the X-ray crystal structure of the 286 kDa nine-subunit human exosome at 3.35 Å resolution reveals the ring architecture and conserved surfaces for RNA decay. Recombinant reconstitution of 9-subunit human exosome, in vitro exoribonuclease assays with multiple RNA substrates, X-ray crystallography at 3.35 Å Cell High 17174896
2006 Mutations in Rrp41 (yeast ortholog of EXOSC4) do not abolish exosome core activity in vitro or cause clear RNA degradation phenotypes in vivo, in contrast to Dis3 mutations; the catalytically conserved phosphorolytic site in Rrp41 is not the primary source of exosome core enzymatic activity in yeast. Active-site mutagenesis of Rrp41 phosphorolytic residues, in vitro exoribonuclease assays, in vivo RNA degradation phenotype analysis Nature structural & molecular biology High 17173052
2006 ZAP antiviral protein recruits the RNA processing exosome (including hRrp41p/EXOSC4) to degrade target viral mRNAs; depletion of hRrp41p by siRNA significantly reduces ZAP's mRNA destabilizing activity; ZAP does not directly interact with hRrp41p but interacts directly with hRrp46p. Sucrose/glycerol gradient co-sedimentation, co-immunoprecipitation, in vitro pull-down assay, siRNA knockdown with mRNA stability readout Proceedings of the National Academy of Sciences of the United States of America Medium 17185417
2006 The RNase PH domain of RRP41 (EXOSC4) specifically binds AU-rich RNA elements (AREs) with affinity similar to other exosomal RNase PH domains; this sequence-specific RNA binding is competed by poly(U) but not other homopolymers. Deletion mutagenesis, in vitro RNA-binding assay with AU-rich element-containing RNAs RNA (New York, N.Y.) Medium 16912217
2006 Microarray analysis of yeast strains with Rrp41p/Ski6p mutation (core exosome) identifies specific nuclear RNA substrates that accumulate, including mRNAs for the Nrd1p RNA-binding protein and read-through transcripts from snoRNA/snRNA genes; the nuclear exosome processes these substrates via Rrp41p-dependent activity. Microarray expression analysis, Northern blotting, primer extension in rrp41/ski6 temperature-sensitive mutant yeast strains Yeast (Chichester, England) Medium 16652390
2007 The Rrp44 N-terminal domain anchors to the Rrp41 subunit (yeast ortholog of EXOSC4) in the 10-subunit exosome, functioning as a roadblock to restrict RNA access to the Rrp44 exoribonuclease active site, as determined by EM reconstructions of yeast core and Rrp44-bound exosome complexes. Electron microscopy reconstruction of core exosome and Rrp44-bound exosome complexes Proceedings of the National Academy of Sciences of the United States of America Medium 17942686
2007 Depletion of hRrp41p (EXOSC4) by siRNA reduces both nuclear and cytoplasmic exosome protein levels (co-depletion of other subunits), demonstrating that hRrp41p is required for maintenance of a stable exosome complex; it is also required for normal turnover of AU-rich element-containing and PTC-containing mRNAs. siRNA knockdown, glycerol gradient sedimentation, mRNA stability assays with reporter mRNAs RNA (New York, N.Y.) Medium 17545563
2007 hDcp2 decapping enzyme preferentially binds and decaps the mRNA encoding Rrp41 (EXOSC4); a 60-nucleotide element at the 5' end of Rrp41 mRNA is a specific Dcp2 substrate that confers more efficient decapping in vitro and in cells, and reduction of hDcp2 levels selectively stabilizes Rrp41 mRNA. In vitro decapping assay, RNA-binding assay, transfection with reporter constructs, siRNA knockdown of hDcp2 with mRNA stability readout Molecular and cellular biology Medium 18039849
2009 Biochemical studies show that RNAs thread through the central channel of the exosome core (involving Rrp41/EXOSC4 ring subunits) to reach the Rrp44 exoribonuclease site; evolutionary conserved residues mediate this channeling mechanism, enabling processive unwinding and degradation of RNA duplexes without additional helicases. X-ray crystallography (3.0 Å structure of Rrp44-Rrp41-Rrp45 complex), biochemical RNA threading assays with channel-blocking mutations Cell High 19879841
2009 Enhanced Dcp2-mediated decapping of the Rrp41 mRNA depends on the structural integrity (stem-loop) of the first 33 nucleotides of the mRNA, not its primary sequence; this demonstrates that Dcp2 recognizes 5' stem-loop structures as a general substrate feature, with Rrp41 mRNA as a validated target. Mutational analysis of 5' stem-loop, in vitro decapping assay, transfection with reporter mRNAs Nucleic acids research Medium 19233875
2012 In vivo UV crosslinking (CRAC) of the yeast exosome structural subunit Rrp41 (ortholog of EXOSC4) identifies its direct RNA-substrate contacts transcriptome-wide, including CUT/SUT noncoding RNAs, pre-tRNAs, snoRNAs, and unspliced pre-mRNAs targeted for oligoadenylation and degradation. In vivo UV crosslinking and cDNA analysis (CRAC) of Rrp41 and other exosome subunits in yeast Molecular cell High 23000172
2013 An Rrp41 (yeast ortholog of EXOSC4) ring subunit mutant with a partially blocked central channel causes thermosensitivity and synthetic lethality with Rrp6 deletion, and leads to accumulation of both nuclear and cytoplasmic exosome substrates including non-stop decay reporter; in vitro experiments with reconstituted exosomes confirm that the central channel controls both exonucleolytic and endonucleolytic Dis3 activities. Rrp41 channel-blocking mutagenesis, genetic epistasis (synthetic lethality with rrp6Δ), RNA accumulation assays, in vitro reconstitution with Chaetomium thermophilum exosomes Nucleic acids research High 23404585
2014 siRNA-mediated depletion of EXOSC4 in human cancer cell lines (liver, breast, bladder) inhibits cancer cell growth and invasive capacity without affecting normal cell growth, demonstrating a functional role for EXOSC4 in cancer cell proliferation and invasion. siRNA/shRNA knockdown, cell viability assay, invasion assay, xenograft tumor growth in mice Clinical cancer research Medium 24763612
2014 Knockdown of RRP41 (EXOSC4 ortholog) in human cells globally upregulates U12-type intron retention and slows the decay kinetics of U12-type intron-containing transcripts, placing EXOSC4/RRP41 in the nuclear surveillance pathway that degrades inefficiently spliced minor intron-containing pre-mRNAs. siRNA knockdown of RRP41, SOLiD RNA sequencing, kinetic decay assays of U12-type intron-containing transcripts Nucleic acids research Medium 24848017
2017 CRAC analysis in yeast shows that Rrp41 (EXOSC4 ortholog) mutations that impede RNA access to the central channel block substrate passage through the channel to Rrp44 specifically for cytoplasmic mRNAs, supporting distinct RNA routing in nuclear versus cytoplasmic exosome complexes; many exosome substrates show clear preference for channel-threading versus direct access routes. In vivo UV crosslinking and cDNA analysis (CRAC) of Rrp41 and other exosome subunits, comparison of channel-blocking Rrp41 mutants PLoS genetics Medium 28355211
2020 EXOSC2/EXOSC4 depletion in cancer cells attenuates P-body formation and stress resistance, coinciding with decreased EXOSC9 protein levels; this places EXOSC4 as required for maintaining exosome complex integrity and P-body-dependent stress adaptation in cancer cells. siRNA knockdown of EXOSC4, microscopic quantification of P-bodies, Western blotting for complex subunits, cell viability under stress conditions Scientific reports Medium 32518284
2020 In budding yeast, the core exosome subunits Rrp41 (EXOSC4 ortholog) and Rrp43 localize largely to the nucleus and strongly accumulate in the nucleolus, as determined by confocal microscopy, suggesting the primary function of these subunits is in early pre-rRNA processing and surveillance. Confocal fluorescence microscopy of tagged Rrp41 and Rrp43 in Saccharomyces cerevisiae The Journal of biological chemistry Medium 32554806
2022 EXOSC4 is amplified across multiple cancer types; EXOSC4 knockdown in pancreatic cancer cells reduces cell viability and acts by repressing BIK expression and destabilizing SESN2 mRNA through promoting its degradation; partial rescue by BIK and SESN2 knockdown confirms these as downstream effectors. siRNA knockdown, mRNA stability assays, rescue knockdown experiments, cell viability assays International journal of molecular sciences Medium 35008922
2024 A missense variant in EXOSC4 (p.Leu187Pro) causes a neurodevelopmental disorder; the corresponding yeast mutation Rrp41-L187P reduces steady-state protein levels, decreases EXOSC4-L187P copurification with other RNA exosome subunits, causes accumulation of RNA exosome target transcripts including the 7S pre-rRNA precursor, and leads to a decrease in actively translating ribosomes with apparent incorporation of 7S pre-rRNA into polysomes. Exome sequencing, yeast modeling of patient variant (Rrp41-L187P), polysome profiling, co-purification assays, RNA accumulation assays, Sanger sequencing for segregation The Journal of biological chemistry High 39009343
2024 EXOSC4 interacts with histone H3 co-modified with K9me3 and acetylations (H3K9me3 + H3K14ac); EXOSC4 depletion leads to downregulation of the RNA surveillance machinery and increased expression of non-coding transcripts including antisense RNAs, suggesting EXOSC4 is recruited via this histone code to surveil non-coding transcription. Multi-dimensional mass spectrometry, EXOSC4 depletion with transcriptomic readout of non-coding RNAs bioRxivpreprint Low bio_10.1101_2024.08.05.606680
2025 EXOSC4 is one of the initiating subunits (along with Exosc2 and Exosc7) in the sequential hierarchical assembly of the mammalian RNA exosome; orphan EXOSC4 subunits not incorporated into the complex are selectively degraded by the ubiquitin-proteasome system. Inducible dual-guide CRISPR/Cas9 depletion system in mouse embryonic stem cells, systematic subunit depletion and co-depletion analysis, proteasome inhibitor rescue experiments bioRxivpreprint Medium bio_10.1101_2025.03.14.643291
2025 In a humanized yeast model, disease-associated EXOSC4 variants can be functionally assessed; some patient-derived EXOSC4 variants cause reduced protein levels while others are expressed normally but show functional defects, indicating both stability-dependent and direct functional contributions of specific EXOSC4 residues to RNA exosome activity. Humanized yeast model (replacement of yeast Rrp41 with human EXOSC4 and disease variants), growth assays, protein level analysis G3 (Bethesda, Md.) Medium 39982806

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The exosome: a conserved eukaryotic RNA processing complex containing multiple 3'-->5' exoribonucleases. Cell 808 9390555
1998 The 3' to 5' degradation of yeast mRNAs is a general mechanism for mRNA turnover that requires the SKI2 DEVH box protein and 3' to 5' exonucleases of the exosome complex. The EMBO journal 545 9482746
2006 Reconstitution, activities, and structure of the eukaryotic RNA exosome. Cell 449 17174896
2006 A single subunit, Dis3, is essentially responsible for yeast exosome core activity. Nature structural & molecular biology 353 17173052
2003 Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities. Molecular cell 307 14527413
1998 Dob1p (Mtr4p) is a putative ATP-dependent RNA helicase required for the 3' end formation of 5.8S rRNA in Saccharomyces cerevisiae. The EMBO journal 279 9463390
2006 The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA. Proceedings of the National Academy of Sciences of the United States of America 233 17185417
2009 The yeast exosome functions as a macromolecular cage to channel RNA substrates for degradation. Cell 207 19879841
1996 The 3' end of yeast 5.8S rRNA is generated by an exonuclease processing mechanism. Genes & development 189 8600032
2005 The archaeal exosome core is a hexameric ring structure with three catalytic subunits. Nature structural & molecular biology 185 15951817
2012 Transcriptome-wide analysis of exosome targets. Molecular cell 164 23000172
2002 Processing of 3'-extended read-through transcripts by the exosome can generate functional mRNAs. Molecular cell 139 12086625
2003 An exosome-like complex in Sulfolobus solfataricus. EMBO reports 118 12947419
2005 Structural basis of 3' end RNA recognition and exoribonucleolytic cleavage by an exosome RNase PH core. Molecular cell 102 16285928
2000 Three novel components of the human exosome. The Journal of biological chemistry 101 11110791
2007 RNA channelling by the archaeal exosome. EMBO reports 99 17380186
2014 Genome-wide study of hypomethylated and induced genes in patients with liver cancer unravels novel anticancer targets. Clinical cancer research : an official journal of the American Association for Cancer Research 92 24763612
2007 Architecture of the yeast Rrp44 exosome complex suggests routes of RNA recruitment for 3' end processing. Proceedings of the National Academy of Sciences of the United States of America 92 17942686
2005 A nuclear surveillance pathway for mRNAs with defective polyadenylation. Molecular and cellular biology 85 16260613
2002 Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. Journal of molecular biology 82 12419256
2007 Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA (New York, N.Y.) 74 17545563
2001 Autoantibodies directed to novel components of the PM/Scl complex, the human exosome. Arthritis research 72 11879549
2006 Microarray detection of novel nuclear RNA substrates for the exosome. Yeast (Chichester, England) 62 16652390
2007 Transcript-specific decapping and regulated stability by the human Dcp2 decapping protein. Molecular and cellular biology 55 18039849
2013 The RNA exosome complex central channel controls both exonuclease and endonuclease Dis3 activities in vivo and in vitro. Nucleic acids research 50 23404585
2008 Insights into the mechanism of progressive RNA degradation by the archaeal exosome. The Journal of biological chemistry 50 18353775
2006 Characterization of native and reconstituted exosome complexes from the hyperthermophilic archaeon Sulfolobus solfataricus. Molecular microbiology 46 17078816
2018 Diversity of copy number variation in the worldwide goat population. Heredity 45 30401973
2024 Genomic hallmarks and therapeutic targets of ribosome biogenesis in cancer. Briefings in bioinformatics 44 38343327
2017 Transcriptome-wide analysis of alternative routes for RNA substrates into the exosome complex. PLoS genetics 36 28355211
2017 RNA degradation by the plant RNA exosome involves both phosphorolytic and hydrolytic activities. Nature communications 35 29255150
2015 Genome-wide screen of DNA methylation identifies novel markers in childhood obesity. Gene 32 25871514
2006 Sequence-specific RNA binding mediated by the RNase PH domain of components of the exosome. RNA (New York, N.Y.) 32 16912217
2014 Structure and function of the archaeal exosome. Wiley interdisciplinary reviews. RNA 30 24789718
2020 EXOSC9 depletion attenuates P-body formation, stress resistance, and tumorigenicity of cancer cells. Scientific reports 29 32518284
2014 Global analysis of the nuclear processing of transcripts with unspliced U12-type introns by the exosome. Nucleic acids research 29 24848017
2022 The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families. Scientific reports 28 36344539
2009 Mutational analysis of a Dcp2-binding element reveals general enhancement of decapping by 5'-end stem-loop structures. Nucleic acids research 25 19233875
2003 The association of the human PM/Scl-75 autoantigen with the exosome is dependent on a newly identified N terminus. The Journal of biological chemistry 24 12788944
2016 TMV induces RNA decay pathways to modulate gene silencing and disease symptoms. The Plant journal : for cell and molecular biology 22 27599263
2012 Heterogeneous complexes of the RNA exosome in Sulfolobus solfataricus. Biochimie 22 22503705
2010 The evolutionarily conserved subunits Rrp4 and Csl4 confer different substrate specificities to the archaeal exosome. FEBS letters 22 20488184
2018 EXOSC4 functions as a potential oncogene in development and progression of colorectal cancer. Molecular carcinogenesis 18 30155936
2010 The archaeal exosome localizes to the membrane. FEBS letters 15 20488181
2022 RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival. International journal of molecular sciences 14 35008922
2019 miR‑148 family members are putative biomarkers for sepsis. Molecular medicine reports 14 31059023
2016 The oligomeric architecture of the archaeal exosome is important for processive and efficient RNA degradation. Nucleic acids research 13 26837575
2021 Nrd1p identifies aberrant and natural exosomal target messages during the nuclear mRNA surveillance in Saccharomyces cerevisiae. Nucleic acids research 11 34664673
2021 Exosome Component 4 Promotes Epithelial Ovarian Cancer Cell Proliferation, Migration, and Invasion via the Wnt Pathway. Frontiers in oncology 10 34956910
2020 Nucleolar localization of the yeast RNA exosome subunit Rrp44 hints at early pre-rRNA processing as its main function. The Journal of biological chemistry 10 32554806
2018 Altered expression of WFS1 and NOTCH2 genes associated with diabetic nephropathy in T2DM patients. Diabetes research and clinical practice 10 29626590
2024 A biallelic variant of the RNA exosome gene, EXOSC4, associated with neurodevelopmental defects impairs RNA exosome function and translation. The Journal of biological chemistry 8 39009343
2020 STX2 drives colorectal cancer proliferation via upregulation of EXOSC4. Life sciences 8 33075373
2024 RUNX3 exerts tumor-suppressive role through inhibiting EXOSC4 expression. Functional & integrative genomics 7 38913281
2011 The archaeal exosome. Advances in experimental medicine and biology 7 21713675
2013 Experimental analysis of co-evolution within protein complexes: the yeast exosome as a model. Proteins 6 23852635
2012 Plant Exosomes and Cofactors. The Enzymes 6 27166439
2010 The archaeal exosome. Advances in experimental medicine and biology 5 21618872
2025 Identification EXOSC4 as a novel autoantigen of interstitial lung disease in rheumatoid arthritis. Journal of translational medicine 4 40640919
2023 In vivo characterization of the critical interaction between the RNA exosome and the essential RNA helicase Mtr4 in Saccharomyces cerevisiae. G3 (Bethesda, Md.) 4 36861343
2021 m6A Regulator Expression Segregates Meningiomas Into Biologically Distinct Subtypes. Frontiers in oncology 4 35004283
2022 The Revelation of Continuously Organized, Co-Overexpressed Protein-Coding Genes with Roles in Cellular Communications in Breast Cancer. Cells 3 36497066
2025 Uncovering the genetic basis of milk production traits in Mexican Holstein cattle based on individual markers and genomic windows. PloS one 2 39899530
2026 Ribosomal Protein RPL29 Promotes Hepatocellular Carcinoma Progression Through Regulation the Expression of Exosome Component 4. Biological procedures online 0 41484694
2026 EXOSC4 as a novel regulator of neddylation in acute myeloid leukemia. Scientific reports 0 42128900
2026 Upregulation of the Mitophagy-Related Gene EXOSC4 Is Associated with Immune Dysregulation in Spinal Cord Injury. Molecular neurobiology 0 42166074
2026 Construction of a diagnostic model for colorectal cancer based on exosome-related genes: integration of immune cell differentials and molecular docking. Translational cancer research 0 42180950
2025 Humanized Saccharomyces cerevisiae provides a facile and effective tool to identify damaging human variants that cause exosomopathies. G3 (Bethesda, Md.) 0 39982806
2023 A Biallelic Variant of the RNA Exosome Gene EXOSC4 Causes Translational Defects Associated with a Neurodevelopmental Disorder. medRxiv : the preprint server for health sciences 0 37961665
2023 [Expression and Clinical Significance of Exosome Component 4 in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma]. Zhongguo shi yan xue ye xue za zhi 0 38071046
2020 Enzymatic Analysis of Reconstituted Archaeal Exosomes. Methods in molecular biology (Clifton, N.J.) 0 31768972

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