Affinage

EXOSC5

Exosome complex component RRP46 · UniProt Q9NQT4

Round 2 corrected
Length
235 aa
Mass
25.2 kDa
Annotated
2026-04-28
37 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EXOSC5 (Rrp46/PM-Scl75) is a structural, non-catalytic subunit of the nine-subunit RNA exosome core complex that functions in 3'→5' RNA processing, surveillance, and degradation. Within the exosome ring, EXOSC5 directly contacts AU-rich elements (AREs) on mRNAs and is required for efficient cytoplasmic ARE-mediated mRNA decay (PMID:11719186, PMID:11782436); the exosome core complex also associates with activation-induced cytidine deaminase (AID) to facilitate immunoglobulin class switch recombination by enabling transcription-dependent DNA deamination of switch regions (PMID:21255825). Biallelic loss-of-function variants in EXOSC5 cause a neurodevelopmental syndrome with cerebellar hypoplasia, and pathogenic variants disrupt exosome complex integrity in yeast and zebrafish models (PMID:32504085). In cancer contexts, EXOSC5 promotes proliferation and stemness through STAT3/AKT signaling and regulation of the NTN4/integrin β1/FAK/SRC/c-MYC axis (PMID:35371329, PMID:38164180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Identification of Rrp46 as a core exosome subunit established that EXOSC5 is part of a conserved multi-subunit 3'→5' exoribonuclease complex present in both nucleus and cytoplasm of eukaryotes.

    Evidence Biochemical fractionation, indirect immunofluorescence, and complementation assays in yeast with identification of human homologs

    PMID:10465791

    Open questions at the time
    • Catalytic versus structural role of individual subunits not resolved
    • Substrate specificity of individual subunits unknown
  2. 2001 High

    Demonstrating that EXOSC5/PM-Scl75 directly binds AU-rich elements and that the exosome complex is required for ARE-mediated mRNA decay answered how specific mRNA substrates are recruited for 3'→5' degradation.

    Evidence Immunodepletion of PM-Scl75 from HeLa cytoplasmic extracts abolished ARE-dependent 3'→5' decay; RNA-protein interaction assays showed direct ARE binding

    PMID:11719186 PMID:11782436

    Open questions at the time
    • Whether EXOSC5 ARE binding is sufficient for recruitment or requires cofactors
    • In vivo target mRNA repertoire not defined
  3. 2006 High

    The crystal structure of the human nine-subunit exosome resolved EXOSC5 as a structural ring component, demonstrating that catalytic activity resides in the Rrp41/Rrp45 heterodimer rather than in EXOSC5 itself.

    Evidence X-ray crystallography at 3.35 Å with reconstitution and biochemical activity assays

    PMID:17174896

    Open questions at the time
    • How EXOSC5 contributes to RNA threading through the channel not resolved
    • Dynamics of subunit assembly in vivo unclear
  4. 2010 High

    Structural and biochemical analysis of EXOSC5 orthologs revealed unexpected homodimerization and DNA-binding capacity, expanding the possible roles of Rrp46-family proteins beyond the exosome ring.

    Evidence Crystal structures of C. elegans CRN-5 and rice Rrp46; site-directed mutagenesis; in vitro nuclease and DNA-binding assays; co-IP

    PMID:20660080

    Open questions at the time
    • Physiological relevance of homodimerization and DNA binding for human EXOSC5 not demonstrated
    • Whether human EXOSC5 possesses latent catalytic activity under specific conditions remains untested
  5. 2011 High

    Discovery that the exosome core associates with AID and accumulates on immunoglobulin switch regions revealed an unexpected role for the RNA exosome—including EXOSC5—in antibody class switch recombination via transcription-dependent DNA deamination.

    Evidence Co-IP, ChIP on switch regions, and in vitro transcription/deamination assay with recombinant exosome core in activated B cells

    PMID:21255825

    Open questions at the time
    • Individual contribution of EXOSC5 versus other ring subunits to AID targeting not dissected
    • Whether exosome facilitates somatic hypermutation through a similar mechanism unclear
  6. 2020 High

    Identification of biallelic EXOSC5 variants causing a neurodevelopmental syndrome with cerebellar hypoplasia established the gene as essential for brain development and demonstrated that pathogenic variants disrupt exosome complex integrity.

    Evidence Zebrafish morpholino knockdown phenocopied features; yeast complementation showed functional deficits; co-IP revealed altered subunit interactions

    PMID:32504085

    Open questions at the time
    • Specific RNA targets dysregulated in developing brain not identified
    • Genotype–phenotype relationships across different EXOSC5 variants not fully defined
  7. 2022 Medium

    EXOSC5 was shown to promote cancer cell proliferation and cell-cycle progression through AKT and STAT3 signaling, suggesting exosome-independent or RNA-target-dependent oncogenic functions.

    Evidence siRNA knockdown in gastric and hepatocellular carcinoma cells with proliferation assays, flow cytometry, Western blotting, xenograft models

    PMID:35371329 PMID:36293016

    Open questions at the time
    • Direct RNA substrates linking EXOSC5 to STAT3/AKT activation not identified
    • Whether these effects are exosome-complex-dependent or subunit-autonomous not tested
    • Single-lab findings for HCC; limited mechanistic depth beyond phospho-Western blots
  8. 2024 Medium

    Linking EXOSC5 to cancer stemness through regulation of NTN4 and the integrin β1/FAK/SRC/c-MYC axis provided a downstream pathway for EXOSC5's pro-tumorigenic activity in endometrial cancer.

    Evidence siRNA knockdown with NTN4 rescue, tumor sphere assays, limiting dilution assays, and tissue correlation in 93 endometrial cancer specimens

    PMID:38164180

    Open questions at the time
    • Whether EXOSC5 regulates NTN4 mRNA stability directly via exosome-mediated decay or through an indirect mechanism not established
    • Generalizability beyond endometrial cancer not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of specific RNA targets whose stability is controlled by EXOSC5 in normal tissues, the mechanism by which EXOSC5 structural variants cause selective neuronal vulnerability, and whether cancer-associated functions depend on the intact exosome complex or on exosome-independent activities.
  • No transcriptome-wide direct target map (e.g., CLIP-seq) for EXOSC5
  • No structural basis for how pathogenic missense variants alter exosome function
  • Exosome-dependent versus -independent oncogenic mechanisms not disambiguated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0005198 structural molecule activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-168256 Immune System 1
Partners
AICDADIS3EXOSC4EXOSC6EXOSC7EXOSC8EXOSC9
Complex memberships
RNA exosome core complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Rrp46 (EXOSC5 ortholog) was identified as one of six novel components of the yeast exosome, a complex of 3'→5' exoribonucleases involved in RNA processing and degradation. Human homologs of nine of the eleven yeast exosome components were identified, and nuclear and cytoplasmic forms of the complex were demonstrated to exist in both yeast and humans. Biochemical fractionation, indirect immunofluorescence, complementation assays Genes & development High 10465791
2001 The human exosome, which includes PM-Scl75 (EXOSC5), was purified and characterized by mass spectrometry. The complex was shown to be required for rapid degradation of ARE-containing mRNAs but not for poly(A) shortening. PM-Scl75 was found to interact specifically with AU-rich elements (AREs), implicating EXOSC5 directly in ARE-mediated mRNA decay. Mass spectrometry, immunodepletion, cell-free RNA decay assay, RNA-protein interaction assays Cell High 11719186 11782436
2002 The human exosome (containing EXOSC5/PM-Scl75) is required for efficient 3'→5' exonucleolytic decay of ARE-containing mRNAs in HeLa cytoplasmic extracts. Immunodepletion of PM-Scl75 abolished this activity, and ARE sequences dramatically stimulated 3'→5' decay, establishing the exosome as the major cytoplasmic 3'→5' RNA decay pathway. In vitro RNA deadenylation/decay assay, immunodepletion with anti-PM-Scl75 antibodies, phosphorothioate-modified RNA trapping The EMBO journal High 11782436
2006 The X-ray crystal structure of the 286 kDa nine-subunit human exosome was determined at 3.35 Å resolution, revealing EXOSC5 (Rrp46) as a structural subunit. Reconstitution experiments showed the human 9-subunit exosome has processive phosphorolytic activity, contributed by the Rrp41/Rrp45 heterodimer, while EXOSC5/Rrp46 plays a structural role within the ring. X-ray crystallography, in vitro reconstitution, biochemical activity assays with diverse RNA substrates Cell High 17174896
2010 Crystal structures of C. elegans CRN-5 (EXOSC5 ortholog) and rice Rrp46 were determined at 3.9 Å and 2.0 Å resolution, respectively. Human Rrp46 (EXOSC5), rice Rrp46, and CRN-5 were found to form homodimers both in recombinant form and in cellular environments, in addition to their association with the exosome complex. Human Rrp46 bound DNA without detectable nuclease activity, while rice Rrp46 had both phosphorolytic RNase and hydrolytic DNase activities. Site-directed mutagenesis (E160Q abolished DNase; K75E/Q76E abolished RNase) confirmed catalytic residues. CRN-5 directly interacted with apoptotic nuclease CRN-4 and enhanced its DNase activity. X-ray crystallography, co-immunoprecipitation, site-directed mutagenesis, in vitro nuclease assays, size-exclusion chromatography RNA (New York, N.Y.) High 20660080
2011 The RNA exosome core complex (including EXOSC5) associates with activation-induced cytidine deaminase (AID) in B cells activated for class switch recombination (CSR). The exosome accumulates on immunoglobulin heavy-chain switch regions in an AID-dependent manner and is required for optimal CSR. A recombinant RNA exosome core complex conferred robust AID- and transcription-dependent DNA deamination of both strands of transcribed substrates in vitro, revealing a role for the exosome in antibody diversity generation. Co-immunoprecipitation, ChIP, in vitro transcription/deamination assay with recombinant exosome core, genetic knockdown of exosome subunits Cell High 21255825
2020 EXOSC5 was identified as a structural (non-catalytic) subunit of the RNA exosome required for brain development. Biallelic loss-of-function variants in EXOSC5 cause a neurodevelopmental syndrome. Loss of exosc5 in zebrafish caused shortened/curved bodies, reduced eye/head size, and edema. Pathogenic EXOSC5 variants modeled in budding yeast caused defects in RNA exosome function and altered interactions with other RNA exosome subunits, demonstrating that specific variants disrupt exosome complex integrity. Zebrafish morpholino knockdown, yeast complementation assays, mammalian cell modeling of variants, interaction assays (co-immunoprecipitation of exosome subunits) Human molecular genetics High 32504085
2020 EXOSC5 was identified as a physical interaction partner of SARS-CoV-2 Nsp8 protein by affinity-purification mass spectrometry, placing it in the host-viral protein interaction network relevant to COVID-19 pathogenesis. Affinity-purification mass spectrometry (AP-MS) of tagged SARS-CoV-2 proteins expressed in human cells Nature Low 32353859
2022 EXOSC5 knockdown in gastric cancer cells inhibited proliferation, induced G1/S phase arrest, increased p21 and p27 levels, and decreased cyclinD1 expression. Mechanistically, EXOSC5 was shown to promote cell cycle progression through activation of AKT and STAT3 signaling pathways. siRNA knockdown, CCK-8 proliferation assay, flow cytometry, Western blotting, GC organoid model, nude mouse xenograft Journal of Cancer Medium 35371329
2022 EXOSC5 knockdown in hepatocellular carcinoma cells inhibited cell growth and proliferation. Mechanistically, EXOSC5 promoted cell proliferation via activation of STAT3 signaling. siRNA knockdown, cell proliferation assays, Western blotting for STAT3 pathway components International journal of molecular sciences Low 36293016
2024 EXOSC5 maintains cancer stem cell (CSC) activity in endometrial cancer by regulating expression of netrin-4 (NTN4). NTN4, when secreted, binds integrin β1 and activates the FAK/SRC signaling axis to elevate c-MYC activity. EXOSC5 knockdown reduced NTN4 levels, diminished CSC self-renewal, reduced c-MYC and SOX2 expression, and curtailed tumorigenicity in tumor spheres. siRNA knockdown, tumor sphere assays, Western blotting, NTN4 rescue experiments, limiting dilution CSC frequency assay, tissue correlation analysis (n=93 EC tissues) International journal of biological sciences Medium 38164180

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2005 Nucleolar proteome dynamics. Nature 934 15635413
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2001 AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 736 11719186
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2006 Reconstitution, activities, and structure of the eukaryotic RNA exosome. Cell 449 17174896
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
1999 The yeast exosome and human PM-Scl are related complexes of 3' --> 5' exonucleases. Genes & development 390 10465791
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2002 The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. The EMBO journal 300 11782436
2011 DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling. Molecular and cellular biology 251 21791617
2011 The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 248 21255825
2020 Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness. Human molecular genetics 29 32504085
2009 Transcript-based cloning of RRP46, a regulator of rRNA processing and R gene-independent cell death in barley-powdery mildew interactions. The Plant cell 22 19861556
2021 Risk of sudden cardiac death in EXOSC5-related disease. American journal of medical genetics. Part A 12 34089229
2010 Structural and biochemical characterization of CRN-5 and Rrp46: an exosome component participating in apoptotic DNA degradation. RNA (New York, N.Y.) 12 20660080
2024 EXOSC5 maintains cancer stem cell activity in endometrial cancer by regulating the NTN4/integrin β1 signalling axis. International journal of biological sciences 10 38164180
2022 EXOSC5 promotes proliferation of gastric cancer through regulating AKT/STAT3 signaling pathways. Journal of Cancer 10 35371329
2022 Integrated Bioinformatic Investigation of EXOSCs in Hepatocellular Carcinoma Followed by the Preliminary Validation of EXOSC5 in Cell Proliferation. International journal of molecular sciences 4 36293016