{"gene":"EXOSC2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"Biallelic missense mutations in EXOSC2 cause a novel syndrome (SHRF), demonstrating that EXOSC2 is a core component of the RNA exosome complex essential for normal development; patient-derived mutations were identified by whole exome sequencing and confirmed to affect EXOSC2 function.","method":"Whole exome sequencing of affected patients; clinical genetics establishing biallelic missense variants in EXOSC2","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — clinical genetic identification with variant confirmation in multiple families; no in vitro biochemical reconstitution reported in this abstract","pmids":["26843489"],"is_preprint":false},{"year":2020,"finding":"The pathogenic EXOSC2 G198D mutation prevents binding to other RNA exosome components, resulting in protein and complex instability; wild-type human EXOSC2 but not the G198D mutant could rescue Drosophila rrp4 loss-of-function phenotypes, establishing that EXOSC2 functions as an essential RNA exosome subunit whose integrity is required for exosome complex stability and autophagy pathway gene regulation.","method":"Co-immunoprecipitation in patient-derived lymphoblasts; CRISPR knockout in fetal keratinocytes; Drosophila rrp4 mutant rescue experiments with wild-type vs. pathogenic human EXOSC2; pharmacological autophagy stimulation (rapamycin rescue)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay showing loss of complex assembly by G198D, cross-species functional rescue distinguishing WT from pathogenic allele, multiple orthogonal methods across human cells and Drosophila model","pmids":["31628467"],"is_preprint":false},{"year":2008,"finding":"The archaeal Rrp4 subunit (ortholog of EXOSC2) is required for efficient RNA degradation but not polyadenylation by the exosome; the Rrp4-containing exosome preferentially degrades poly(A) RNA, while the catalytically active hexameric ring alone is insufficient for efficient phosphorolysis of structured or natural RNA substrates.","method":"In vitro biochemical reconstitution of archaeal exosome subcomplexes (hexamer vs. Rrp4-exosome vs. Csl4-exosome); RNA degradation and polyadenylation assays under varying conditions","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined subcomplexes, multiple substrate and condition comparisons; single lab but rigorous biochemical dissection","pmids":["19053279"],"is_preprint":false},{"year":2010,"finding":"The archaeal Rrp4 subunit (ortholog of EXOSC2) confers poly(A)-RNA substrate preference to the exosome complex, distinct from the Csl4 subunit which prefers A-poor 3'-ends; high C-content and polyuridylation negatively influence processing by all complexes, and the Rrp4-exosome prefers longer substrates.","method":"In vitro RNA processing assays comparing hexameric exosome core with Rrp4-exosome and Csl4-exosome using defined RNA substrates","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematically varied substrates; single lab replicating and extending findings from prior study","pmids":["20488184"],"is_preprint":false},{"year":2017,"finding":"The trimeric Rrp4 cap (archaeal ortholog of EXOSC2-containing cap) recruits RNA substrates via a 50-Å long RNA binding path on each Rrp4 protomer, allowing simultaneous recruitment of three substrates; interaction energy increases from the cap periphery toward the active sites, and substrate binding to the cap is weakened upon entry into the catalytic barrel to reduce friction during translocation.","method":"Methyl-TROSY NMR spectroscopy identifying RNA binding path on Rrp4; quantitative binding measurements of exosome-substrate interactions at defined steps","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure-function study with mechanistic dissection of substrate channeling, rigorous quantitative binding measurements, single lab with multiple orthogonal NMR methods","pmids":["28288106"],"is_preprint":false}],"current_model":"EXOSC2 (RRP4) is an essential cap subunit of the RNA exosome complex that directly binds RNA substrates via a defined binding path, confers poly(A)-RNA substrate preference to the complex, and is required for efficient RNA degradation (but not polyadenylation) by channeling substrates toward the catalytic core; pathogenic missense mutations (e.g., G198D) disrupt binding to other exosome subunits, destabilize the complex, and dysregulate autophagy pathway genes, causing the SHRF syndrome."},"narrative":{"mechanistic_narrative":"EXOSC2 (RRP4) is an essential cap subunit of the RNA exosome complex required for efficient RNA degradation and normal development [PMID:31628467, PMID:19053279]. Through its archaeal ortholog, EXOSC2 directly binds RNA substrates along an extended ~50-A binding path on each cap protomer, recruiting substrates at the cap periphery and progressively releasing them as they enter the catalytic barrel to reduce friction during translocation toward the active sites [PMID:28288106]. The EXOSC2-containing cap confers a substrate preference for poly(A) RNA and longer substrates, and is required for efficient phosphorolytic degradation of structured and natural RNAs that the catalytic hexameric ring cannot process alone, while being dispensable for polyadenylation [PMID:19053279, PMID:20488184]. Integrity of EXOSC2 is required for assembly and stability of the entire exosome: the pathogenic G198D mutation abolishes binding to other exosome subunits and destabilizes the complex, and wild-type but not G198D human EXOSC2 rescues Drosophila rrp4 loss of function [PMID:31628467]. Biallelic EXOSC2 missense mutations cause the SHRF syndrome, with loss of exosome function dysregulating autophagy pathway gene expression [PMID:26843489, PMID:31628467].","teleology":[{"year":2008,"claim":"Established that the Rrp4/EXOSC2 cap subunit is functionally required for efficient RNA degradation, answering whether the catalytic core alone suffices for exosome activity.","evidence":"In vitro reconstitution of archaeal exosome subcomplexes with RNA degradation and polyadenylation assays","pmids":["19053279"],"confidence":"High","gaps":["Done in archaeal system; human EXOSC2-specific contributions not directly tested","Mechanism by which the cap enables degradation of structured substrates not resolved"]},{"year":2010,"claim":"Defined that the Rrp4/EXOSC2 cap dictates substrate selectivity, showing it imparts poly(A)-RNA and long-substrate preference distinct from the Csl4 cap.","evidence":"In vitro RNA processing assays comparing hexameric core, Rrp4-exosome and Csl4-exosome with defined substrates","pmids":["20488184"],"confidence":"High","gaps":["Archaeal model; selectivity in human exosome not directly confirmed","Structural basis of preference not addressed"]},{"year":2016,"claim":"Connected EXOSC2 to human disease, establishing it as a developmentally essential exosome component by linking biallelic missense variants to the SHRF syndrome.","evidence":"Whole exome sequencing of affected patients with variant confirmation across families","pmids":["26843489"],"confidence":"Medium","gaps":["No in vitro biochemical mechanism for the variants in this study","Cellular consequence of mutations not established"]},{"year":2017,"claim":"Resolved how the cap physically channels substrates, mapping a 50-A RNA binding path per protomer and a binding-affinity gradient that hands substrates to the catalytic barrel.","evidence":"Methyl-TROSY NMR spectroscopy with quantitative substrate-binding measurements at defined steps","pmids":["28288106"],"confidence":"High","gaps":["Archaeal Rrp4 structure; human EXOSC2 path not directly mapped","Coupling of cap binding to catalytic turnover kinetics not fully resolved"]},{"year":2020,"claim":"Demonstrated the mechanism of pathogenicity, showing G198D abolishes exosome assembly and dysregulates autophagy genes, and that wild-type EXOSC2 integrity is required for complex stability.","evidence":"Co-IP in patient lymphoblasts, CRISPR knockout in keratinocytes, Drosophila rrp4 cross-species rescue, and rapamycin autophagy stimulation","pmids":["31628467"],"confidence":"High","gaps":["Direct link between exosome loss and specific autophagy gene transcripts not fully defined","Tissue-specific basis of SHRF phenotypes unresolved"]},{"year":null,"claim":"Whether the substrate-channeling and selectivity properties characterized in archaeal Rrp4 operate identically in the human EXOSC2-containing exosome, and how these connect mechanistically to the autophagy dysregulation seen in SHRF, remains open.","evidence":"","pmids":[],"confidence":"High","gaps":["No human EXOSC2 structural binding-path study in the corpus","Direct RNA substrate repertoire of human EXOSC2-exosome not defined","Mechanistic link between exosome substrate handling and autophagy gene regulation unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3]}],"complexes":["RNA exosome"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13868","full_name":"Exosome complex component RRP4","aliases":["Exosome component 2","Ribosomal RNA-processing protein 4"],"length_aa":293,"mass_kda":32.8,"function":"Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC2 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC4 and EXOSC7","subcellular_location":"Cytoplasm; Nucleus, nucleolus; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13868/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOSC2","classification":"Common Essential","n_dependent_lines":1185,"n_total_lines":1208,"dependency_fraction":0.9809602649006622},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DRG1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM7","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SFPQ","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EXOSC2","total_profiled":1310},"omim":[{"mim_id":"617763","title":"SHORT STATURE, HEARING LOSS, RETINITIS PIGMENTOSA, AND DISTINCTIVE FACIES; SHRF","url":"https://www.omim.org/entry/617763"},{"mim_id":"614183","title":"DIS3-LIKE EXOSOME 3-PRIME-5-PRIME EXORIBONUCLEASE; DIS3L","url":"https://www.omim.org/entry/614183"},{"mim_id":"602238","title":"EXOSOME COMPONENT 2; EXOSC2","url":"https://www.omim.org/entry/602238"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EXOSC2"},"hgnc":{"alias_symbol":["hRrp4p","Rrp4p","RRP4","p7"],"prev_symbol":[]},"alphafold":{"accession":"Q13868","domains":[{"cath_id":"2.40.50.100","chopping":"25-70","consensus_level":"high","plddt":88.2417,"start":25,"end":70}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13868","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13868-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13868-F1-predicted_aligned_error_v6.png","plddt_mean":81.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOSC2","jax_strain_url":"https://www.jax.org/strain/search?query=EXOSC2"},"sequence":{"accession":"Q13868","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13868.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13868/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13868"}},"corpus_meta":[{"pmid":"12560074","id":"PMC_12560074","title":"The p7 protein 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secretion of IL-1β in macrophages.","date":"2014","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/25146005","citation_count":30,"is_preprint":false},{"pmid":"12655100","id":"PMC_12655100","title":"Assembly of single-shelled cores and double-shelled virus-like particles after baculovirus expression of major structural proteins P3, P7 and P8 of Rice dwarf virus.","date":"2003","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/12655100","citation_count":30,"is_preprint":false},{"pmid":"25053050","id":"PMC_25053050","title":"A cell-penetrating peptide analogue, P7, exerts antimicrobial activity against Escherichia coli ATCC25922 via penetrating cell membrane and targeting intracellular DNA.","date":"2014","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25053050","citation_count":29,"is_preprint":false},{"pmid":"23271163","id":"PMC_23271163","title":"The secretory pathway and the actomyosin motility system are required for plasmodesmatal localization of the P7-1 of rice black-streaked dwarf virus.","date":"2012","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23271163","citation_count":28,"is_preprint":false},{"pmid":"16406630","id":"PMC_16406630","title":"Lack of cross-reactivity between the Bacillus thuringiensis derived protein Cry1F in maize grain and dust mite Der p7 protein with human sera positive for Der p7-IgE.","date":"2006","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/16406630","citation_count":28,"is_preprint":false},{"pmid":"24176102","id":"PMC_24176102","title":"Nonstructural protein P7-2 encoded by Rice black-streaked dwarf virus interacts with SKP1, a core subunit of SCF ubiquitin ligase.","date":"2013","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/24176102","citation_count":28,"is_preprint":false},{"pmid":"10809733","id":"PMC_10809733","title":"Inactivation of HIV-1 nucleocapsid protein P7 by pyridinioalkanoyl thioesters. Characterization of reaction products and proposed mechanism of action.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10809733","citation_count":28,"is_preprint":false},{"pmid":"10400638","id":"PMC_10400638","title":"Peptide specificity determinants at P-7 and P-6 enhance the catalytic efficiency of Ca2+/calmodulin-dependent protein kinase I in the absence of activation loop phosphorylation.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10400638","citation_count":28,"is_preprint":false},{"pmid":"28159892","id":"PMC_28159892","title":"Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28159892","citation_count":28,"is_preprint":false},{"pmid":"22896624","id":"PMC_22896624","title":"Packaging accessory protein P7 and polymerase P2 have mutually occluding binding sites inside the bacteriophage 6 procapsid.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22896624","citation_count":27,"is_preprint":false},{"pmid":"23246447","id":"PMC_23246447","title":"The p7 protein of the hepatitis C virus induces cell death differently from the influenza A virus viroporin M2.","date":"2012","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/23246447","citation_count":27,"is_preprint":false},{"pmid":"11279121","id":"PMC_11279121","title":"Structural properties of carnation mottle virus p7 movement protein and its RNA-binding domain.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11279121","citation_count":27,"is_preprint":false},{"pmid":"8573160","id":"PMC_8573160","title":"The Vpr protein of human immunodeficiency virus type 1 binds to nucleocapsid protein p7 in vitro.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8573160","citation_count":27,"is_preprint":false},{"pmid":"24189547","id":"PMC_24189547","title":"Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function.","date":"2013","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/24189547","citation_count":27,"is_preprint":false},{"pmid":"32223157","id":"PMC_32223157","title":"Assessment of the Multifunctional Behavior of Lupin Peptide P7 and Its Metabolite Using an Integrated Strategy.","date":"2020","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32223157","citation_count":27,"is_preprint":false},{"pmid":"35659720","id":"PMC_35659720","title":"DTX-P7, a peptide-drug conjugate, is highly effective for non-small cell lung cancer.","date":"2022","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35659720","citation_count":26,"is_preprint":false},{"pmid":"10521557","id":"PMC_10521557","title":"DNA damage and DNA damage-inducible protein Gadd45 following ischemia in the P7 neonatal rat.","date":"1999","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/10521557","citation_count":26,"is_preprint":false},{"pmid":"20727848","id":"PMC_20727848","title":"Comparative NMR studies demonstrate profound differences between two viroporins: p7 of HCV and Vpu of HIV-1.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20727848","citation_count":26,"is_preprint":false},{"pmid":"19053279","id":"PMC_19053279","title":"Rrp4 and Csl4 are needed for efficient degradation but not for polyadenylation of synthetic and natural RNA by the archaeal exosome.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19053279","citation_count":25,"is_preprint":false},{"pmid":"31575882","id":"PMC_31575882","title":"HCV p7 as a novel vaccine-target inducing multifunctional CD4+ and CD8+ T-cells targeting liver cells expressing the viral antigen.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31575882","citation_count":25,"is_preprint":false},{"pmid":"38445906","id":"PMC_38445906","title":"Identification and characterization of a fungal cutinase-like enzyme CpCut1 from Cladosporium sp. P7 for polyurethane degradation.","date":"2024","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38445906","citation_count":24,"is_preprint":false},{"pmid":"20560141","id":"PMC_20560141","title":"Expression and purification of the membrane protein p7 from hepatitis C virus.","date":"2011","source":"Biopolymers","url":"https://pubmed.ncbi.nlm.nih.gov/20560141","citation_count":24,"is_preprint":false},{"pmid":"1459462","id":"PMC_1459462","title":"Transcriptional control via translational repression by c4 antisense RNA of bacteriophages P1 and P7.","date":"1992","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/1459462","citation_count":24,"is_preprint":false},{"pmid":"25772504","id":"PMC_25772504","title":"Genotype-specific differences in structural features of hepatitis C virus (HCV) p7 membrane protein.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25772504","citation_count":24,"is_preprint":false},{"pmid":"3749335","id":"PMC_3749335","title":"Sequence relations among the IncY plasmid p15B, P1, and P7 prophages.","date":"1986","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/3749335","citation_count":24,"is_preprint":false},{"pmid":"31628467","id":"PMC_31628467","title":"Genetic and genomic studies of pathogenic EXOSC2 mutations in the newly described disease SHRF implicate the autophagy pathway in disease pathogenesis.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31628467","citation_count":23,"is_preprint":false},{"pmid":"23583663","id":"PMC_23583663","title":"Viroporin activity and membrane topology of classic swine fever virus p7 protein.","date":"2013","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23583663","citation_count":23,"is_preprint":false},{"pmid":"29709564","id":"PMC_29709564","title":"Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with β3 integrin.","date":"2018","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/29709564","citation_count":23,"is_preprint":false},{"pmid":"16492760","id":"PMC_16492760","title":"Functional analyses of GB virus B p13 protein: development of a recombinant GB virus B hepatitis virus with a p7 protein.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16492760","citation_count":23,"is_preprint":false},{"pmid":"26193629","id":"PMC_26193629","title":"Complete genome sequence of Clostridium carboxidivorans P7(T), a syngas-fermenting bacterium capable of producing long-chain alcohols.","date":"2015","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26193629","citation_count":23,"is_preprint":false},{"pmid":"23907396","id":"PMC_23907396","title":"Mutations in hepatitis C virus p7 reduce both the egress and infectivity of assembled particles via impaired proton channel function.","date":"2013","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/23907396","citation_count":23,"is_preprint":false},{"pmid":"20488184","id":"PMC_20488184","title":"The evolutionarily conserved subunits Rrp4 and Csl4 confer different substrate specificities to the archaeal exosome.","date":"2010","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/20488184","citation_count":22,"is_preprint":false},{"pmid":"12131366","id":"PMC_12131366","title":"A recombinant adenovirus expressing p7(Kip1) induces cell cycle arrest and apoptosis in human 786-0 renal carcinoma cells.","date":"2002","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/12131366","citation_count":22,"is_preprint":false},{"pmid":"31254744","id":"PMC_31254744","title":"P7 and P8 proteins of High Plains wheat mosaic virus, a negative-strand RNA virus, employ distinct mechanisms of RNA silencing suppression.","date":"2019","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/31254744","citation_count":21,"is_preprint":false},{"pmid":"25462337","id":"PMC_25462337","title":"Docking assay of small molecule antivirals to p7 of HCV.","date":"2014","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25462337","citation_count":21,"is_preprint":false},{"pmid":"8224242","id":"PMC_8224242","title":"The antirepressor of phage P1. Isolation and interaction with the C1 repressor of P1 and P7.","date":"1993","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8224242","citation_count":20,"is_preprint":false},{"pmid":"18793644","id":"PMC_18793644","title":"Roles of the minor capsid protein P7 in the assembly and replication of double-stranded RNA bacteriophage phi6.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18793644","citation_count":20,"is_preprint":false},{"pmid":"26464198","id":"PMC_26464198","title":"Ion channel activity of the CSFV p7 viroporin in surrogates of the ER lipid bilayer.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26464198","citation_count":20,"is_preprint":false},{"pmid":"8435043","id":"PMC_8435043","title":"Sequence analysis of selected regions of the env (V3 loop and gp41) and gag (p7) reading frames of Ethiopian human immunodeficiency virus type 1 strains.","date":"1993","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8435043","citation_count":20,"is_preprint":false},{"pmid":"11878916","id":"PMC_11878916","title":"Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.","date":"2002","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/11878916","citation_count":20,"is_preprint":false},{"pmid":"18647606","id":"PMC_18647606","title":"Structure and dynamics of the P7 protein from the bacteriophage phi 12.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18647606","citation_count":19,"is_preprint":false},{"pmid":"21604991","id":"PMC_21604991","title":"The influence of different lipid environments on the structure and function of the hepatitis C virus p7 ion channel protein.","date":"2011","source":"Molecular membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/21604991","citation_count":19,"is_preprint":false},{"pmid":"23946462","id":"PMC_23946462","title":"Efficiency of E2-p7 processing modulates production of infectious hepatitis C virus.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23946462","citation_count":19,"is_preprint":false},{"pmid":"24409277","id":"PMC_24409277","title":"Two different conformations in hepatitis C virus p7 protein account for proton transport and dye release.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24409277","citation_count":18,"is_preprint":false},{"pmid":"15060070","id":"PMC_15060070","title":"Characterization of GB virus B polyprotein processing reveals the existence of a novel 13-kDa protein with partial homology to hepatitis C virus p7 protein.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15060070","citation_count":18,"is_preprint":false},{"pmid":"28288106","id":"PMC_28288106","title":"The Rrp4-exosome complex recruits and channels substrate RNA by a unique mechanism.","date":"2017","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28288106","citation_count":17,"is_preprint":false},{"pmid":"22053912","id":"PMC_22053912","title":"Aldo-keto reductases protect lung adenocarcinoma cells from the acute toxicity of B[a]P-7,8-trans-dihydrodiol.","date":"2011","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/22053912","citation_count":17,"is_preprint":false},{"pmid":"17097709","id":"PMC_17097709","title":"A 2a/1b full-length p7 inter-genotypic chimeric genome of hepatitis C virus is infectious in vitro.","date":"2006","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/17097709","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47180,"output_tokens":1673,"usd":0.083318,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8147,"output_tokens":2425,"usd":0.05068,"stage2_stop_reason":"end_turn"},"total_usd":0.133998,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about EXOSC2 (also known as RRP4, hRrp4p, Rrp4p, p7). The vast majority of papers in this corpus are about HCV p7, HIV NC p7, bacteriophage P7 proteins, plant virus P7, or other unrelated \"p7\" proteins — none of which are the EXOSC2/RRP4 protein.\n\nThe relevant papers for EXOSC2 are:\n- PMID 26843489: Clinical mutations in EXOSC2 causing SHRF syndrome\n- PMID 31628467: Mechanistic study of EXOSC2 mutations, binding to exosome components, autophagy pathway\n- PMID 19053279: Archaeal Rrp4 (ortholog) functional studies\n- PMID 20488184: Archaeal Rrp4 substrate specificity\n- PMID 28288106: Rrp4-exosome RNA binding mechanism (archaeal ortholog)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic missense mutations in EXOSC2 cause a novel syndrome (SHRF), demonstrating that EXOSC2 is a core component of the RNA exosome complex essential for normal development; patient-derived mutations were identified by whole exome sequencing and confirmed to affect EXOSC2 function.\",\n      \"method\": \"Whole exome sequencing of affected patients; clinical genetics establishing biallelic missense variants in EXOSC2\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clinical genetic identification with variant confirmation in multiple families; no in vitro biochemical reconstitution reported in this abstract\",\n      \"pmids\": [\"26843489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The pathogenic EXOSC2 G198D mutation prevents binding to other RNA exosome components, resulting in protein and complex instability; wild-type human EXOSC2 but not the G198D mutant could rescue Drosophila rrp4 loss-of-function phenotypes, establishing that EXOSC2 functions as an essential RNA exosome subunit whose integrity is required for exosome complex stability and autophagy pathway gene regulation.\",\n      \"method\": \"Co-immunoprecipitation in patient-derived lymphoblasts; CRISPR knockout in fetal keratinocytes; Drosophila rrp4 mutant rescue experiments with wild-type vs. pathogenic human EXOSC2; pharmacological autophagy stimulation (rapamycin rescue)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay showing loss of complex assembly by G198D, cross-species functional rescue distinguishing WT from pathogenic allele, multiple orthogonal methods across human cells and Drosophila model\",\n      \"pmids\": [\"31628467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The archaeal Rrp4 subunit (ortholog of EXOSC2) is required for efficient RNA degradation but not polyadenylation by the exosome; the Rrp4-containing exosome preferentially degrades poly(A) RNA, while the catalytically active hexameric ring alone is insufficient for efficient phosphorolysis of structured or natural RNA substrates.\",\n      \"method\": \"In vitro biochemical reconstitution of archaeal exosome subcomplexes (hexamer vs. Rrp4-exosome vs. Csl4-exosome); RNA degradation and polyadenylation assays under varying conditions\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined subcomplexes, multiple substrate and condition comparisons; single lab but rigorous biochemical dissection\",\n      \"pmids\": [\"19053279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The archaeal Rrp4 subunit (ortholog of EXOSC2) confers poly(A)-RNA substrate preference to the exosome complex, distinct from the Csl4 subunit which prefers A-poor 3'-ends; high C-content and polyuridylation negatively influence processing by all complexes, and the Rrp4-exosome prefers longer substrates.\",\n      \"method\": \"In vitro RNA processing assays comparing hexameric exosome core with Rrp4-exosome and Csl4-exosome using defined RNA substrates\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematically varied substrates; single lab replicating and extending findings from prior study\",\n      \"pmids\": [\"20488184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The trimeric Rrp4 cap (archaeal ortholog of EXOSC2-containing cap) recruits RNA substrates via a 50-Å long RNA binding path on each Rrp4 protomer, allowing simultaneous recruitment of three substrates; interaction energy increases from the cap periphery toward the active sites, and substrate binding to the cap is weakened upon entry into the catalytic barrel to reduce friction during translocation.\",\n      \"method\": \"Methyl-TROSY NMR spectroscopy identifying RNA binding path on Rrp4; quantitative binding measurements of exosome-substrate interactions at defined steps\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure-function study with mechanistic dissection of substrate channeling, rigorous quantitative binding measurements, single lab with multiple orthogonal NMR methods\",\n      \"pmids\": [\"28288106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOSC2 (RRP4) is an essential cap subunit of the RNA exosome complex that directly binds RNA substrates via a defined binding path, confers poly(A)-RNA substrate preference to the complex, and is required for efficient RNA degradation (but not polyadenylation) by channeling substrates toward the catalytic core; pathogenic missense mutations (e.g., G198D) disrupt binding to other exosome subunits, destabilize the complex, and dysregulate autophagy pathway genes, causing the SHRF syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOSC2 (RRP4) is an essential cap subunit of the RNA exosome complex required for efficient RNA degradation and normal development [#1, #2]. Through its archaeal ortholog, EXOSC2 directly binds RNA substrates along an extended ~50-Å binding path on each cap protomer, recruiting substrates at the cap periphery and progressively releasing them as they enter the catalytic barrel to reduce friction during translocation toward the active sites [#4]. The EXOSC2-containing cap confers a substrate preference for poly(A) RNA and longer substrates, and is required for efficient phosphorolytic degradation of structured and natural RNAs that the catalytic hexameric ring cannot process alone, while being dispensable for polyadenylation [#2, #3]. Integrity of EXOSC2 is required for assembly and stability of the entire exosome: the pathogenic G198D mutation abolishes binding to other exosome subunits, destabilizing the complex, and wild-type but not G198D human EXOSC2 rescues Drosophila rrp4 loss of function [#1]. Biallelic EXOSC2 missense mutations cause the SHRF syndrome, with loss of exosome function dysregulating autophagy pathway gene expression [#0, #1].\"\n}\n\n```json\n{\n  \"mechanistic_narrative\": \"EXOSC2 (RRP4) is an essential cap subunit of the RNA exosome complex required for efficient RNA degradation and normal development [#1, #2]. Through its archaeal ortholog, EXOSC2 directly binds RNA substrates along an extended ~50-A binding path on each cap protomer, recruiting substrates at the cap periphery and progressively releasing them as they enter the catalytic barrel to reduce friction during translocation toward the active sites [#4]. The EXOSC2-containing cap confers a substrate preference for poly(A) RNA and longer substrates, and is required for efficient phosphorolytic degradation of structured and natural RNAs that the catalytic hexameric ring cannot process alone, while being dispensable for polyadenylation [#2, #3]. Integrity of EXOSC2 is required for assembly and stability of the entire exosome: the pathogenic G198D mutation abolishes binding to other exosome subunits and destabilizes the complex, and wild-type but not G198D human EXOSC2 rescues Drosophila rrp4 loss of function [#1]. Biallelic EXOSC2 missense mutations cause the SHRF syndrome, with loss of exosome function dysregulating autophagy pathway gene expression [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that the Rrp4/EXOSC2 cap subunit is functionally required for efficient RNA degradation, answering whether the catalytic core alone suffices for exosome activity.\",\n      \"evidence\": \"In vitro reconstitution of archaeal exosome subcomplexes with RNA degradation and polyadenylation assays\",\n      \"pmids\": [\"19053279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done in archaeal system; human EXOSC2-specific contributions not directly tested\", \"Mechanism by which the cap enables degradation of structured substrates not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined that the Rrp4/EXOSC2 cap dictates substrate selectivity, showing it imparts poly(A)-RNA and long-substrate preference distinct from the Csl4 cap.\",\n      \"evidence\": \"In vitro RNA processing assays comparing hexameric core, Rrp4-exosome and Csl4-exosome with defined substrates\",\n      \"pmids\": [\"20488184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Archaeal model; selectivity in human exosome not directly confirmed\", \"Structural basis of preference not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected EXOSC2 to human disease, establishing it as a developmentally essential exosome component by linking biallelic missense variants to the SHRF syndrome.\",\n      \"evidence\": \"Whole exome sequencing of affected patients with variant confirmation across families\",\n      \"pmids\": [\"26843489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro biochemical mechanism for the variants in this study\", \"Cellular consequence of mutations not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how the cap physically channels substrates, mapping a 50-A RNA binding path per protomer and a binding-affinity gradient that hands substrates to the catalytic barrel.\",\n      \"evidence\": \"Methyl-TROSY NMR spectroscopy with quantitative substrate-binding measurements at defined steps\",\n      \"pmids\": [\"28288106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Archaeal Rrp4 structure; human EXOSC2 path not directly mapped\", \"Coupling of cap binding to catalytic turnover kinetics not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated the mechanism of pathogenicity, showing G198D abolishes exosome assembly and dysregulates autophagy genes, and that wild-type EXOSC2 integrity is required for complex stability.\",\n      \"evidence\": \"Co-IP in patient lymphoblasts, CRISPR knockout in keratinocytes, Drosophila rrp4 cross-species rescue, and rapamycin autophagy stimulation\",\n      \"pmids\": [\"31628467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between exosome loss and specific autophagy gene transcripts not fully defined\", \"Tissue-specific basis of SHRF phenotypes unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the substrate-channeling and selectivity properties characterized in archaeal Rrp4 operate identically in the human EXOSC2-containing exosome, and how these connect mechanistically to the autophagy dysregulation seen in SHRF, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No human EXOSC2 structural binding-path study in the corpus\", \"Direct RNA substrate repertoire of human EXOSC2-exosome not defined\", \"Mechanistic link between exosome substrate handling and autophagy gene regulation unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"RNA exosome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}