{"gene":"RPS10","run_date":"2026-06-10T07:46:27","timeline":{"discoveries":[{"year":2010,"finding":"RPS10 is required for 18S rRNA processing; mutations in RPS10 (identified in Diamond-Blackfan anemia patients) cause accumulation of 18S-E pre-rRNA, a phenotype replicated by siRNA knockdown of RPS10 in HeLa cells, indicating RPS10 functions in the 18S rRNA maturation step.","method":"Pre-rRNA analysis in patient lymphoblastoid cells and siRNA knockdown in HeLa cells with rRNA processing assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal systems (patient cells and siRNA KD), replicated processing defect, consistent across multiple mutations","pmids":["20116044"],"is_preprint":false},{"year":2015,"finding":"Gcn1 directly contacts the small ribosomal protein Rps10 (yeast ortholog of RPS10) via Gcn1 residues 1060–1777; this interaction is RNA-independent and is required for full activation of the eIF2α kinase Gcn2 under amino acid starvation, placing Rps10 in the Gcn1–Gcn2 signaling axis on the ribosome.","method":"Yeast two-hybrid, in vitro co-precipitation, genetic epistasis (rps10AΔ/rps10BΔ strains with eIF2α phosphorylation assay, eEF3 overexpression, growth assays under starvation)","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-precipitation (RNA-independent), Y2H, and multiple genetic epistasis experiments in a single focused study","pmids":["25437641"],"is_preprint":false},{"year":2019,"finding":"Cancer-associated mutations in the N-terminal tail (NTT) of eIF1A diminish its interaction with RPS10 (and RPS3), which are implicated in scanning arrest; reduced RPS10 binding retains the 43S pre-initiation complex in an open/scanning state and facilitates translation of long 5′ UTR-containing cell cycle mRNAs.","method":"Co-immunoprecipitation of eIF1A NTT mutants with RPS10/RPS3, ribosome profiling, luciferase reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding assay plus ribosome profiling functional readout, single lab study","pmids":["30420357"],"is_preprint":false},{"year":2012,"finding":"HIV-1 Nef protein physically interacts with RPS10 (component of the 40S ribosomal subunit) and with 18S rRNA; Nef/RPS10 complexes also contain tRNAs, and Nef impairs in vitro translation, suggesting RPS10 binding contributes to Nef-mediated translational inhibition.","method":"Co-immunoprecipitation, RT-PCR detection of 18S rRNA and tRNAs in complexes, in vitro translation assay","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and in vitro translation assay in a single lab; interaction shown but mechanistic dissection limited","pmids":["22672539"],"is_preprint":false},{"year":2023,"finding":"Znf598 (E3 ubiquitin ligase) ubiquitinates Rps10/eS10 in zebrafish; Rps10/eS10 ubiquitination-site mutations reduce overall ribosome ubiquitination during development, identifying RPS10 as a key substrate of Znf598-mediated ribosome ubiquitination that contributes to ribosome-associated quality control (RQC).","method":"Affinity purification of FLAG-tagged ribosomes from endogenous locus knock-in zebrafish, immunoblotting, ubiquitination-site mutation analysis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous-locus FLAG-tagged ribosomes, site-directed ubiquitination mutants with functional readout, orthogonal methods in a focused study","pmids":["37751929"],"is_preprint":false},{"year":2025,"finding":"Herpesvirus-encoded ubiquitin deconjugases (vDUBs) counteract RPS10 ubiquitination induced by translational stress (anisomycin treatment); inhibition of RPS10 ubiquitination by vDUBs correlates with rescue of RQC substrates from degradation and promotion of readthrough of stall-inducing mRNAs, implicating RPS10 ubiquitination as a trigger of ribosome-associated quality control.","method":"Ubiquitination assay with vDUB overexpression, RQC substrate rescue assays, mRNA readthrough reporters in cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple functional readouts in a single preprint study; not yet peer-reviewed","pmids":["bio_10.1101_2025.03.04.641470"],"is_preprint":true},{"year":2025,"finding":"A de novo nonsense variant in RPS10 (p.Trp69Ter) causes haploinsufficiency, rRNA processing defects, downregulation of GATA1, and upregulation of TP53, establishing that loss of RPS10 function activates the p53 pathway in DBA pathogenesis.","method":"Whole exome sequencing, Sanger confirmation, quantitative RT-PCR of TP53/GATA1/RPS10, rRNA processing analysis in patient cells","journal":"Molecular genetics and genomics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal functional assays in a single patient/lab; novel variant with functional validation but not independently replicated","pmids":["40960598"],"is_preprint":false}],"current_model":"RPS10 (eS10) is a component of the 40S ribosomal small subunit required for 18S rRNA processing; it serves as a direct binding partner of Gcn1 to facilitate Gcn2/eIF2α kinase activation during amino acid starvation, interacts with eIF1A to mediate scanning arrest during translation initiation, and is ubiquitinated by the E3 ligase ZNF598 as a key trigger of ribosome-associated quality control (RQC); loss-of-function mutations cause Diamond-Blackfan anemia through haploinsufficiency, rRNA processing failure, and p53 pathway activation."},"narrative":{"mechanistic_narrative":"RPS10 (eS10) is a structural component of the 40S small ribosomal subunit that participates in 18S rRNA maturation and in surveillance pathways that monitor ribosome function during translation [PMID:20116044, PMID:37751929]. It is required for processing of the 18S-E pre-rRNA, and loss of RPS10 function disrupts this maturation step [PMID:20116044]. On the assembled ribosome, RPS10 acts as a docking site for regulatory and quality-control machinery: it directly and RNA-independently contacts Gcn1 to enable full activation of the eIF2α kinase Gcn2 during amino acid starvation [PMID:25437641], and it engages the N-terminal tail of eIF1A in a manner linked to scanning arrest, where weakened RPS10–eIF1A binding favors an open, scanning-competent 43S pre-initiation complex [PMID:30420357]. RPS10 is a principal substrate of the E3 ubiquitin ligase ZNF598/Znf598, whose ubiquitination of eS10 triggers ribosome-associated quality control (RQC), an event that herpesvirus-encoded ubiquitin deconjugases reverse to rescue stalled ribosomes and stall-inducing mRNAs from degradation [PMID:37751929, PMID:bio_10.1101_2025.03.04.641470]. Heterozygous loss-of-function mutations in RPS10 cause Diamond-Blackfan anemia through haploinsufficiency, with defective rRNA processing accompanied by GATA1 downregulation and p53 pathway activation [PMID:20116044, PMID:40960598].","teleology":[{"year":2010,"claim":"Established that RPS10 is functionally required for ribosome biogenesis rather than merely a passive structural subunit, by linking its loss to a specific rRNA maturation defect and to human disease.","evidence":"Pre-rRNA processing analysis in Diamond-Blackfan anemia patient lymphoblastoid cells and siRNA knockdown in HeLa cells","pmids":["20116044"],"confidence":"High","gaps":["Does not resolve which step of small-subunit assembly RPS10 acts at structurally","Mechanistic link between processing failure and the erythroid-specific disease phenotype not established here"]},{"year":2012,"claim":"Identified RPS10 as a target exploited by HIV-1 Nef, raising the possibility that the 40S subunit is co-opted for viral translational control.","evidence":"Co-immunoprecipitation, RT-PCR detection of 18S rRNA and tRNAs in complexes, and in vitro translation assay","pmids":["22672539"],"confidence":"Medium","gaps":["Direct versus ribosome-bridged interaction not distinguished","Functional contribution of RPS10 binding to Nef-mediated translation inhibition not isolated","Single-lab co-IP without reciprocal validation"]},{"year":2015,"claim":"Resolved RPS10 as the physical ribosomal anchor for Gcn1, placing it within the Gcn1–Gcn2 nutrient-sensing signaling axis on the ribosome.","evidence":"Yeast two-hybrid, in vitro co-precipitation, and genetic epistasis in rps10AΔ/rps10BΔ yeast strains with eIF2α phosphorylation readouts","pmids":["25437641"],"confidence":"High","gaps":["Structural basis of the Rps10–Gcn1 contact not defined","Whether the interaction is conserved and operates identically in human cells not tested"]},{"year":2019,"claim":"Connected RPS10 to translation initiation fidelity by showing its eIF1A-dependent role in scanning arrest, providing a mechanism by which initiation-factor mutations reshape mRNA selection.","evidence":"Co-immunoprecipitation of eIF1A N-terminal-tail mutants with RPS10/RPS3, ribosome profiling, and luciferase reporter assays","pmids":["30420357"],"confidence":"Medium","gaps":["Direct RPS10 contribution not separated from RPS3","Structural model of the scanning-arrest contact lacking","Single-lab study"]},{"year":2023,"claim":"Defined RPS10 as a principal in vivo substrate of ZNF598/Znf598-mediated ribosome ubiquitination, marking it as a molecular trigger point for ribosome-associated quality control.","evidence":"Affinity purification of FLAG-tagged ribosomes from endogenous-locus knock-in zebrafish with ubiquitination-site mutation analysis","pmids":["37751929"],"confidence":"High","gaps":["Downstream RQC effectors recruited by ubiquitinated eS10 not enumerated here","Developmental phenotype of ubiquitination-site mutants not fully characterized"]},{"year":2025,"claim":"Showed that RPS10 ubiquitination is a reversible, actively contested switch by demonstrating that viral deubiquitinases erase it to abort RQC and permit readthrough of stalled mRNAs.","evidence":"Ubiquitination assays with vDUB overexpression, RQC substrate rescue assays, and mRNA readthrough reporters in cells (preprint)","pmids":["bio_10.1101_2025.03.04.641470"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Direct vDUB activity on eS10-linked ubiquitin chains versus indirect effects not fully separated"]},{"year":2025,"claim":"Reinforced the haploinsufficiency mechanism of RPS10 in Diamond-Blackfan anemia by tying a nonsense variant to rRNA processing failure, GATA1 loss, and p53 activation.","evidence":"Whole exome sequencing with Sanger confirmation and quantitative RT-PCR of TP53/GATA1/RPS10 plus rRNA processing analysis in patient cells","pmids":["40960598"],"confidence":"Medium","gaps":["Single patient/lab, not independently replicated","Causal chain from p53 activation to erythroid failure not mechanistically dissected"]},{"year":null,"claim":"How RPS10's distinct roles—rRNA processing, Gcn2 activation, scanning arrest, and ZNF598-triggered RQC—are structurally coordinated on a single subunit, and why its loss produces an erythroid-specific disease, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model placing the Gcn1, eIF1A, and ubiquitination sites on eS10","Tissue specificity of the DBA phenotype unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,4]}],"complexes":["40S ribosomal subunit"],"partners":["GCN1","EIF1A","ZNF598","NEF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46783","full_name":"Small ribosomal subunit protein eS10","aliases":["40S ribosomal protein S10"],"length_aa":165,"mass_kda":18.9,"function":"Component of the 40S ribosomal subunit (PubMed:23636399). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399)","subcellular_location":"Cytoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P46783/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPS10","classification":"Common Essential","n_dependent_lines":383,"n_total_lines":383,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RPS10","total_profiled":1310},"omim":[{"mim_id":"617508","title":"ZINC FINGER PROTEIN 598; ZNF598","url":"https://www.omim.org/entry/617508"},{"mim_id":"614900","title":"DIAMOND-BLACKFAN ANEMIA 11; DBA11","url":"https://www.omim.org/entry/614900"},{"mim_id":"613309","title":"DIAMOND-BLACKFAN ANEMIA 10; DBA10","url":"https://www.omim.org/entry/613309"},{"mim_id":"613308","title":"DIAMOND-BLACKFAN ANEMIA 9; DBA9","url":"https://www.omim.org/entry/613308"},{"mim_id":"603701","title":"RIBOSOMAL PROTEIN S26; RPS26","url":"https://www.omim.org/entry/603701"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPS10"},"hgnc":{"alias_symbol":["MGC88819","S10","eS10"],"prev_symbol":[]},"alphafold":{"accession":"P46783","domains":[{"cath_id":"1.10.10.10","chopping":"4-86","consensus_level":"high","plddt":93.7342,"start":4,"end":86}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46783","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46783-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46783-F1-predicted_aligned_error_v6.png","plddt_mean":73.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPS10","jax_strain_url":"https://www.jax.org/strain/search?query=RPS10"},"sequence":{"accession":"P46783","fasta_url":"https://rest.uniprot.org/uniprotkb/P46783.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46783/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46783"}},"corpus_meta":[{"pmid":"15302823","id":"PMC_15302823","title":"Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus.","date":"2004","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/15302823","citation_count":242,"is_preprint":false},{"pmid":"20116044","id":"PMC_20116044","title":"Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20116044","citation_count":192,"is_preprint":false},{"pmid":"2386485","id":"PMC_2386485","title":"Nucleotide sequence of cDNA coding for rat liver pI 6.1 esterase (ES-10), a carboxylesterase located in the lumen of the endoplasmic reticulum.","date":"1990","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2386485","citation_count":106,"is_preprint":false},{"pmid":"405970","id":"PMC_405970","title":"Mapping of nucleoside phosphorylase (Np-1) and esterase 10 (Es-10) on mouse chromosome 14.","date":"1977","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/405970","citation_count":79,"is_preprint":false},{"pmid":"2570031","id":"PMC_2570031","title":"The murine retinoblastoma homolog maps to chromosome 14 near Es-10.","date":"1989","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/2570031","citation_count":37,"is_preprint":false},{"pmid":"7553943","id":"PMC_7553943","title":"Splicing and editing of rps10 transcripts in potato mitochondria.","date":"1995","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7553943","citation_count":33,"is_preprint":false},{"pmid":"23936102","id":"PMC_23936102","title":"Identification and candidate gene analysis of a novel phytophthora resistance gene Rps10 in a Chinese soybean cultivar.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23936102","citation_count":32,"is_preprint":false},{"pmid":"10852496","id":"PMC_10852496","title":"Transfer of the mitochondrial rps10 gene to the nucleus in rice: acquisition of the 5' untranslated region followed by gene duplication.","date":"2000","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/10852496","citation_count":30,"is_preprint":false},{"pmid":"30420357","id":"PMC_30420357","title":"Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes.","date":"2019","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30420357","citation_count":24,"is_preprint":false},{"pmid":"1765383","id":"PMC_1765383","title":"The 5-HT2 serotonin receptor gene Htr-2 is tightly linked to Es-10 on mouse chromosome 14.","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1765383","citation_count":23,"is_preprint":false},{"pmid":"25437641","id":"PMC_25437641","title":"Gcn1 contacts the small ribosomal protein Rps10, which is required for full activation of the protein kinase Gcn2.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/25437641","citation_count":22,"is_preprint":false},{"pmid":"22672539","id":"PMC_22672539","title":"The HIV-1 Nef protein interacts with two components of the 40S small ribosomal subunit, the RPS10 protein and the 18S rRNA.","date":"2012","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/22672539","citation_count":20,"is_preprint":false},{"pmid":"11522369","id":"PMC_11522369","title":"Altered expression of the carboxylesterases ES-4 and ES-10 by peroxisome proliferator chemicals.","date":"2001","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/11522369","citation_count":18,"is_preprint":false},{"pmid":"1907893","id":"PMC_1907893","title":"rps10, unreported for plastid DNAs, is located on the cyanelle genome of Cyanophora paradoxa and is cotranscribed with the str operon genes.","date":"1991","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1907893","citation_count":12,"is_preprint":false},{"pmid":"3925939","id":"PMC_3925939","title":"Purine nucleoside phosphorylase (Np) in the mouse: linkage relationship of Np-2 to esterase-10 (Es-10) and Np-1 on chromosome 14.","date":"1985","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3925939","citation_count":8,"is_preprint":false},{"pmid":"2566156","id":"PMC_2566156","title":"A restriction fragment length polymorphism at murine Glud locus co-segregates with Rib-1, Es-10, and Tcra on chromosome 14.","date":"1989","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2566156","citation_count":8,"is_preprint":false},{"pmid":"37376976","id":"PMC_37376976","title":"Identification of novel mutations in patients with Diamond-Blackfan anemia and literature review of RPS10 and RPS26 mutations.","date":"2023","source":"International journal of laboratory hematology","url":"https://pubmed.ncbi.nlm.nih.gov/37376976","citation_count":7,"is_preprint":false},{"pmid":"37751929","id":"PMC_37751929","title":"Znf598-mediated Rps10/eS10 ubiquitination contributes to the ribosome ubiquitination dynamics during zebrafish development.","date":"2023","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37751929","citation_count":6,"is_preprint":false},{"pmid":"40960598","id":"PMC_40960598","title":"A de novo nonsense variant in RPS10 causes Diamond-Blackfan anaemia in an Indian patient: clinical and functional evidence.","date":"2025","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/40960598","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.04.641470","title":"Differential regulation of translational stress responses by herpesvirus ubiquitin deconjugases","date":"2025-03-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.04.641470","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.28.645676","title":"Alternative splicing generates a Ribosomal Protein S24 isoform induced by neuroinflammation and neurodegeneration","date":"2025-04-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.645676","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11708,"output_tokens":1900,"usd":0.031812,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8768,"output_tokens":2817,"usd":0.057133,"stage2_stop_reason":"end_turn"},"total_usd":0.088945,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"RPS10 is required for 18S rRNA processing; mutations in RPS10 (identified in Diamond-Blackfan anemia patients) cause accumulation of 18S-E pre-rRNA, a phenotype replicated by siRNA knockdown of RPS10 in HeLa cells, indicating RPS10 functions in the 18S rRNA maturation step.\",\n      \"method\": \"Pre-rRNA analysis in patient lymphoblastoid cells and siRNA knockdown in HeLa cells with rRNA processing assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal systems (patient cells and siRNA KD), replicated processing defect, consistent across multiple mutations\",\n      \"pmids\": [\"20116044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Gcn1 directly contacts the small ribosomal protein Rps10 (yeast ortholog of RPS10) via Gcn1 residues 1060–1777; this interaction is RNA-independent and is required for full activation of the eIF2α kinase Gcn2 under amino acid starvation, placing Rps10 in the Gcn1–Gcn2 signaling axis on the ribosome.\",\n      \"method\": \"Yeast two-hybrid, in vitro co-precipitation, genetic epistasis (rps10AΔ/rps10BΔ strains with eIF2α phosphorylation assay, eEF3 overexpression, growth assays under starvation)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-precipitation (RNA-independent), Y2H, and multiple genetic epistasis experiments in a single focused study\",\n      \"pmids\": [\"25437641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cancer-associated mutations in the N-terminal tail (NTT) of eIF1A diminish its interaction with RPS10 (and RPS3), which are implicated in scanning arrest; reduced RPS10 binding retains the 43S pre-initiation complex in an open/scanning state and facilitates translation of long 5′ UTR-containing cell cycle mRNAs.\",\n      \"method\": \"Co-immunoprecipitation of eIF1A NTT mutants with RPS10/RPS3, ribosome profiling, luciferase reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding assay plus ribosome profiling functional readout, single lab study\",\n      \"pmids\": [\"30420357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HIV-1 Nef protein physically interacts with RPS10 (component of the 40S ribosomal subunit) and with 18S rRNA; Nef/RPS10 complexes also contain tRNAs, and Nef impairs in vitro translation, suggesting RPS10 binding contributes to Nef-mediated translational inhibition.\",\n      \"method\": \"Co-immunoprecipitation, RT-PCR detection of 18S rRNA and tRNAs in complexes, in vitro translation assay\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and in vitro translation assay in a single lab; interaction shown but mechanistic dissection limited\",\n      \"pmids\": [\"22672539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Znf598 (E3 ubiquitin ligase) ubiquitinates Rps10/eS10 in zebrafish; Rps10/eS10 ubiquitination-site mutations reduce overall ribosome ubiquitination during development, identifying RPS10 as a key substrate of Znf598-mediated ribosome ubiquitination that contributes to ribosome-associated quality control (RQC).\",\n      \"method\": \"Affinity purification of FLAG-tagged ribosomes from endogenous locus knock-in zebrafish, immunoblotting, ubiquitination-site mutation analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous-locus FLAG-tagged ribosomes, site-directed ubiquitination mutants with functional readout, orthogonal methods in a focused study\",\n      \"pmids\": [\"37751929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Herpesvirus-encoded ubiquitin deconjugases (vDUBs) counteract RPS10 ubiquitination induced by translational stress (anisomycin treatment); inhibition of RPS10 ubiquitination by vDUBs correlates with rescue of RQC substrates from degradation and promotion of readthrough of stall-inducing mRNAs, implicating RPS10 ubiquitination as a trigger of ribosome-associated quality control.\",\n      \"method\": \"Ubiquitination assay with vDUB overexpression, RQC substrate rescue assays, mRNA readthrough reporters in cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple functional readouts in a single preprint study; not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.04.641470\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A de novo nonsense variant in RPS10 (p.Trp69Ter) causes haploinsufficiency, rRNA processing defects, downregulation of GATA1, and upregulation of TP53, establishing that loss of RPS10 function activates the p53 pathway in DBA pathogenesis.\",\n      \"method\": \"Whole exome sequencing, Sanger confirmation, quantitative RT-PCR of TP53/GATA1/RPS10, rRNA processing analysis in patient cells\",\n      \"journal\": \"Molecular genetics and genomics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal functional assays in a single patient/lab; novel variant with functional validation but not independently replicated\",\n      \"pmids\": [\"40960598\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPS10 (eS10) is a component of the 40S ribosomal small subunit required for 18S rRNA processing; it serves as a direct binding partner of Gcn1 to facilitate Gcn2/eIF2α kinase activation during amino acid starvation, interacts with eIF1A to mediate scanning arrest during translation initiation, and is ubiquitinated by the E3 ligase ZNF598 as a key trigger of ribosome-associated quality control (RQC); loss-of-function mutations cause Diamond-Blackfan anemia through haploinsufficiency, rRNA processing failure, and p53 pathway activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPS10 (eS10) is a structural component of the 40S small ribosomal subunit that participates in 18S rRNA maturation and in surveillance pathways that monitor ribosome function during translation [#0, #4]. It is required for processing of the 18S-E pre-rRNA, and loss of RPS10 function disrupts this maturation step [#0]. On the assembled ribosome, RPS10 acts as a docking site for regulatory and quality-control machinery: it directly and RNA-independently contacts Gcn1 to enable full activation of the eIF2\\u03b1 kinase Gcn2 during amino acid starvation [#1], and it engages the N-terminal tail of eIF1A in a manner linked to scanning arrest, where weakened RPS10\\u2013eIF1A binding favors an open, scanning-competent 43S pre-initiation complex [#2]. RPS10 is a principal substrate of the E3 ubiquitin ligase ZNF598/Znf598, whose ubiquitination of eS10 triggers ribosome-associated quality control (RQC), an event that herpesvirus-encoded ubiquitin deconjugases reverse to rescue stalled ribosomes and stall-inducing mRNAs from degradation [#4, #5]. Heterozygous loss-of-function mutations in RPS10 cause Diamond-Blackfan anemia through haploinsufficiency, with defective rRNA processing accompanied by GATA1 downregulation and p53 pathway activation [#0, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that RPS10 is functionally required for ribosome biogenesis rather than merely a passive structural subunit, by linking its loss to a specific rRNA maturation defect and to human disease.\",\n      \"evidence\": \"Pre-rRNA processing analysis in Diamond-Blackfan anemia patient lymphoblastoid cells and siRNA knockdown in HeLa cells\",\n      \"pmids\": [\"20116044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which step of small-subunit assembly RPS10 acts at structurally\", \"Mechanistic link between processing failure and the erythroid-specific disease phenotype not established here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified RPS10 as a target exploited by HIV-1 Nef, raising the possibility that the 40S subunit is co-opted for viral translational control.\",\n      \"evidence\": \"Co-immunoprecipitation, RT-PCR detection of 18S rRNA and tRNAs in complexes, and in vitro translation assay\",\n      \"pmids\": [\"22672539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus ribosome-bridged interaction not distinguished\", \"Functional contribution of RPS10 binding to Nef-mediated translation inhibition not isolated\", \"Single-lab co-IP without reciprocal validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved RPS10 as the physical ribosomal anchor for Gcn1, placing it within the Gcn1\\u2013Gcn2 nutrient-sensing signaling axis on the ribosome.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro co-precipitation, and genetic epistasis in rps10A\\u0394/rps10B\\u0394 yeast strains with eIF2\\u03b1 phosphorylation readouts\",\n      \"pmids\": [\"25437641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Rps10\\u2013Gcn1 contact not defined\", \"Whether the interaction is conserved and operates identically in human cells not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected RPS10 to translation initiation fidelity by showing its eIF1A-dependent role in scanning arrest, providing a mechanism by which initiation-factor mutations reshape mRNA selection.\",\n      \"evidence\": \"Co-immunoprecipitation of eIF1A N-terminal-tail mutants with RPS10/RPS3, ribosome profiling, and luciferase reporter assays\",\n      \"pmids\": [\"30420357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RPS10 contribution not separated from RPS3\", \"Structural model of the scanning-arrest contact lacking\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined RPS10 as a principal in vivo substrate of ZNF598/Znf598-mediated ribosome ubiquitination, marking it as a molecular trigger point for ribosome-associated quality control.\",\n      \"evidence\": \"Affinity purification of FLAG-tagged ribosomes from endogenous-locus knock-in zebrafish with ubiquitination-site mutation analysis\",\n      \"pmids\": [\"37751929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream RQC effectors recruited by ubiquitinated eS10 not enumerated here\", \"Developmental phenotype of ubiquitination-site mutants not fully characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that RPS10 ubiquitination is a reversible, actively contested switch by demonstrating that viral deubiquitinases erase it to abort RQC and permit readthrough of stalled mRNAs.\",\n      \"evidence\": \"Ubiquitination assays with vDUB overexpression, RQC substrate rescue assays, and mRNA readthrough reporters in cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.04.641470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Direct vDUB activity on eS10-linked ubiquitin chains versus indirect effects not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reinforced the haploinsufficiency mechanism of RPS10 in Diamond-Blackfan anemia by tying a nonsense variant to rRNA processing failure, GATA1 loss, and p53 activation.\",\n      \"evidence\": \"Whole exome sequencing with Sanger confirmation and quantitative RT-PCR of TP53/GATA1/RPS10 plus rRNA processing analysis in patient cells\",\n      \"pmids\": [\"40960598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient/lab, not independently replicated\", \"Causal chain from p53 activation to erythroid failure not mechanistically dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RPS10's distinct roles\\u2014rRNA processing, Gcn2 activation, scanning arrest, and ZNF598-triggered RQC\\u2014are structurally coordinated on a single subunit, and why its loss produces an erythroid-specific disease, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model placing the Gcn1, eIF1A, and ubiquitination sites on eS10\", \"Tissue specificity of the DBA phenotype unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\"40S ribosomal subunit\"],\n    \"partners\": [\"GCN1\", \"EIF1A\", \"ZNF598\", \"Nef\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}