{"gene":"TSR2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2014,"finding":"Tsr2 is a nuclear carrier (escortin) that dissociates importin:eS26 complexes via an atypical RanGTP-independent mechanism, then binds and shields the released eS26 from proteolysis, and delivers it to the 90S pre-ribosome for assembly.","method":"In vitro dissociation assays, yeast genetics, nuclear import reconstitution, co-immunoprecipitation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical reconstitution of importin:eS26 disassembly, combined with in vivo yeast genetics and multiple orthogonal methods in a single rigorous study","pmids":["25144938"],"is_preprint":false},{"year":2018,"finding":"NMR structure of the eukaryotic-specific segment (ESS) of eS26 in complex with Tsr2 revealed how ESS recruits Tsr2 specifically to importin:eS26 complexes entering the nucleus to trigger RanGTP-independent disassembly; Tsr2 then sequesters eS26 and prevents rebinding to importin via an allosteric mechanism. A Diamond-Blackfan anemia-associated Tsr2 mutant is impaired in binding to ESS.","method":"NMR structure determination, cross-linking mass spectrometry, mutational analysis, binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional mutagenesis and multiple orthogonal methods (NMR + XL-MS + binding assays) in a single rigorous study","pmids":["30201955"],"is_preprint":false},{"year":2016,"finding":"Tsr2 is required for incorporation of eS26 into the 90S pre-ribosome; Fap7 ATPase organizes uS11:eS26 subcomplex prior to delivery, and Tsr2-dependent pathway ensures stoichiometric eS26 integration. Fap7 depletion precludes eS26 incorporation and renders uS11 susceptible to proteolysis.","method":"In vitro ATPase assays, yeast genetics (depletion), co-immunoprecipitation, ribosome assembly assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo depletion with defined assembly phenotype and in vitro reconstitution, single lab but orthogonal methods; Tsr2 role is secondary to Fap7 focus in this paper","pmids":["27929371"],"is_preprint":false},{"year":2022,"finding":"The chaperone Tsr2 releases Rps26 from fully assembled ribosomes under high Na+, sorbitol, or pH stress in vitro, and is required for Rps26 release in vivo; Tsr2 also stores free Rps26 and promotes its reincorporation into ribosomes after stress subsides, thereby repairing ribosome subunits.","method":"In vitro Rps26 release assays, yeast genetics (Tsr2 deletion/depletion), ribosome fractionation, in vivo stress assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical demonstration combined with in vivo genetic depletion and multiple orthogonal readouts, single lab with rigorous controls","pmids":["35213229"],"is_preprint":false},{"year":2023,"finding":"Under oxidative stress, Tsr2 releases oxidized (non-functional) Rps26 from mature ribosomes, and damaged ribosomes are subsequently repaired by incorporation of newly synthesized Rps26; ablation of this Tsr2-mediated repair pathway impairs growth, especially under oxidative stress.","method":"Chemical proteomics (cysteine oxidation detection), yeast genetics (chaperone deletion), ribosome fractionation, growth assays under oxidative stress","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chemical proteomics + genetic loss-of-function + ribosome fractionation with defined phenotypic readout, multiple orthogonal methods","pmids":["37086725"],"is_preprint":false},{"year":2024,"finding":"Released Rps26 from the Rps26•Tsr2 complex is degraded via the Pro/N-degron pathway; the GID-complex E3 ubiquitin ligase and its adaptor Gid4 mediate polyubiquitination of Rps26 at Lys66 and Lys70, and this ubiquitination is required for Rps26 degradation, enabling accumulation of Rps26-deficient ribosomes and high-salt stress resistance. This degradation also recycles Tsr2 for multiple rounds of Rps26 release.","method":"Yeast genetics (N-degron mutants, GID complex deletions), ubiquitination assays, ribosome fractionation, stress resistance assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and biochemical methods, single lab, preprint not yet peer-reviewed","pmids":["39185221"],"is_preprint":true},{"year":2014,"finding":"TSR2 encodes a direct binding partner of RPS26 (eS26); X-linked mutations in TSR2 cause Diamond-Blackfan anemia with mandibulofacial dysostosis phenotype, placing TSR2 functionally in the ribosome biogenesis pathway.","method":"Whole exome sequencing, Sanger sequencing, genetic analysis of DBA families","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic identification across multiple unrelated families establishes gene-disease link and binding partner claim, but binding partner assertion relies on prior literature rather than direct experiment in this paper","pmids":["24942156"],"is_preprint":false},{"year":2015,"finding":"A splice-site mutation in exon 5 of bovine TSR2 produces frameshift/premature stop mutant transcripts and causes hairless streaks along lines of Blaschko, identifying TSR2 as a regulator of hair follicle development. TSR2 protein is expressed in skin and hair, and Tsr2 mRNA is expressed during pre- and post-natal phases of hair follicle development in mice.","method":"Whole genome sequencing, linkage analysis, RT-PCR characterization of mutant transcripts, immunohistochemistry, RNA in situ hybridization in mice","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — natural loss-of-function with defined tissue phenotype and expression characterization, but no direct mechanistic rescue experiment","pmids":["26203908"],"is_preprint":false},{"year":2025,"finding":"Depletion of TSR2 (the RPS26 chaperone) modulates FMRpolyG (polyglycine-containing toxic protein) production from CGG-repeat RAN translation, implicating Tsr2-mediated RPS26 function in noncanonical translation of CGG-expanded FMR1 mRNA.","method":"RNA-tagging/mass spectrometry screen, siRNA knockdown of TSR2 and RPS26, FMRpolyG reporter assays in cell culture","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct siRNA knockdown with reporter readout, but mechanistic connection to Tsr2's chaperone role is inferred rather than biochemically reconstituted","pmids":["40377206"],"is_preprint":false},{"year":2011,"finding":"Overexpression of human TSR2 in HEp-2 cells inhibited NF-κB transcriptional activity (with or without TNFα stimulus) and induced apoptosis, suggesting TSR2 participates in the NF-κB signaling pathway.","method":"Overexpression in HEp-2 cells, NF-κB luciferase reporter assay, apoptosis assay","journal":"Molekuliarnaia biologiia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach, no pathway placement by epistasis or identification of direct molecular target","pmids":["21790011"],"is_preprint":false}],"current_model":"TSR2 (also called Tsr2) functions primarily as a nuclear escortin/chaperone that dissociates importin:eS26 (RPS26) complexes via a RanGTP-independent mechanism upon nuclear entry, sequesters eS26 to protect it from proteolysis, and delivers it to the 90S pre-ribosome for assembly; additionally, Tsr2 dynamically releases Rps26 from fully assembled ribosomes under osmotic or oxidative stress to generate specialized ribosome populations, stores free Rps26, and promotes its reincorporation to repair ribosomes after stress, with the released Rps26 being degraded by the GID-complex/Pro-N-degron pathway to recycle Tsr2 for multiple rounds of release; loss-of-function mutations in TSR2 cause X-linked Diamond-Blackfan anemia and hair follicle defects in mammals."},"narrative":{"mechanistic_narrative":"TSR2 is a dedicated ribosomal protein chaperone (escortin) that controls the assembly, surveillance, and stress-adaptive remodeling of the small ribosomal subunit protein eS26/Rps26 [PMID:25144938, PMID:35213229]. Upon nuclear entry of importin:eS26 complexes, Tsr2 dissociates them through an atypical RanGTP-independent mechanism, then shields the released eS26 from proteolysis and delivers it to the 90S pre-ribosome for stoichiometric incorporation [PMID:25144938, PMID:27929371]. The eukaryote-specific segment (ESS) of eS26 recruits Tsr2 specifically to importin:eS26, and after disassembly Tsr2 allosterically sequesters eS26 to prevent importin rebinding [PMID:30201955]. Beyond biogenesis, Tsr2 acts on mature ribosomes: under high-salt, sorbitol, pH, or oxidative stress it extracts Rps26 from fully assembled ribosomes, stores the free protein, and promotes its reincorporation when stress subsides, thereby generating specialized Rps26-deficient ribosome populations and repairing damaged subunits [PMID:35213229, PMID:37086725]. In humans, X-linked loss-of-function mutations in TSR2 cause Diamond-Blackfan anemia with a mandibulofacial dysostosis phenotype, and a DBA-associated mutant is defective in binding the eS26 ESS [PMID:30201955, PMID:24942156].","teleology":[{"year":2014,"claim":"Established the core molecular identity of Tsr2 as a nuclear escortin that disassembles importin:eS26 without RanGTP and chaperones the freed protein into the pre-ribosome, defining a new mode of ribosomal protein delivery.","evidence":"In vitro dissociation assays, nuclear import reconstitution, yeast genetics, and co-IP","pmids":["25144938"],"confidence":"High","gaps":["Structural basis of the RanGTP-independent disassembly not resolved at this stage","How eS26 is specifically recognized over other importin cargo not defined"]},{"year":2014,"claim":"Linked TSR2 to human disease, showing X-linked mutations cause Diamond-Blackfan anemia and placing the gene in the ribosome biogenesis pathway as an RPS26 partner.","evidence":"Whole-exome and Sanger sequencing of DBA families","pmids":["24942156"],"confidence":"Medium","gaps":["Binding-partner claim rests on prior literature, not direct experiment here","Mechanism by which mutations impair function not tested in this study"]},{"year":2015,"claim":"Extended TSR2 function beyond hematopoiesis to hair follicle development, demonstrating a tissue-level requirement via a natural loss-of-function allele.","evidence":"Whole-genome sequencing, linkage analysis, mutant transcript characterization, IHC and in situ hybridization in bovine/mouse","pmids":["26203908"],"confidence":"Medium","gaps":["No mechanistic rescue linking the hair phenotype to ribosome assembly","Cell type driving the follicle defect not defined"]},{"year":2016,"claim":"Placed Tsr2 within the eS26 assembly hierarchy, showing it is required for stoichiometric eS26 incorporation into the 90S pre-ribosome downstream of Fap7-mediated uS11:eS26 organization.","evidence":"In vitro ATPase assays, yeast depletion, co-IP, ribosome assembly assays","pmids":["27929371"],"confidence":"Medium","gaps":["Tsr2 role secondary to the Fap7 focus of the study","Order and coordination of Tsr2 and Fap7 handoff not fully resolved"]},{"year":2018,"claim":"Provided the structural mechanism of cargo recognition and release, showing the eS26 ESS recruits Tsr2 and that Tsr2 allosterically blocks importin rebinding, and connected a DBA mutant to defective ESS binding.","evidence":"NMR structure determination, cross-linking mass spectrometry, mutational and binding assays","pmids":["30201955"],"confidence":"High","gaps":["How allosteric sequestration is relieved at the pre-ribosome not defined","Structural state of the delivery complex on the 90S not resolved"]},{"year":2022,"claim":"Revealed a post-assembly role: Tsr2 dynamically extracts Rps26 from mature ribosomes under stress and reincorporates it afterward, establishing Tsr2 as a generator and repairer of specialized ribosome populations.","evidence":"In vitro Rps26 release assays, yeast deletion/depletion, ribosome fractionation, in vivo stress assays","pmids":["35213229"],"confidence":"High","gaps":["How specific stresses trigger release mechanistically not defined","Functional consequences of Rps26-deficient ribosomes on translation specificity not detailed"]},{"year":2023,"claim":"Defined a ribosome quality-control function, showing Tsr2 removes oxidatively damaged Rps26 to enable repair by newly synthesized protein, with loss impairing growth under oxidative stress.","evidence":"Chemical proteomics of cysteine oxidation, chaperone deletion genetics, ribosome fractionation, oxidative-stress growth assays","pmids":["37086725"],"confidence":"High","gaps":["Whether Tsr2 senses oxidation directly or recognizes a downstream signal unknown","Selectivity for damaged versus intact Rps26 not biochemically dissected"]},{"year":2024,"claim":"Identified the fate of released Rps26 and the basis for Tsr2 recycling, showing GID-complex/Gid4-mediated Pro/N-degron ubiquitination degrades free Rps26 to enable repeated Tsr2 release cycles and accumulation of Rps26-deficient ribosomes.","evidence":"Yeast N-degron and GID-complex mutants, ubiquitination assays, ribosome fractionation, stress resistance assays (preprint)","pmids":["39185221"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How Tsr2 hands off Rps26 to the GID machinery not defined"]},{"year":2025,"claim":"Connected Tsr2-mediated RPS26 function to noncanonical translation, showing TSR2 depletion modulates FMRpolyG production from CGG-repeat RAN translation.","evidence":"RNA-tagging/MS screen plus siRNA knockdown of TSR2 and RPS26 with FMRpolyG reporter assays in cell culture","pmids":["40377206"],"confidence":"Medium","gaps":["Mechanistic link to Tsr2's chaperone role inferred, not reconstituted","Whether the effect is via ribosome composition or another route unresolved"]},{"year":null,"claim":"How Tsr2's biogenesis (escortin) and post-assembly (stress remodeling) activities are partitioned and regulated within cells, and how its loss produces tissue-specific human phenotypes, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism linking ribosome chaperone activity to the DBA or hair-follicle phenotypes","Regulatory switch between assembly and stress-release modes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["RPS26"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969E8","full_name":"Pre-rRNA-processing protein TSR2 homolog","aliases":[],"length_aa":191,"mass_kda":20.9,"function":"May be involved in 20S pre-rRNA processing","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q969E8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TSR2","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000158526","cell_line_id":"CID001096","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"RPS26","stoichiometry":0.2},{"gene":"DYNC1H1","stoichiometry":0.2},{"gene":"NPC2","stoichiometry":0.2},{"gene":"GMDS","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001096","total_profiled":1310},"omim":[{"mim_id":"613309","title":"DIAMOND-BLACKFAN ANEMIA 10; DBA10","url":"https://www.omim.org/entry/613309"},{"mim_id":"606184","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 12; ADAMTS12","url":"https://www.omim.org/entry/606184"},{"mim_id":"606164","title":"DIAMOND-BLACKFAN ANEMIA 15 WITH MANDIBULOFACIAL DYSOSTOSIS; DBA15","url":"https://www.omim.org/entry/606164"},{"mim_id":"603701","title":"RIBOSOMAL PROTEIN S26; RPS26","url":"https://www.omim.org/entry/603701"},{"mim_id":"603685","title":"RIBOSOMAL PROTEIN S28; RPS28","url":"https://www.omim.org/entry/603685"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TSR2"},"hgnc":{"alias_symbol":["DT1P1A10","RP1-112K5.2","WGG1"],"prev_symbol":[]},"alphafold":{"accession":"Q969E8","domains":[{"cath_id":"-","chopping":"1-122","consensus_level":"medium","plddt":86.7166,"start":1,"end":122}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969E8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969E8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969E8-F1-predicted_aligned_error_v6.png","plddt_mean":74.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TSR2","jax_strain_url":"https://www.jax.org/strain/search?query=TSR2"},"sequence":{"accession":"Q969E8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969E8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969E8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969E8"}},"corpus_meta":[{"pmid":"8522587","id":"PMC_8522587","title":"Mutations in twinstar, a 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research","url":"https://pubmed.ncbi.nlm.nih.gov/38575106","citation_count":3,"is_preprint":false},{"pmid":"38814181","id":"PMC_38814181","title":"Higher expression of TSR2 aggravating hypertension via the PPAR signaling pathway.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38814181","citation_count":2,"is_preprint":false},{"pmid":"38061385","id":"PMC_38061385","title":"Genomic characterization of three bacterial isolates antagonistic to the pea root rot pathogen Aphanomyces euteiches.","date":"2023","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38061385","citation_count":2,"is_preprint":false},{"pmid":"39568018","id":"PMC_39568018","title":"A novel nonsense RPS26 mutation in a patient with Diamond-Blackfan anemia: a case report.","date":"2024","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/39568018","citation_count":1,"is_preprint":false},{"pmid":"38862449","id":"PMC_38862449","title":"[TSR2 overexpression inhibits proliferation and invasion of gastric cancer cells by downregulating the PI3K/AKT signaling pathway].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/38862449","citation_count":0,"is_preprint":false},{"pmid":"42075433","id":"PMC_42075433","title":"Selection and Validation of Suitable Reference Genes for RT-qPCR Normalization in Euonymus bungeanus Across Various Tissues and Under Abiotic Stress/Hormone Treatments.","date":"2026","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/42075433","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23524,"output_tokens":2635,"usd":0.055049,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9824,"output_tokens":3096,"usd":0.06326,"stage2_stop_reason":"end_turn"},"total_usd":0.118309,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Tsr2 is a nuclear carrier (escortin) that dissociates importin:eS26 complexes via an atypical RanGTP-independent mechanism, then binds and shields the released eS26 from proteolysis, and delivers it to the 90S pre-ribosome for assembly.\",\n      \"method\": \"In vitro dissociation assays, yeast genetics, nuclear import reconstitution, co-immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical reconstitution of importin:eS26 disassembly, combined with in vivo yeast genetics and multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"25144938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NMR structure of the eukaryotic-specific segment (ESS) of eS26 in complex with Tsr2 revealed how ESS recruits Tsr2 specifically to importin:eS26 complexes entering the nucleus to trigger RanGTP-independent disassembly; Tsr2 then sequesters eS26 and prevents rebinding to importin via an allosteric mechanism. A Diamond-Blackfan anemia-associated Tsr2 mutant is impaired in binding to ESS.\",\n      \"method\": \"NMR structure determination, cross-linking mass spectrometry, mutational analysis, binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional mutagenesis and multiple orthogonal methods (NMR + XL-MS + binding assays) in a single rigorous study\",\n      \"pmids\": [\"30201955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tsr2 is required for incorporation of eS26 into the 90S pre-ribosome; Fap7 ATPase organizes uS11:eS26 subcomplex prior to delivery, and Tsr2-dependent pathway ensures stoichiometric eS26 integration. Fap7 depletion precludes eS26 incorporation and renders uS11 susceptible to proteolysis.\",\n      \"method\": \"In vitro ATPase assays, yeast genetics (depletion), co-immunoprecipitation, ribosome assembly assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo depletion with defined assembly phenotype and in vitro reconstitution, single lab but orthogonal methods; Tsr2 role is secondary to Fap7 focus in this paper\",\n      \"pmids\": [\"27929371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The chaperone Tsr2 releases Rps26 from fully assembled ribosomes under high Na+, sorbitol, or pH stress in vitro, and is required for Rps26 release in vivo; Tsr2 also stores free Rps26 and promotes its reincorporation into ribosomes after stress subsides, thereby repairing ribosome subunits.\",\n      \"method\": \"In vitro Rps26 release assays, yeast genetics (Tsr2 deletion/depletion), ribosome fractionation, in vivo stress assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical demonstration combined with in vivo genetic depletion and multiple orthogonal readouts, single lab with rigorous controls\",\n      \"pmids\": [\"35213229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Under oxidative stress, Tsr2 releases oxidized (non-functional) Rps26 from mature ribosomes, and damaged ribosomes are subsequently repaired by incorporation of newly synthesized Rps26; ablation of this Tsr2-mediated repair pathway impairs growth, especially under oxidative stress.\",\n      \"method\": \"Chemical proteomics (cysteine oxidation detection), yeast genetics (chaperone deletion), ribosome fractionation, growth assays under oxidative stress\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chemical proteomics + genetic loss-of-function + ribosome fractionation with defined phenotypic readout, multiple orthogonal methods\",\n      \"pmids\": [\"37086725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Released Rps26 from the Rps26•Tsr2 complex is degraded via the Pro/N-degron pathway; the GID-complex E3 ubiquitin ligase and its adaptor Gid4 mediate polyubiquitination of Rps26 at Lys66 and Lys70, and this ubiquitination is required for Rps26 degradation, enabling accumulation of Rps26-deficient ribosomes and high-salt stress resistance. This degradation also recycles Tsr2 for multiple rounds of Rps26 release.\",\n      \"method\": \"Yeast genetics (N-degron mutants, GID complex deletions), ubiquitination assays, ribosome fractionation, stress resistance assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and biochemical methods, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"39185221\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TSR2 encodes a direct binding partner of RPS26 (eS26); X-linked mutations in TSR2 cause Diamond-Blackfan anemia with mandibulofacial dysostosis phenotype, placing TSR2 functionally in the ribosome biogenesis pathway.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, genetic analysis of DBA families\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic identification across multiple unrelated families establishes gene-disease link and binding partner claim, but binding partner assertion relies on prior literature rather than direct experiment in this paper\",\n      \"pmids\": [\"24942156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A splice-site mutation in exon 5 of bovine TSR2 produces frameshift/premature stop mutant transcripts and causes hairless streaks along lines of Blaschko, identifying TSR2 as a regulator of hair follicle development. TSR2 protein is expressed in skin and hair, and Tsr2 mRNA is expressed during pre- and post-natal phases of hair follicle development in mice.\",\n      \"method\": \"Whole genome sequencing, linkage analysis, RT-PCR characterization of mutant transcripts, immunohistochemistry, RNA in situ hybridization in mice\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — natural loss-of-function with defined tissue phenotype and expression characterization, but no direct mechanistic rescue experiment\",\n      \"pmids\": [\"26203908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Depletion of TSR2 (the RPS26 chaperone) modulates FMRpolyG (polyglycine-containing toxic protein) production from CGG-repeat RAN translation, implicating Tsr2-mediated RPS26 function in noncanonical translation of CGG-expanded FMR1 mRNA.\",\n      \"method\": \"RNA-tagging/mass spectrometry screen, siRNA knockdown of TSR2 and RPS26, FMRpolyG reporter assays in cell culture\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct siRNA knockdown with reporter readout, but mechanistic connection to Tsr2's chaperone role is inferred rather than biochemically reconstituted\",\n      \"pmids\": [\"40377206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of human TSR2 in HEp-2 cells inhibited NF-κB transcriptional activity (with or without TNFα stimulus) and induced apoptosis, suggesting TSR2 participates in the NF-κB signaling pathway.\",\n      \"method\": \"Overexpression in HEp-2 cells, NF-κB luciferase reporter assay, apoptosis assay\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach, no pathway placement by epistasis or identification of direct molecular target\",\n      \"pmids\": [\"21790011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TSR2 (also called Tsr2) functions primarily as a nuclear escortin/chaperone that dissociates importin:eS26 (RPS26) complexes via a RanGTP-independent mechanism upon nuclear entry, sequesters eS26 to protect it from proteolysis, and delivers it to the 90S pre-ribosome for assembly; additionally, Tsr2 dynamically releases Rps26 from fully assembled ribosomes under osmotic or oxidative stress to generate specialized ribosome populations, stores free Rps26, and promotes its reincorporation to repair ribosomes after stress, with the released Rps26 being degraded by the GID-complex/Pro-N-degron pathway to recycle Tsr2 for multiple rounds of release; loss-of-function mutations in TSR2 cause X-linked Diamond-Blackfan anemia and hair follicle defects in mammals.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TSR2 is a dedicated ribosomal protein chaperone (escortin) that controls the assembly, surveillance, and stress-adaptive remodeling of the small ribosomal subunit protein eS26/Rps26 [#0, #3]. Upon nuclear entry of importin:eS26 complexes, Tsr2 dissociates them through an atypical RanGTP-independent mechanism, then shields the released eS26 from proteolysis and delivers it to the 90S pre-ribosome for stoichiometric incorporation [#0, #2]. The eukaryote-specific segment (ESS) of eS26 recruits Tsr2 specifically to importin:eS26, and after disassembly Tsr2 allosterically sequesters eS26 to prevent importin rebinding [#1]. Beyond biogenesis, Tsr2 acts on mature ribosomes: under high-salt, sorbitol, pH, or oxidative stress it extracts Rps26 from fully assembled ribosomes, stores the free protein, and promotes its reincorporation when stress subsides, thereby generating specialized Rps26-deficient ribosome populations and repairing damaged subunits [#3, #4]. In humans, X-linked loss-of-function mutations in TSR2 cause Diamond-Blackfan anemia with a mandibulofacial dysostosis phenotype, and a DBA-associated mutant is defective in binding the eS26 ESS [#1, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the core molecular identity of Tsr2 as a nuclear escortin that disassembles importin:eS26 without RanGTP and chaperones the freed protein into the pre-ribosome, defining a new mode of ribosomal protein delivery.\",\n      \"evidence\": \"In vitro dissociation assays, nuclear import reconstitution, yeast genetics, and co-IP\",\n      \"pmids\": [\"25144938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RanGTP-independent disassembly not resolved at this stage\", \"How eS26 is specifically recognized over other importin cargo not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked TSR2 to human disease, showing X-linked mutations cause Diamond-Blackfan anemia and placing the gene in the ribosome biogenesis pathway as an RPS26 partner.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing of DBA families\",\n      \"pmids\": [\"24942156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-partner claim rests on prior literature, not direct experiment here\", \"Mechanism by which mutations impair function not tested in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended TSR2 function beyond hematopoiesis to hair follicle development, demonstrating a tissue-level requirement via a natural loss-of-function allele.\",\n      \"evidence\": \"Whole-genome sequencing, linkage analysis, mutant transcript characterization, IHC and in situ hybridization in bovine/mouse\",\n      \"pmids\": [\"26203908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic rescue linking the hair phenotype to ribosome assembly\", \"Cell type driving the follicle defect not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed Tsr2 within the eS26 assembly hierarchy, showing it is required for stoichiometric eS26 incorporation into the 90S pre-ribosome downstream of Fap7-mediated uS11:eS26 organization.\",\n      \"evidence\": \"In vitro ATPase assays, yeast depletion, co-IP, ribosome assembly assays\",\n      \"pmids\": [\"27929371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tsr2 role secondary to the Fap7 focus of the study\", \"Order and coordination of Tsr2 and Fap7 handoff not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural mechanism of cargo recognition and release, showing the eS26 ESS recruits Tsr2 and that Tsr2 allosterically blocks importin rebinding, and connected a DBA mutant to defective ESS binding.\",\n      \"evidence\": \"NMR structure determination, cross-linking mass spectrometry, mutational and binding assays\",\n      \"pmids\": [\"30201955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How allosteric sequestration is relieved at the pre-ribosome not defined\", \"Structural state of the delivery complex on the 90S not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a post-assembly role: Tsr2 dynamically extracts Rps26 from mature ribosomes under stress and reincorporates it afterward, establishing Tsr2 as a generator and repairer of specialized ribosome populations.\",\n      \"evidence\": \"In vitro Rps26 release assays, yeast deletion/depletion, ribosome fractionation, in vivo stress assays\",\n      \"pmids\": [\"35213229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific stresses trigger release mechanistically not defined\", \"Functional consequences of Rps26-deficient ribosomes on translation specificity not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a ribosome quality-control function, showing Tsr2 removes oxidatively damaged Rps26 to enable repair by newly synthesized protein, with loss impairing growth under oxidative stress.\",\n      \"evidence\": \"Chemical proteomics of cysteine oxidation, chaperone deletion genetics, ribosome fractionation, oxidative-stress growth assays\",\n      \"pmids\": [\"37086725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tsr2 senses oxidation directly or recognizes a downstream signal unknown\", \"Selectivity for damaged versus intact Rps26 not biochemically dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the fate of released Rps26 and the basis for Tsr2 recycling, showing GID-complex/Gid4-mediated Pro/N-degron ubiquitination degrades free Rps26 to enable repeated Tsr2 release cycles and accumulation of Rps26-deficient ribosomes.\",\n      \"evidence\": \"Yeast N-degron and GID-complex mutants, ubiquitination assays, ribosome fractionation, stress resistance assays (preprint)\",\n      \"pmids\": [\"39185221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How Tsr2 hands off Rps26 to the GID machinery not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected Tsr2-mediated RPS26 function to noncanonical translation, showing TSR2 depletion modulates FMRpolyG production from CGG-repeat RAN translation.\",\n      \"evidence\": \"RNA-tagging/MS screen plus siRNA knockdown of TSR2 and RPS26 with FMRpolyG reporter assays in cell culture\",\n      \"pmids\": [\"40377206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link to Tsr2's chaperone role inferred, not reconstituted\", \"Whether the effect is via ribosome composition or another route unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Tsr2's biogenesis (escortin) and post-assembly (stress remodeling) activities are partitioned and regulated within cells, and how its loss produces tissue-specific human phenotypes, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism linking ribosome chaperone activity to the DBA or hair-follicle phenotypes\", \"Regulatory switch between assembly and stress-release modes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RPS26\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}