{"gene":"TSR2","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2014,"finding":"Tsr2 is a conserved nuclear carrier (escortin) that dissociates importin:eS26 (RPS26) complexes via a RanGTP-independent mechanism to terminate nuclear import, then binds the released eS26, shields it from proteolysis, and delivers it to the 90S pre-ribosome for assembly.","method":"In vitro dissociation assays, yeast genetics, depletion experiments, biochemical reconstitution","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of importin disassembly, proteolysis protection assays, and in vivo genetic depletion with defined ribosome assembly phenotype","pmids":["25144938"],"is_preprint":false},{"year":2018,"finding":"NMR structure of the eukaryotic-specific segment (ESS) of eS26 (RPS26) in complex with Tsr2 reveals how ESS attracts Tsr2 to importin:eS26 complexes in the nucleus to trigger RanGTP-independent disassembly; Tsr2 then sequesters eS26 and prevents rebinding to importin. A Diamond-Blackfan anemia-associated Tsr2 mutant is impaired in ESS binding.","method":"NMR structure determination, cross-linking mass spectrometry, binding assays with DBA mutant Tsr2","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional mutagenesis and DBA mutant validation, multiple orthogonal methods in one study","pmids":["30201955"],"is_preprint":false},{"year":2022,"finding":"The chaperone Tsr2 releases Rps26 (eS26) from fully assembled ribosomes in response to high Na+, sorbitol, or pH stress in vitro and in vivo, stores free Rps26, and promotes its reincorporation to repair ribosomes after stress subsides, generating a physiologically relevant Rps26-deficient ribosome population that supports a stress-specific translational response.","method":"In vitro Rps26 release assays with purified Tsr2, yeast genetics (in vivo Rps26 release assay), ribosome profiling, stress-response phenotypic analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of Rps26 release plus in vivo genetic evidence with defined translational phenotype","pmids":["35213229"],"is_preprint":false},{"year":2023,"finding":"Tsr2 releases oxidized Rps26 from mature ribosomes, enabling chaperone-mediated ribosome repair by reincorporation of newly synthesized Rps26; ablation of this pathway impairs growth under oxidative stress.","method":"Chemical proteomics (cysteine oxidation profiling), yeast genetics, ribosome fractionation, growth assays under oxidative stress","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — chemical proteomics identification of oxidized cysteines, combined with genetic ablation and defined growth phenotype","pmids":["37086725"],"is_preprint":false},{"year":2024,"finding":"Released Rps26 from the Tsr2:Rps26 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, enabling accumulation of Rps26-deficient ribosomes and resistance to high salt stress.","method":"Yeast genetics, ubiquitination assays, proteasome inhibitor experiments, mutational analysis (N-terminal proline substitution, lysine substitution)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic and biochemical methods but preprint, not yet peer-reviewed","pmids":["39185221"],"is_preprint":true},{"year":2016,"finding":"The ATPase Fap7 organizes interactions between uS11 and eS26 (RPS26) prior to 90S delivery; Tsr2 is required for eS26 incorporation into the 90S pre-ribosome, as Fap7 depletion precludes eS26 incorporation.","method":"Yeast genetics (depletion strains), in vitro reconstitution of uS11:eS26 subcomplex, ATPase assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and biochemical evidence for Tsr2's role in eS26 delivery, but Tsr2 is not the primary focus of the paper","pmids":["27929371"],"is_preprint":false},{"year":2014,"finding":"TSR2 encodes a direct binding partner of RPS26 (eS26); X-linked mutations in TSR2 cause Diamond-Blackfan anemia with mandibulofacial dysostosis, implicating TSR2 in ribosome biogenesis and erythropoiesis.","method":"Whole exome sequencing, Sanger sequencing, genetic analysis in human patients","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 — genetic identification of TSR2 as RPS26 binding partner in human disease; no direct biochemical assay in this paper, but consistent with mechanistic studies","pmids":["24942156"],"is_preprint":false},{"year":2015,"finding":"A splice-site mutation in bovine TSR2 that truncates ~25% of the protein causes hairless streaks in cattle; TSR2 protein is specifically expressed in skin and hair follicles during pre- and post-natal development in mice, implicating TSR2 in hair follicle formation.","method":"Linkage analysis, whole genome sequencing, RT-PCR of mutant transcripts, immunohistochemistry, RNA in situ hybridization in mice","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function mutation with defined phenotype and localization data; functional consequence demonstrated in vivo","pmids":["26203908"],"is_preprint":false},{"year":2025,"finding":"Depletion of RPS26 and its chaperone TSR2 modulates FMRpolyG (polyglycine-containing protein) production in fragile X-associated conditions; TSR2 is required for RPS26-dependent noncanonical CGG-repeat RAN translation.","method":"siRNA knockdown, RAN translation reporter assays, mass spectrometry interactome screen","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 — single study, knockdown with reporter assay, no direct biochemical mechanism for TSR2 in this context","pmids":["40377206"],"is_preprint":false},{"year":2011,"finding":"Overexpression of human TSR2 in HEp-2 cells inhibits NF-κB transcriptional activity (with or without TNFα stimulus) and induces apoptosis.","method":"Overexpression, NF-κB luciferase reporter assay, apoptosis assays","journal":"Molekuliarnaia biologiia","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single overexpression approach, no endogenous pathway placement or direct binding partner identified","pmids":["21790011"],"is_preprint":false}],"current_model":"TSR2 is a nuclear escortin/chaperone that uses a RanGTP-independent mechanism to disassemble importin:eS26(RPS26) complexes upon nuclear entry (via binding to the eukaryotic-specific segment of eS26, as revealed by NMR structure), then shields eS26 from proteolysis and delivers it to the 90S pre-ribosome; additionally, Tsr2 dynamically releases Rps26 from mature ribosomes under osmotic or oxidative stress conditions to generate specialized ribosome populations and facilitates ribosome repair by storing and reincorporating undamaged Rps26, with loss-of-function mutations in TSR2 causing Diamond-Blackfan anemia through impaired RPS26 chaperoning."},"narrative":{"teleology":[{"year":2011,"claim":"An early study raised the possibility that TSR2 has broader cellular effects, showing that overexpression inhibits NF-κB activity and induces apoptosis, but provided no mechanistic link to a defined pathway.","evidence":"Overexpression in HEp-2 cells with NF-κB luciferase reporter and apoptosis assays","pmids":["21790011"],"confidence":"Low","gaps":["Single overexpression study without endogenous validation or identification of direct targets","No connection to ribosome biology established","Not independently replicated"]},{"year":2014,"claim":"Two independent studies established that TSR2/Tsr2 is a nuclear chaperone for eS26 (RPS26): biochemical reconstitution showed it dissociates importin:eS26 complexes without RanGTP, protects eS26 from degradation, and delivers it to 90S pre-ribosomes, while human genetics identified TSR2 mutations as causative for X-linked Diamond-Blackfan anemia, linking its eS26-chaperoning function to disease.","evidence":"In vitro dissociation assays, yeast depletion genetics, proteolysis protection (eLife); whole-exome sequencing of DBA patients (Am J Med Genet A)","pmids":["25144938","24942156"],"confidence":"High","gaps":["Structural basis of TSR2:eS26 recognition unknown at this point","How TSR2 discriminates importin-bound eS26 from free eS26 not resolved","Mechanism of DBA-causing mutations not biochemically characterized"]},{"year":2016,"claim":"Placement of TSR2 in a defined handoff pathway was clarified: the ATPase Fap7 organizes the uS11:eS26 interface prior to 90S incorporation, and TSR2-mediated eS26 delivery is prerequisite for this step.","evidence":"Yeast depletion strains, in vitro reconstitution of uS11:eS26, ATPase assays","pmids":["27929371"],"confidence":"Medium","gaps":["Direct physical interaction between TSR2 and Fap7 not demonstrated","Order-of-events (TSR2 release of eS26 vs. Fap7 engagement) not kinetically resolved"]},{"year":2018,"claim":"The NMR structure of TSR2 bound to the eukaryotic-specific segment (ESS) of eS26 revealed how TSR2 is attracted to importin:eS26 complexes and prevents eS26 rebinding to importin; a DBA-associated TSR2 mutant was shown to be specifically impaired in ESS binding, mechanistically explaining disease pathogenesis.","evidence":"NMR structure determination, cross-linking mass spectrometry, binding assays with DBA mutant TSR2","pmids":["30201955"],"confidence":"High","gaps":["Full-length complex structure not determined","Whether additional nuclear factors cooperate with TSR2 in vivo not addressed"]},{"year":2022,"claim":"TSR2's function was extended beyond biogenesis: Tsr2 was shown to extract Rps26 from fully assembled mature ribosomes under osmotic, salt, or pH stress, store the free subunit, and reincorporate it after stress, generating specialized Rps26-deficient ribosomes with altered translational output.","evidence":"In vitro Rps26 release assays with purified Tsr2, yeast in vivo release assays, ribosome profiling","pmids":["35213229"],"confidence":"High","gaps":["Signal that activates TSR2 to extract eS26 from mature ribosomes not identified","Whether this mechanism operates in mammalian cells not tested","Translational targets of Rps26-deficient ribosomes only partially characterized"]},{"year":2023,"claim":"The ribosome repair function of TSR2 was shown to involve quality control: Tsr2 specifically removes oxidized Rps26 from ribosomes under oxidative stress, enabling replacement with newly synthesized undamaged copies, directly linking TSR2 to a chaperone-mediated ribosome repair pathway.","evidence":"Chemical proteomics (cysteine oxidation profiling), yeast genetics, ribosome fractionation, oxidative stress growth assays","pmids":["37086725"],"confidence":"High","gaps":["Whether TSR2 senses oxidation on eS26 directly or is activated by an upstream signal unknown","Fate of the oxidized Rps26 after release not fully defined at this point"]},{"year":2024,"claim":"The degradation fate of TSR2-released Rps26 was identified: the Pro/N-degron pathway via the GID-complex E3 ligase and adaptor Gid4 polyubiquitinates Rps26 at Lys66/Lys70, coupling TSR2-mediated extraction to proteasomal clearance and enabling stable accumulation of Rps26-deficient ribosomes.","evidence":"Yeast ubiquitination assays, proteasome inhibitor experiments, N-terminal proline and lysine mutational analysis (preprint)","pmids":["39185221"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Whether GID-dependent degradation applies to mammalian cells not tested","Relative flux through reincorporation vs. degradation pathways not quantified"]},{"year":null,"claim":"Key open questions include the signal or conformational change that activates TSR2 to extract eS26 from mature ribosomes under stress, whether the biogenesis and repair functions of TSR2 are conserved in mammalian systems, and the full repertoire of mRNAs differentially translated by Rps26-deficient ribosomes.","evidence":"","pmids":[],"confidence":"Low","gaps":["Activation mechanism for TSR2-mediated eS26 extraction from mature ribosomes unknown","Mammalian in vivo validation of ribosome repair function lacking","Complete translational program of Rps26-deficient ribosomes not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["RPS26","FAP7","GID4"],"other_free_text":[]},"mechanistic_narrative":"TSR2 is a dedicated nuclear chaperone (escortin) for the small ribosomal subunit protein eS26 (RPS26) that operates at the intersection of ribosome biogenesis and stress-adaptive translation. In the nucleus, TSR2 dissociates importin:eS26 complexes through a RanGTP-independent mechanism—binding the eukaryotic-specific segment of eS26 as revealed by NMR—shields free eS26 from proteolysis, and delivers it to the 90S pre-ribosome in coordination with the ATPase Fap7 [PMID:25144938, PMID:30201955, PMID:27929371]. Beyond biogenesis, TSR2 dynamically extracts eS26 from mature ribosomes under osmotic, pH, or oxidative stress, stores the released subunit, and reincorporates undamaged eS26 to repair ribosomes once stress subsides, thereby generating specialized Rps26-deficient ribosome populations with altered translational programs [PMID:35213229, PMID:37086725]. Loss-of-function mutations in TSR2 cause X-linked Diamond-Blackfan anemia with mandibulofacial dysostosis, consistent with impaired eS26 chaperoning during erythropoiesis [PMID:24942156, PMID:30201955]."},"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 Drosophila gene encoding a cofilin/ADF homologue, result in defects in centrosome migration and cytokinesis.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8522587","citation_count":258,"is_preprint":false},{"pmid":"11691800","id":"PMC_11691800","title":"Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11691800","citation_count":115,"is_preprint":false},{"pmid":"24942156","id":"PMC_24942156","title":"Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.","date":"2014","source":"American journal of medical genetics. 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ubiquitin-proteasome system regulates the formation of specialized ribosomes during high salt stress in yeast.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39185221","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":"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":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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22271,"output_tokens":2379,"usd":0.051249},"stage2":{"model":"claude-opus-4-6","input_tokens":5704,"output_tokens":2302,"usd":0.129105},"total_usd":0.180354,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Tsr2 is a conserved nuclear carrier (escortin) that dissociates importin:eS26 (RPS26) complexes via a RanGTP-independent mechanism to terminate nuclear import, then binds the released eS26, shields it from proteolysis, and delivers it to the 90S pre-ribosome for assembly.\",\n      \"method\": \"In vitro dissociation assays, yeast genetics, depletion experiments, biochemical reconstitution\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of importin disassembly, proteolysis protection assays, and in vivo genetic depletion with defined ribosome assembly phenotype\",\n      \"pmids\": [\"25144938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NMR structure of the eukaryotic-specific segment (ESS) of eS26 (RPS26) in complex with Tsr2 reveals how ESS attracts Tsr2 to importin:eS26 complexes in the nucleus to trigger RanGTP-independent disassembly; Tsr2 then sequesters eS26 and prevents rebinding to importin. A Diamond-Blackfan anemia-associated Tsr2 mutant is impaired in ESS binding.\",\n      \"method\": \"NMR structure determination, cross-linking mass spectrometry, binding assays with DBA mutant Tsr2\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional mutagenesis and DBA mutant validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30201955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The chaperone Tsr2 releases Rps26 (eS26) from fully assembled ribosomes in response to high Na+, sorbitol, or pH stress in vitro and in vivo, stores free Rps26, and promotes its reincorporation to repair ribosomes after stress subsides, generating a physiologically relevant Rps26-deficient ribosome population that supports a stress-specific translational response.\",\n      \"method\": \"In vitro Rps26 release assays with purified Tsr2, yeast genetics (in vivo Rps26 release assay), ribosome profiling, stress-response phenotypic analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of Rps26 release plus in vivo genetic evidence with defined translational phenotype\",\n      \"pmids\": [\"35213229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tsr2 releases oxidized Rps26 from mature ribosomes, enabling chaperone-mediated ribosome repair by reincorporation of newly synthesized Rps26; ablation of this pathway impairs growth under oxidative stress.\",\n      \"method\": \"Chemical proteomics (cysteine oxidation profiling), yeast genetics, ribosome fractionation, growth assays under oxidative stress\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — chemical proteomics identification of oxidized cysteines, combined with genetic ablation and defined growth phenotype\",\n      \"pmids\": [\"37086725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Released Rps26 from the Tsr2:Rps26 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, enabling accumulation of Rps26-deficient ribosomes and resistance to high salt stress.\",\n      \"method\": \"Yeast genetics, ubiquitination assays, proteasome inhibitor experiments, mutational analysis (N-terminal proline substitution, lysine substitution)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and biochemical methods but preprint, not yet peer-reviewed\",\n      \"pmids\": [\"39185221\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The ATPase Fap7 organizes interactions between uS11 and eS26 (RPS26) prior to 90S delivery; Tsr2 is required for eS26 incorporation into the 90S pre-ribosome, as Fap7 depletion precludes eS26 incorporation.\",\n      \"method\": \"Yeast genetics (depletion strains), in vitro reconstitution of uS11:eS26 subcomplex, ATPase assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and biochemical evidence for Tsr2's role in eS26 delivery, but Tsr2 is not the primary focus of the paper\",\n      \"pmids\": [\"27929371\"],\n      \"is_preprint\": false\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, implicating TSR2 in ribosome biogenesis and erythropoiesis.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, genetic analysis in human patients\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic identification of TSR2 as RPS26 binding partner in human disease; no direct biochemical assay in this paper, but consistent with mechanistic studies\",\n      \"pmids\": [\"24942156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A splice-site mutation in bovine TSR2 that truncates ~25% of the protein causes hairless streaks in cattle; TSR2 protein is specifically expressed in skin and hair follicles during pre- and post-natal development in mice, implicating TSR2 in hair follicle formation.\",\n      \"method\": \"Linkage analysis, whole genome sequencing, RT-PCR of mutant transcripts, immunohistochemistry, RNA in situ hybridization in mice\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function mutation with defined phenotype and localization data; functional consequence demonstrated in vivo\",\n      \"pmids\": [\"26203908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Depletion of RPS26 and its chaperone TSR2 modulates FMRpolyG (polyglycine-containing protein) production in fragile X-associated conditions; TSR2 is required for RPS26-dependent noncanonical CGG-repeat RAN translation.\",\n      \"method\": \"siRNA knockdown, RAN translation reporter assays, mass spectrometry interactome screen\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single study, knockdown with reporter assay, no direct biochemical mechanism for TSR2 in this context\",\n      \"pmids\": [\"40377206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of human TSR2 in HEp-2 cells inhibits NF-κB transcriptional activity (with or without TNFα stimulus) and induces apoptosis.\",\n      \"method\": \"Overexpression, NF-κB luciferase reporter assay, apoptosis assays\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single overexpression approach, no endogenous pathway placement or direct binding partner identified\",\n      \"pmids\": [\"21790011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TSR2 is a nuclear escortin/chaperone that uses a RanGTP-independent mechanism to disassemble importin:eS26(RPS26) complexes upon nuclear entry (via binding to the eukaryotic-specific segment of eS26, as revealed by NMR structure), then shields eS26 from proteolysis and delivers it to the 90S pre-ribosome; additionally, Tsr2 dynamically releases Rps26 from mature ribosomes under osmotic or oxidative stress conditions to generate specialized ribosome populations and facilitates ribosome repair by storing and reincorporating undamaged Rps26, with loss-of-function mutations in TSR2 causing Diamond-Blackfan anemia through impaired RPS26 chaperoning.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TSR2 is a dedicated nuclear chaperone (escortin) for the small ribosomal subunit protein eS26 (RPS26) that operates at the intersection of ribosome biogenesis and stress-adaptive translation. In the nucleus, TSR2 dissociates importin:eS26 complexes through a RanGTP-independent mechanism—binding the eukaryotic-specific segment of eS26 as revealed by NMR—shields free eS26 from proteolysis, and delivers it to the 90S pre-ribosome in coordination with the ATPase Fap7 [PMID:25144938, PMID:30201955, PMID:27929371]. Beyond biogenesis, TSR2 dynamically extracts eS26 from mature ribosomes under osmotic, pH, or oxidative stress, stores the released subunit, and reincorporates undamaged eS26 to repair ribosomes once stress subsides, thereby generating specialized Rps26-deficient ribosome populations with altered translational programs [PMID:35213229, PMID:37086725]. Loss-of-function mutations in TSR2 cause X-linked Diamond-Blackfan anemia with mandibulofacial dysostosis, consistent with impaired eS26 chaperoning during erythropoiesis [PMID:24942156, PMID:30201955].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"An early study raised the possibility that TSR2 has broader cellular effects, showing that overexpression inhibits NF-κB activity and induces apoptosis, but provided no mechanistic link to a defined pathway.\",\n      \"evidence\": \"Overexpression in HEp-2 cells with NF-κB luciferase reporter and apoptosis assays\",\n      \"pmids\": [\"21790011\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression study without endogenous validation or identification of direct targets\", \"No connection to ribosome biology established\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two independent studies established that TSR2/Tsr2 is a nuclear chaperone for eS26 (RPS26): biochemical reconstitution showed it dissociates importin:eS26 complexes without RanGTP, protects eS26 from degradation, and delivers it to 90S pre-ribosomes, while human genetics identified TSR2 mutations as causative for X-linked Diamond-Blackfan anemia, linking its eS26-chaperoning function to disease.\",\n      \"evidence\": \"In vitro dissociation assays, yeast depletion genetics, proteolysis protection (eLife); whole-exome sequencing of DBA patients (Am J Med Genet A)\",\n      \"pmids\": [\"25144938\", \"24942156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TSR2:eS26 recognition unknown at this point\", \"How TSR2 discriminates importin-bound eS26 from free eS26 not resolved\", \"Mechanism of DBA-causing mutations not biochemically characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placement of TSR2 in a defined handoff pathway was clarified: the ATPase Fap7 organizes the uS11:eS26 interface prior to 90S incorporation, and TSR2-mediated eS26 delivery is prerequisite for this step.\",\n      \"evidence\": \"Yeast depletion strains, in vitro reconstitution of uS11:eS26, ATPase assays\",\n      \"pmids\": [\"27929371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between TSR2 and Fap7 not demonstrated\", \"Order-of-events (TSR2 release of eS26 vs. Fap7 engagement) not kinetically resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The NMR structure of TSR2 bound to the eukaryotic-specific segment (ESS) of eS26 revealed how TSR2 is attracted to importin:eS26 complexes and prevents eS26 rebinding to importin; a DBA-associated TSR2 mutant was shown to be specifically impaired in ESS binding, mechanistically explaining disease pathogenesis.\",\n      \"evidence\": \"NMR structure determination, cross-linking mass spectrometry, binding assays with DBA mutant TSR2\",\n      \"pmids\": [\"30201955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length complex structure not determined\", \"Whether additional nuclear factors cooperate with TSR2 in vivo not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TSR2's function was extended beyond biogenesis: Tsr2 was shown to extract Rps26 from fully assembled mature ribosomes under osmotic, salt, or pH stress, store the free subunit, and reincorporate it after stress, generating specialized Rps26-deficient ribosomes with altered translational output.\",\n      \"evidence\": \"In vitro Rps26 release assays with purified Tsr2, yeast in vivo release assays, ribosome profiling\",\n      \"pmids\": [\"35213229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that activates TSR2 to extract eS26 from mature ribosomes not identified\", \"Whether this mechanism operates in mammalian cells not tested\", \"Translational targets of Rps26-deficient ribosomes only partially characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The ribosome repair function of TSR2 was shown to involve quality control: Tsr2 specifically removes oxidized Rps26 from ribosomes under oxidative stress, enabling replacement with newly synthesized undamaged copies, directly linking TSR2 to a chaperone-mediated ribosome repair pathway.\",\n      \"evidence\": \"Chemical proteomics (cysteine oxidation profiling), yeast genetics, ribosome fractionation, oxidative stress growth assays\",\n      \"pmids\": [\"37086725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TSR2 senses oxidation on eS26 directly or is activated by an upstream signal unknown\", \"Fate of the oxidized Rps26 after release not fully defined at this point\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The degradation fate of TSR2-released Rps26 was identified: the Pro/N-degron pathway via the GID-complex E3 ligase and adaptor Gid4 polyubiquitinates Rps26 at Lys66/Lys70, coupling TSR2-mediated extraction to proteasomal clearance and enabling stable accumulation of Rps26-deficient ribosomes.\",\n      \"evidence\": \"Yeast ubiquitination assays, proteasome inhibitor experiments, N-terminal proline and lysine mutational analysis (preprint)\",\n      \"pmids\": [\"39185221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Whether GID-dependent degradation applies to mammalian cells not tested\", \"Relative flux through reincorporation vs. degradation pathways not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the signal or conformational change that activates TSR2 to extract eS26 from mature ribosomes under stress, whether the biogenesis and repair functions of TSR2 are conserved in mammalian systems, and the full repertoire of mRNAs differentially translated by Rps26-deficient ribosomes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Activation mechanism for TSR2-mediated eS26 extraction from mature ribosomes unknown\", \"Mammalian in vivo validation of ribosome repair function lacking\", \"Complete translational program of Rps26-deficient ribosomes not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RPS26\", \"FAP7\", \"GID4\"],\n    \"other_free_text\": []\n  }\n}\n```"}