Affinage

TSR2

Pre-rRNA-processing protein TSR2 homolog · UniProt Q969E8

Length
191 aa
Mass
20.9 kDa
Annotated
2026-06-10
43 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 High

    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

    PMID:25144938

    Open questions at the time
    • Structural basis of the RanGTP-independent disassembly not resolved at this stage
    • How eS26 is specifically recognized over other importin cargo not defined
  2. 2014 Medium

    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

    PMID:24942156

    Open questions at the time
    • Binding-partner claim rests on prior literature, not direct experiment here
    • Mechanism by which mutations impair function not tested in this study
  3. 2015 Medium

    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

    PMID:26203908

    Open questions at the time
    • No mechanistic rescue linking the hair phenotype to ribosome assembly
    • Cell type driving the follicle defect not defined
  4. 2016 Medium

    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

    PMID:27929371

    Open questions at the time
    • Tsr2 role secondary to the Fap7 focus of the study
    • Order and coordination of Tsr2 and Fap7 handoff not fully resolved
  5. 2018 High

    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

    PMID:30201955

    Open questions at the time
    • How allosteric sequestration is relieved at the pre-ribosome not defined
    • Structural state of the delivery complex on the 90S not resolved
  6. 2022 High

    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

    PMID:35213229

    Open questions at the time
    • How specific stresses trigger release mechanistically not defined
    • Functional consequences of Rps26-deficient ribosomes on translation specificity not detailed
  7. 2023 High

    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

    PMID:37086725

    Open questions at the time
    • Whether Tsr2 senses oxidation directly or recognizes a downstream signal unknown
    • Selectivity for damaged versus intact Rps26 not biochemically dissected
  8. 2024 Medium

    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)

    PMID:39185221

    Open questions at the time
    • Preprint not yet peer-reviewed
    • How Tsr2 hands off Rps26 to the GID machinery not defined
  9. 2025 Medium

    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

    PMID:40377206

    Open questions at the time
    • Mechanistic link to Tsr2's chaperone role inferred, not reconstituted
    • Whether the effect is via ribosome composition or another route unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No mechanism linking ribosome chaperone activity to the DBA or hair-follicle phenotypes
  • Regulatory switch between assembly and stress-release modes undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0140313 molecular sequestering activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
RPS26

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. In vitro dissociation assays, yeast genetics, nuclear import reconstitution, co-immunoprecipitation eLife High 25144938
2018 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. NMR structure determination, cross-linking mass spectrometry, mutational analysis, binding assays Nature communications High 30201955
2016 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. In vitro ATPase assays, yeast genetics (depletion), co-immunoprecipitation, ribosome assembly assays eLife Medium 27929371
2022 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. In vitro Rps26 release assays, yeast genetics (Tsr2 deletion/depletion), ribosome fractionation, in vivo stress assays Science advances High 35213229
2023 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. Chemical proteomics (cysteine oxidation detection), yeast genetics (chaperone deletion), ribosome fractionation, growth assays under oxidative stress Molecular cell High 37086725
2024 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. Yeast genetics (N-degron mutants, GID complex deletions), ubiquitination assays, ribosome fractionation, stress resistance assays bioRxivpreprint Medium 39185221
2014 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. Whole exome sequencing, Sanger sequencing, genetic analysis of DBA families American journal of medical genetics. Part A Medium 24942156
2015 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. Whole genome sequencing, linkage analysis, RT-PCR characterization of mutant transcripts, immunohistochemistry, RNA in situ hybridization in mice PLoS genetics Medium 26203908
2025 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. RNA-tagging/mass spectrometry screen, siRNA knockdown of TSR2 and RPS26, FMRpolyG reporter assays in cell culture eLife Medium 40377206
2011 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. Overexpression in HEp-2 cells, NF-κB luciferase reporter assay, apoptosis assay Molekuliarnaia biologiia Low 21790011

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutations in twinstar, a Drosophila gene encoding a cofilin/ADF homologue, result in defects in centrosome migration and cytokinesis. The Journal of cell biology 258 8522587
2001 Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer research 116 11691800
2014 Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. American journal of medical genetics. Part A 113 24942156
2007 O-fucosylation is required for ADAMTS13 secretion. The Journal of biological chemistry 87 17395589
2004 The tryptophan-rich motifs of the thrombospondin type 1 repeats bind VLAL motifs in the latent transforming growth factor-beta complex. The Journal of biological chemistry 69 15342643
2007 O-fucosylation of thrombospondin type 1 repeats in ADAMTS-like-1/punctin-1 regulates secretion: implications for the ADAMTS superfamily. The Journal of biological chemistry 66 17395588
2012 ADAMTS5 functions as an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity. The American journal of pathology 65 22796434
2014 A RanGTP-independent mechanism allows ribosomal protein nuclear import for ribosome assembly. eLife 62 25144938
2023 Chaperone-directed ribosome repair after oxidative damage. Molecular cell 55 37086725
2004 Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta. The American journal of pathology 49 15277228
2022 The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress. Science advances 42 35213229
2013 Molecular basis of antiangiogenic thrombospondin-1 type 1 repeat domain interactions with CD36. Arteriosclerosis, thrombosis, and vascular biology 41 23640500
2023 Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia. Leukemia 33 37973818
2019 Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b. Frontiers in immunology 33 31552043
2015 Global comparison of chromosome X genes of pulmonary telocytes with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes. Journal of translational medicine 31 26416664
2016 Prefabrication of a ribosomal protein subcomplex essential for eukaryotic ribosome formation. eLife 24 27929371
2006 Halofuginone inhibits tumor growth in the polyoma middle T antigen mouse via a thrombospondin-1 independent mechanism. Cancer biology & therapy 24 16418571
2018 Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2. Nature communications 22 30201955
2004 Use of a monoclonal antibody specific for activated endothelial cells to quantitate angiogenesis in vivo in zebrafish after drug treatment. Angiogenesis 20 15609079
2012 Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects. PloS one 19 22509329
2015 Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation. PLoS genetics 16 26203908
2011 Expression, purification and structural characterization of functionally replete thrombospondin-1 type 1 repeats in a bacterial expression system. Protein expression and purification 15 21821127
2023 Inhibition of ribosome biogenesis in the epidermis is sufficient to trigger organism-wide growth quiescence independently of nutritional status in C. elegans. PLoS biology 14 37651423
2017 TSR2 Induces laryngeal cancer cell apoptosis through inhibiting NF-κB signaling pathway. The Laryngoscope 11 29280495
2011 The novel protein TSR2 inhibits the transcriptional activity of nuclear factor-kappaB and induces apoptosis. Molekuliarnaia biologiia 10 21790011
2023 Efficient PAM-Less Base Editing for Zebrafish Modeling of Human Genetic Disease with zSpRY-ABE8e. Journal of visualized experiments : JoVE 8 36876933
2023 p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes. International journal of molecular sciences 7 37834388
2010 Alternative chemistries for the synthesis of thrombospondin-1 type 1 repeats. Biopolymers 7 20593462
2023 The Diverse Genomic Landscape of Diamond-Blackfan Anemia: Two Novel Variants and a Mini-Review. Children (Basel, Switzerland) 6 38002903
2009 Chemical synthesis and biotinylation of the thrombospondin domain TSR2. Protein science : a publication of the Protein Society 6 19384999
1992 Two regions in human DNA polymerase beta mRNA suppress translation in Escherichia coli. Nucleic acids research 6 1408801
2025 Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions. eLife 5 40377206
2023 A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities. Disease models & mechanisms 4 37661832
2022 Splice-site variant in the RPS7 5'-UTR leads to a decrease in the mRNA level and development of Diamond-Blackfan anemia. Clinical genetics 4 36057918
2016 Toward RNA Repair of Diamond Blackfan Anemia Hematopoietic Stem Cells. Human gene therapy 4 27550323
2001 Functional organisation of anterior thoracic stretch receptors in the deep-sea isopod Bathynomus doederleini: behavioural, morphological and physiological studies. The Journal of experimental biology 4 11707493
2024 Transcriptomic insights into multiple system atrophy from a PLP-α-synuclein transgenic mouse model. Brain research 3 38575106
2024 The ubiquitin-proteasome system regulates the formation of specialized ribosomes during high salt stress in yeast. bioRxiv : the preprint server for biology 3 39185221
2024 Higher expression of TSR2 aggravating hypertension via the PPAR signaling pathway. Aging 2 38814181
2023 Genomic characterization of three bacterial isolates antagonistic to the pea root rot pathogen Aphanomyces euteiches. Canadian journal of microbiology 2 38061385
2024 A novel nonsense RPS26 mutation in a patient with Diamond-Blackfan anemia: a case report. Journal of medical case reports 1 39568018
2026 Selection and Validation of Suitable Reference Genes for RT-qPCR Normalization in Euonymus bungeanus Across Various Tissues and Under Abiotic Stress/Hormone Treatments. Plants (Basel, Switzerland) 0 42075433
2024 [TSR2 overexpression inhibits proliferation and invasion of gastric cancer cells by downregulating the PI3K/AKT signaling pathway]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 38862449

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