Affinage

TSR2

Pre-rRNA-processing protein TSR2 homolog · UniProt Q969E8

Length
191 aa
Mass
20.9 kDa
Annotated
2026-04-28
42 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2011 Low

    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

    PMID:21790011

    Open questions at the time
    • Single overexpression study without endogenous validation or identification of direct targets
    • No connection to ribosome biology established
    • Not independently replicated
  2. 2014 High

    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)

    PMID:24942156 PMID:25144938

    Open questions at the time
    • 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
  3. 2016 Medium

    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

    PMID:27929371

    Open questions at the time
    • Direct physical interaction between TSR2 and Fap7 not demonstrated
    • Order-of-events (TSR2 release of eS26 vs. Fap7 engagement) not kinetically resolved
  4. 2018 High

    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

    PMID:30201955

    Open questions at the time
    • Full-length complex structure not determined
    • Whether additional nuclear factors cooperate with TSR2 in vivo not addressed
  5. 2022 High

    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

    PMID:35213229

    Open questions at the time
    • 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
  6. 2023 High

    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

    PMID:37086725

    Open questions at the time
    • 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
  7. 2024 Medium

    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)

    PMID:39185221

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Whether GID-dependent degradation applies to mammalian cells not tested
    • Relative flux through reincorporation vs. degradation pathways not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
FAP7GID4RPS26

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. In vitro dissociation assays, yeast genetics, depletion experiments, biochemical reconstitution eLife High 25144938
2018 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. NMR structure determination, cross-linking mass spectrometry, binding assays with DBA mutant Tsr2 Nature communications High 30201955
2022 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. In vitro Rps26 release assays with purified Tsr2, yeast genetics (in vivo Rps26 release assay), ribosome profiling, stress-response phenotypic analysis Science advances High 35213229
2023 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. Chemical proteomics (cysteine oxidation profiling), yeast genetics, ribosome fractionation, growth assays under oxidative stress Molecular cell High 37086725
2024 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. Yeast genetics, ubiquitination assays, proteasome inhibitor experiments, mutational analysis (N-terminal proline substitution, lysine substitution) bioRxivpreprint Medium 39185221
2016 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. Yeast genetics (depletion strains), in vitro reconstitution of uS11:eS26 subcomplex, ATPase assays eLife Medium 27929371
2014 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. Whole exome sequencing, Sanger sequencing, genetic analysis in human patients American journal of medical genetics. Part A Medium 24942156
2015 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. Linkage analysis, whole genome sequencing, RT-PCR of mutant transcripts, immunohistochemistry, RNA in situ hybridization in mice PLoS genetics Medium 26203908
2025 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. siRNA knockdown, RAN translation reporter assays, mass spectrometry interactome screen eLife Low 40377206
2011 Overexpression of human TSR2 in HEp-2 cells inhibits NF-κB transcriptional activity (with or without TNFα stimulus) and induces apoptosis. Overexpression, NF-κB luciferase reporter assay, apoptosis assays Molekuliarnaia biologiia Low 21790011

Source papers

Stage 0 corpus · 42 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 115 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 112 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 60 25144938
2023 Chaperone-directed ribosome repair after oxidative damage. Molecular cell 53 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
2013 Molecular basis of antiangiogenic thrombospondin-1 type 1 repeat domain interactions with CD36. Arteriosclerosis, thrombosis, and vascular biology 41 23640500
2022 The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress. Science advances 40 35213229
2023 Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia. Leukemia 32 37973818
2019 Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b. Frontiers in immunology 32 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
2006 Halofuginone inhibits tumor growth in the polyoma middle T antigen mouse via a thrombospondin-1 independent mechanism. Cancer biology & therapy 24 16418571
2016 Prefabrication of a ribosomal protein subcomplex essential for eukaryotic ribosome formation. eLife 23 27929371
2018 Molecular basis for disassembly of an importin:ribosomal protein complex by the escortin Tsr2. Nature communications 20 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 13 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
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
2023 The Diverse Genomic Landscape of Diamond-Blackfan Anemia: Two Novel Variants and a Mini-Review. Children (Basel, Switzerland) 5 38002903
2025 Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions. eLife 4 40377206
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
2023 A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities. Disease models & mechanisms 3 37661832
2024 Higher expression of TSR2 aggravating hypertension via the PPAR signaling pathway. Aging 2 38814181
2024 The ubiquitin-proteasome system regulates the formation of specialized ribosomes during high salt stress in yeast. bioRxiv : the preprint server for biology 2 39185221
2024 A novel nonsense RPS26 mutation in a patient with Diamond-Blackfan anemia: a case report. Journal of medical case reports 1 39568018
2023 Genomic characterization of three bacterial isolates antagonistic to the pea root rot pathogen Aphanomyces euteiches. Canadian journal of microbiology 1 38061385
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