Affinage

XPOT

Exportin-T · UniProt O43592

Length
962 aa
Mass
110.0 kDa
Annotated
2026-06-11
30 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

XPOT (Exportin-T) is a RanGTP-dependent nuclear export receptor that delivers mature tRNAs from the nucleus to the cytoplasm and thereby couples nuclear tRNA processing to cytoplasmic protein synthesis (PMID:9857198). It binds tRNA cooperatively with GTP-loaded Ran, contacting the backbone of the TΨC and acceptor arms and the correctly processed 5' and 3' ends, a recognition strategy that selects mature tRNAs while discriminating against improperly processed precursors; aminoacylation is dispensable for binding (PMID:9857198). Crystal structures of both functional states show that cargo loading drives a large conformational change in which the receptor wraps around the tRNA, while RanGTP hydrolysis in the cytoplasm reverses this transition to release cargo (PMID:19680239). Transit through the nuclear pore is supported by two distinct nucleoporin-interaction surfaces: a RanGTP-dependent N-terminal interaction with Nup153 and RanBP2/Nup358 and a Ran-independent C-terminal interaction with CAN/Nup214 (PMID:12138183). Beyond bulk tRNA export, XPOT exports selected tRNA isodecoders to control translation of specific proteins such as TTC19, linking cargo-selective tRNA export to cytokinesis (PMID:37928256), and it mediates tonicity-dependent nuclear export of the transcription factor NFAT5 in a process requiring RUVBL2 as a chaperone (PMID:35635291). Loss of XPOT causes nuclear accumulation of tRNAs that suppresses mTORC1 activity and activates autophagy independently of nutritional status (PMID:20714220). XPOT depletion across multiple cancer cell models impairs proliferation and invasion and arrests cells in G0/G1 with downregulation of cyclins and CDKs (PMID:30334580).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 High

    Established XPOT as a tRNA export receptor and defined how it distinguishes mature from immature tRNA, answering how the cell ensures only processed tRNAs leave the nucleus.

    Evidence Footprinting, modification interference, and Xenopus oocyte nuclear export assays with antibody blocking and mutant/precursor tRNAs

    PMID:9857198

    Open questions at the time
    • Did not resolve the atomic basis of end recognition
    • The 'at least two mechanisms' discriminating pre-tRNAs were not molecularly defined
  2. 2002 Medium

    Defined how the export complex docks at and traverses the NPC, identifying separate Ran-dependent and Ran-independent nucleoporin contacts.

    Evidence In vitro binding assays with peripheral nucleoporins plus subcellular localization in a single lab

    PMID:12138183

    Open questions at the time
    • Single lab in vitro binding without structural mapping of the interfaces
    • Functional contribution of each nucleoporin contact to net export rate not quantified
  3. 2009 High

    Provided the structural basis for cargo recognition and directional transport by capturing both the tRNA/RanGTP-bound and unbound states.

    Evidence X-ray crystallography of S. pombe Xpot at 3.2 Å (bound) and 3.1 Å (free)

    PMID:19680239

    Open questions at the time
    • Static snapshots do not reveal the release trajectory
    • Human XPOT structure not solved in this work
  4. 2010 Medium

    Connected XPOT-controlled tRNA localization to nutrient signaling, showing tRNA export status itself modulates mTORC1 and autophagy.

    Evidence siRNA knockdown in human fibroblasts with mTORC1, autophagy, and tRNA localization readouts

    PMID:20714220

    Open questions at the time
    • Molecular link between nuclear tRNA pool and mTORC1 not defined
    • Single study, single cell type
  5. 2011 Medium

    Placed the XPOT ortholog upstream of a transcriptional nutritional-stress response, linking perturbed tRNA processing/export to amino acid metabolism gene control.

    Evidence Genetic epistasis (overexpression suppression), mRNA profiling, and growth assays in S. pombe

    PMID:22160596

    Open questions at the time
    • Mechanism connecting nuclear tRNA levels to Atf1p/Pcr1p signaling unresolved
    • Conservation of this circuit in human cells not tested here
  6. 2016 Low

    Modeled the cargo-release transition, proposing how RanGTP hydrolysis propagates conformational changes through hinge regions to open the receptor.

    Evidence All-atom and accelerated molecular dynamics simulations on published crystal structures

    PMID:27028637

    Open questions at the time
    • Computational only, no experimental validation of the proposed hinges
    • Predicted release intermediates not captured structurally
  7. 2018 Medium

    Linked XPOT to cancer cell proliferation, showing depletion arrests cells in G0/G1 with broad cyclin/CDK downregulation.

    Evidence siRNA knockdown with proliferation, migration, xenograft, flow cytometry, and Western blot in HCC lines

    PMID:30334580

    Open questions at the time
    • Did not establish whether the cell-cycle effect is via tRNA export or another XPOT function
    • Direct molecular targets driving cyclin loss not identified
  8. 2022 Medium

    Revealed a non-canonical XPOT function exporting the transcription factor NFAT5 under hypotonicity, requiring RUVBL2 as a chaperone.

    Evidence siRNA screening, proteomics, co-IP, fractionation, and tonicity-response assays

    PMID:35635291

    Open questions at the time
    • Structural basis for protein (versus tRNA) cargo recognition unknown
    • RanGTP dependence of NFAT5 export not defined
  9. 2023 Medium

    Demonstrated cargo-selective tRNA export, where XPOT preferentially exports specific isodecoders to control translation of defined proteins and thereby cytokinesis.

    Evidence siRNA knockdown with tRNA-seq, RNA-seq, mass spectrometry, codon analysis, and cytokinesis assays in TNBC cells

    PMID:37928256

    Open questions at the time
    • Basis for isodecoder selectivity by XPOT not mechanistically resolved
    • Generality of the TTC19/cytokinesis axis beyond TNBC untested
  10. 2025 Low

    Extended XPOT's pro-tumor role in breast cancer to PI3K/AKT/mTOR signaling and to pyroptosis suppression.

    Evidence siRNA knockdown with CCK-8, Transwell, Western blot for PI3K/AKT/mTOR and pyroptosis markers, and inhibitor rescue

    PMID:40416714 PMID:41438360

    Open questions at the time
    • No direct binding or reconstitution linking XPOT to PI3K/AKT/mTOR or pyroptosis machinery
    • Whether effects depend on tRNA export not established
    • Single-lab correlative Western-blot readouts

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XPOT mechanistically selects specific tRNA isodecoders and protein cargoes, and how its export activity is transduced into mTORC1, cytokinesis, and cell-cycle outcomes, remains unresolved.
  • No structural model for isodecoder-selective or protein-cargo recognition
  • Causal chain from nuclear tRNA accumulation to mTORC1/autophagy undefined
  • Human XPOT structures in alternative cargo states lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0140104 molecular carrier activity 3 GO:0005215 transporter activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-9609507 Protein localization 3
Partners
NFAT5NUP153NUP214RANRANBP2RUVBL2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Exportin-t (Xpo-t) binds mature tRNA cooperatively with GTP-loaded Ran to form a nuclear export complex; the interaction involves the backbone of the TΨC and acceptor arms of tRNA. Accurate 5' and 3' end-processing of tRNA is required for Xpo-t–RanGTP interaction and nuclear export, whereas aminoacylation is not essential. Intron-containing, end-processed pre-tRNAs can be bound and exported if Xpo-t is in excess, suggesting at least two mechanisms discriminate pre-tRNAs from mature tRNAs. Chemical and enzymatic footprinting, phosphate modification interference, Xenopus oocyte nuclear export assays with Xpo-t antibody blocking, mutant/precursor tRNA binding assays The EMBO journal High 9857198
2009 Crystal structures of S. pombe Xpot in the nuclear state (3.2 Å; bound to tRNA and RanGTP) and cytosolic state (3.1 Å; unbound) show that Xpot undergoes a large conformational change on cargo binding, wrapping around the tRNA and specifically contacting the tRNA 5' and 3' ends, explaining how it recognizes all mature tRNAs while discriminating against improperly processed tRNAs. X-ray crystallography (3.2 Å and 3.1 Å resolution crystal structures) Nature High 19680239
2002 Xpo-t steady-state nuclear localization depends on its interaction with RanGTP. Two distinct NPC-interaction domains were identified: the N-terminus binds Nup153 and RanBP2/Nup358 in a RanGTP-dependent manner, while the C-terminus binds CAN/Nup214 independently of Ran, increasing the concentration of tRNA export complexes near NPCs. In vitro binding assays with peripherally localized nucleoporins, subcellular fractionation/localization, RanGTP-dependence assays Molecular and cellular biology Medium 12138183
2001 Xpo-t/RanGTP binds tRNA-attached ribozymes (tRNA-Rz) with extended 3' ends both in vitro and in somatic cells, mediating their cytoplasmic export. An inhibitor present in Xenopus oocyte nuclear extract blocks Xpo-t-dependent export of tRNA-Rz but not of mature tRNAs, suggesting a proofreading mechanism in oocytes. In vitro binding assays (co-IP of Xpo-t/RanGTP with tRNA-Rz), somatic cell export assays, Xenopus oocyte nuclear extract injection experiments Biomacromolecules Medium 11777397
2010 Knockdown of Xpo-t in human fibroblasts causes nuclear accumulation of tRNAs, reduced mTORC1 activity, and upregulated autophagy, demonstrating that tRNA subcellular localization controlled by Xpo-t regulates mTORC1 signaling and autophagy independently of actual nutritional status. siRNA knockdown of Xpo-t in human fibroblasts, mTORC1 activity assays, autophagy assays, tRNA localization Cell cycle (Georgetown, Tex.) Medium 20714220
2011 Modest overexpression of S. pombe los1+ (Xpo-t ortholog) in sla1-Δ cells suppresses the reduction in pre-tRNA levels, suppresses amino acid metabolism (AAM) gene upregulation driven by Atf1p/Pcr1p, and rescues slow growth, placing Xpo-t/Los1p upstream of a nutritional stress transcriptional response triggered by perturbed nuclear tRNA processing/export. Genetic epistasis (overexpression suppressor assay), mRNA profiling, growth assays in S. pombe Molecular biology of the cell Medium 22160596
2016 Molecular dynamics simulations of Xpot reveal that cargo release post-RanGTP hydrolysis involves a cascade of local conformational changes in RanGTP and loss of critical contacts at the Xpot/tRNA interface; two structural hinge regions mediate the transition from the nuclear (closed, cargo-bound) to cytosolic (open) conformation. Classical all-atom and accelerated molecular dynamics simulations based on published crystal structures Biophysical journal Low 27028637
2022 XPOT (Exportin-T) drives nuclear export of NFAT5 under hypotonicity; siRNA screening and proteomics identified XPOT as the export receptor and RUVBL2 as an indispensable chaperone for this process, which is distinct from canonical tRNA export and represents an unconventional tonicity-dependent nucleocytoplasmic trafficking pathway. siRNA screening, proteomics (mass spectrometry), co-IP, subcellular fractionation, functional tonicity-response assays Journal of cell science Medium 35635291
2018 XPOT knockdown in HCC cell lines inhibits tumor proliferation and invasion in vitro and in xenograft models; knockdown causes G0/G1 cell cycle arrest accompanied by downregulation of CDK1, CDK2, CDK4, CyclinA1, CyclinB1, CyclinB2, and CyclinE2. siRNA knockdown, CCK-8 proliferation assay, wound healing/migration assays, subcutaneous xenograft, flow cytometry, Western blot Molecular carcinogenesis Medium 30334580
2023 XPOT knockdown in TNBC cells specifically reduces nuclear export of a subset of tRNA isodecoders including tRNA-Ala-AGC-10-1; this leads to decreased translation of TTC19 (identified via codon preference analysis and proteomics), causing cytokinesis failure and inhibiting proliferation, establishing a cargo-selective tRNA export–translation–cytokinesis axis. siRNA knockdown, high-throughput tRNA sequencing, RNA-seq, protein mass spectrometry, codon preference analysis, cell cycle/cytokinesis assays International journal of biological sciences Medium 37928256
2025 XPOT knockdown in BC cells (MDA-MB-468/231) reduces proliferation and invasion; Western blotting shows decreased phosphorylation of PI3K/AKT/mTOR pathway components and reduced cyclin D and CDK4/6, placing XPOT upstream of PI3K/AKT/mTOR-driven cell cycle progression in breast cancer. siRNA knockdown, CCK-8, Transwell assay, Western blotting for PI3K/AKT/mTOR and CDK4/6 signaling components Journal of inflammation research Low 40416714
2025 Silencing XPOT in MCF-7 breast cancer cells reduces viability, migration, and invasion, and promotes pyroptosis as evidenced by increased IL-1β and IL-18 secretion, elevated GSDMD N-terminal cleavage, and upregulation of NLRP3, ASC, and cleaved-caspase-1; these effects are reversed by the pyroptosis inhibitor azalamellarin N. siRNA knockdown, CCK-8, TUNEL, Transwell, ELISA (IL-1β, IL-18), Western blot (GSDMD, NLRP3, ASC, caspase-1), pyroptosis inhibitor rescue Central-European journal of immunology Low 41438360

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The role of exportin-t in selective nuclear export of mature tRNAs. The EMBO journal 181 9857198
2011 Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Human molecular genetics 175 21447600
2009 Structures of the tRNA export factor in the nuclear and cytosolic states. Nature 109 19680239
2015 RNA Export through the NPC in Eukaryotes. Genes 89 25802992
2000 Review: transport of tRNA out of the nucleus-direct channeling to the ribosome? Journal of structural biology 58 10806079
2002 Steady-state nuclear localization of exportin-t involves RanGTP binding and two distinct nuclear pore complex interaction domains. Molecular and cellular biology 38 12138183
2011 Copy number variations and primary open-angle glaucoma. Investigative ophthalmology & visual science 33 21310917
2010 Linking tRNA localization with activation of nutritional stress responses. Cell cycle (Georgetown, Tex.) 32 20714220
2014 Expression status of candidate genes in mesothelioma tissues and cell lines. Mutation research 29 25771974
2018 Exportin-T promotes tumor proliferation and invasion in hepatocellular carcinoma. Molecular carcinogenesis 24 30334580
2001 Recognition of engineered tRNAs with an extended 3' end by Exportin-t (Xpo-t) and transport of tRNA-attached ribozymes to the cytoplasm in somatic cells. Biomacromolecules 22 11777397
2011 Altered nuclear tRNA metabolism in La-deleted Schizosaccharomyces pombe is accompanied by a nutritional stress response involving Atf1p and Pcr1p that is suppressible by Xpo-t/Los1p. Molecular biology of the cell 21 22160596
2019 The general mRNA exporters Mex67 and Mtr2 play distinct roles in nuclear export of tRNAs in Trypanosoma brucei. Nucleic acids research 19 31392978
2013 TBK1 and flanking genes in human retina. Ophthalmic genetics 15 23421332
2012 Integration analysis of quantitative proteomics and transcriptomics data identifies potential targets of frizzled-8 protein-related antiproliferative factor in vivo. BJU international 14 22738385
2021 Molecular profiling of nucleocytoplasmic transport factor genes in breast cancer. Heliyon 12 33553736
2023 Virus-induced lncRNA-BTX allows viral replication by regulating intracellular translocation of DHX9 and ILF3 to induce innate escape. Cell reports 11 37864796
2023 XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure. International journal of biological sciences 7 37928256
2017 Clinical and molecular characterization of a second family with the 12q14 microdeletion syndrome and review of the literature. American journal of medical genetics. Part A 7 28407409
2022 Unconventional tonicity-regulated nuclear trafficking of NFAT5 mediated by KPNB1, XPOT and RUVBL2. Journal of cell science 6 35635291
2022 Attenuated Viral Replication of Avian Infectious Bronchitis Virus with a Novel 82-Nucleotide Deletion in the 5a Gene Indicates a Critical Role for 5a in Virus-Host Interactions. Microbiology spectrum 6 35766501
2016 Insights into the Structural Dynamics of Nucleocytoplasmic Transport of tRNA by Exportin-t. Biophysical journal 5 27028637
2025 Integrating single-cell and bulk RNA sequencing data establishes a cuproptosis-related gene predictive signature in breast cancer. Discover oncology 2 41021161
2013 Characterization of export receptor exportins (XPOs) in the parasite Schistosoma mansoni. Parasitology research 2 24013345
2010 Flexibility of the exportins Cse1p and Xpot depicted by elastic network model. Journal of molecular modeling 2 21058036
2025 Exportin-T Promotes Breast Cancer Progression via PI3K/AKT/mTOR Signaling Pathway. Journal of inflammation research 1 40416714
2013 The intrinsic dynamics of Cse1p and Xpot elucidated by coarse-grained models. Computational biology and chemistry 1 24334215
2025 Uncovering genomic traces of local adaptation and milk production traits in the Comisana Sheep, a Mediterranean dairy breed. Animal : an international journal of animal bioscience 0 41380350
2025 Inhibition of XPOT promotes breast cancer cell pyroptosis to suppress cancer progression. Central-European journal of immunology 0 41438360
2025 Surviving the Heat: Genetic Diversity and Adaptation in Sudanese Butana Cattle. Genes 0 41465102

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