{"gene":"XPOT","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1998,"finding":"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.","method":"Chemical and enzymatic footprinting, phosphate modification interference, Xenopus oocyte nuclear export assays with Xpo-t antibody blocking, mutant/precursor tRNA binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (footprinting, interference, in vivo oocyte export blockade, mutant tRNA analysis) in a single rigorous study","pmids":["9857198"],"is_preprint":false},{"year":2009,"finding":"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.","method":"X-ray crystallography (3.2 Å and 3.1 Å resolution crystal structures)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures of both functional states with direct mechanistic interpretation, published in a high-rigor venue","pmids":["19680239"],"is_preprint":false},{"year":2002,"finding":"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.","method":"In vitro binding assays with peripherally localized nucleoporins, subcellular fractionation/localization, RanGTP-dependence assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding assays for two domains combined with localization data, single lab","pmids":["12138183"],"is_preprint":false},{"year":2001,"finding":"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.","method":"In vitro binding assays (co-IP of Xpo-t/RanGTP with tRNA-Rz), somatic cell export assays, Xenopus oocyte nuclear extract injection experiments","journal":"Biomacromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding and functional export assays in two cell systems, single lab","pmids":["11777397"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown of Xpo-t in human fibroblasts, mTORC1 activity assays, autophagy assays, tRNA localization","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (mTORC1, autophagy), single lab, single study","pmids":["20714220"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Genetic epistasis (overexpression suppressor assay), mRNA profiling, growth assays in S. pombe","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple phenotypic readouts (tRNA levels, transcriptomics, growth), single lab","pmids":["22160596"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Classical all-atom and accelerated molecular dynamics simulations based on published crystal structures","journal":"Biophysical journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation","pmids":["27028637"],"is_preprint":false},{"year":2022,"finding":"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.","method":"siRNA screening, proteomics (mass spectrometry), co-IP, subcellular fractionation, functional tonicity-response assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen plus proteomics plus direct interaction assays for novel NFAT5 cargo, single lab, multiple orthogonal methods","pmids":["35635291"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown, CCK-8 proliferation assay, wound healing/migration assays, subcutaneous xenograft, flow cytometry, Western blot","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined in vitro and in vivo phenotypes and molecular readouts, single lab","pmids":["30334580"],"is_preprint":false},{"year":2023,"finding":"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.","method":"siRNA knockdown, high-throughput tRNA sequencing, RNA-seq, protein mass spectrometry, codon preference analysis, cell cycle/cytokinesis assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (tRNA-seq, proteomics, functional assays) in a single study, single lab","pmids":["37928256"],"is_preprint":false},{"year":2025,"finding":"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.","method":"siRNA knockdown, CCK-8, Transwell assay, Western blotting for PI3K/AKT/mTOR and CDK4/6 signaling components","journal":"Journal of inflammation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily KD + Western blot, no reconstitution or direct binding evidence for PI3K pathway connection","pmids":["40416714"],"is_preprint":false},{"year":2025,"finding":"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.","method":"siRNA knockdown, CCK-8, TUNEL, Transwell, ELISA (IL-1β, IL-18), Western blot (GSDMD, NLRP3, ASC, caspase-1), pyroptosis inhibitor rescue","journal":"Central-European journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD + downstream readouts with inhibitor rescue, no direct mechanistic link between tRNA export and pyroptosis established","pmids":["41438360"],"is_preprint":false}],"current_model":"XPOT (Exportin-T) is a karyopherin-β family nuclear export receptor that wraps around mature, 5'- and 3'-end-processed tRNAs—contacting the acceptor and TΨC arms—cooperatively with RanGTP to form an export-competent complex; after transit through the NPC (facilitated by N-terminal interactions with Nup153/RanBP2 and C-terminal interactions with Nup214), RanGTP hydrolysis in the cytoplasm triggers a large conformational opening that releases tRNA cargo. Beyond canonical tRNA export, XPOT selectively exports subsets of tRNA isodecoders to control translation of specific proteins (e.g., TTC19) and thereby regulates cytokinesis, and it has been found to mediate tonicity-dependent nuclear export of the transcription factor NFAT5 in a process requiring RUVBL2 as a chaperone; nuclear accumulation of tRNAs caused by XPOT loss also suppresses mTORC1 and activates autophagy."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9857198"],"confidence":"High","gaps":["Did not resolve the atomic basis of end recognition","The 'at least two mechanisms' discriminating pre-tRNAs were not molecularly defined"]},{"year":2002,"claim":"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","pmids":["12138183"],"confidence":"Medium","gaps":["Single lab in vitro binding without structural mapping of the interfaces","Functional contribution of each nucleoporin contact to net export rate not quantified"]},{"year":2009,"claim":"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)","pmids":["19680239"],"confidence":"High","gaps":["Static snapshots do not reveal the release trajectory","Human XPOT structure not solved in this work"]},{"year":2010,"claim":"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","pmids":["20714220"],"confidence":"Medium","gaps":["Molecular link between nuclear tRNA pool and mTORC1 not defined","Single study, single cell type"]},{"year":2011,"claim":"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","pmids":["22160596"],"confidence":"Medium","gaps":["Mechanism connecting nuclear tRNA levels to Atf1p/Pcr1p signaling unresolved","Conservation of this circuit in human cells not tested here"]},{"year":2016,"claim":"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","pmids":["27028637"],"confidence":"Low","gaps":["Computational only, no experimental validation of the proposed hinges","Predicted release intermediates not captured structurally"]},{"year":2018,"claim":"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","pmids":["30334580"],"confidence":"Medium","gaps":["Did not establish whether the cell-cycle effect is via tRNA export or another XPOT function","Direct molecular targets driving cyclin loss not identified"]},{"year":2022,"claim":"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","pmids":["35635291"],"confidence":"Medium","gaps":["Structural basis for protein (versus tRNA) cargo recognition unknown","RanGTP dependence of NFAT5 export not defined"]},{"year":2023,"claim":"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","pmids":["37928256"],"confidence":"Medium","gaps":["Basis for isodecoder selectivity by XPOT not mechanistically resolved","Generality of the TTC19/cytokinesis axis beyond TNBC untested"]},{"year":2025,"claim":"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","pmids":["40416714","41438360"],"confidence":"Low","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,7]}],"complexes":[],"partners":["RAN","NUP153","RANBP2","NUP214","NFAT5","RUVBL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43592","full_name":"Exportin-T","aliases":["Exportin(tRNA)","tRNA exportin"],"length_aa":962,"mass_kda":110.0,"function":"Mediates the nuclear export of aminoacylated tRNAs. In the nucleus binds to tRNA and to the GTPase Ran in its active GTP-bound form. Docking of this trimeric complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the tRNA from the export receptor. XPOT then return to the nuclear compartment and mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43592/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/XPOT","classification":"Common Essential","n_dependent_lines":704,"n_total_lines":1208,"dependency_fraction":0.5827814569536424},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000184575","cell_line_id":"CID001583","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ERF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001583","total_profiled":1310},"omim":[{"mim_id":"611449","title":"EXPORTIN 4; XPO4","url":"https://www.omim.org/entry/611449"},{"mim_id":"604834","title":"TANK-BINDING KINASE 1; TBK1","url":"https://www.omim.org/entry/604834"},{"mim_id":"603180","title":"EXPORTIN, tRNA; XPOT","url":"https://www.omim.org/entry/603180"},{"mim_id":"177700","title":"GLAUCOMA 1, OPEN ANGLE, P; GLC1P","url":"https://www.omim.org/entry/177700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/XPOT"},"hgnc":{"alias_symbol":["XPO3"],"prev_symbol":[]},"alphafold":{"accession":"O43592","domains":[{"cath_id":"1.20.1050","chopping":"272-386_397-419","consensus_level":"medium","plddt":94.6911,"start":272,"end":419},{"cath_id":"1.20.930","chopping":"422-548","consensus_level":"medium","plddt":91.176,"start":422,"end":548},{"cath_id":"1.25.40","chopping":"819-962","consensus_level":"medium","plddt":91.1044,"start":819,"end":962}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43592","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43592-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43592-F1-predicted_aligned_error_v6.png","plddt_mean":91.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=XPOT","jax_strain_url":"https://www.jax.org/strain/search?query=XPOT"},"sequence":{"accession":"O43592","fasta_url":"https://rest.uniprot.org/uniprotkb/O43592.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43592/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43592"}},"corpus_meta":[{"pmid":"9857198","id":"PMC_9857198","title":"The role of exportin-t in selective nuclear export of mature tRNAs.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9857198","citation_count":181,"is_preprint":false},{"pmid":"21447600","id":"PMC_21447600","title":"Copy number variations on chromosome 12q14 in patients with normal tension glaucoma.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21447600","citation_count":175,"is_preprint":false},{"pmid":"19680239","id":"PMC_19680239","title":"Structures of the tRNA export factor in the nuclear and cytosolic states.","date":"2009","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/19680239","citation_count":109,"is_preprint":false},{"pmid":"25802992","id":"PMC_25802992","title":"RNA Export through the NPC in Eukaryotes.","date":"2015","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/25802992","citation_count":89,"is_preprint":false},{"pmid":"10806079","id":"PMC_10806079","title":"Review: transport of tRNA out of the nucleus-direct channeling to the ribosome?","date":"2000","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/10806079","citation_count":58,"is_preprint":false},{"pmid":"12138183","id":"PMC_12138183","title":"Steady-state nuclear localization of exportin-t involves RanGTP binding and two distinct nuclear pore complex interaction domains.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12138183","citation_count":38,"is_preprint":false},{"pmid":"21310917","id":"PMC_21310917","title":"Copy number variations and primary open-angle glaucoma.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/21310917","citation_count":33,"is_preprint":false},{"pmid":"20714220","id":"PMC_20714220","title":"Linking tRNA localization with activation of nutritional stress responses.","date":"2010","source":"Cell cycle (Georgetown, 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28407409","citation_count":7,"is_preprint":false},{"pmid":"35635291","id":"PMC_35635291","title":"Unconventional tonicity-regulated nuclear trafficking of NFAT5 mediated by KPNB1, XPOT and RUVBL2.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/35635291","citation_count":6,"is_preprint":false},{"pmid":"35766501","id":"PMC_35766501","title":"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.","date":"2022","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/35766501","citation_count":6,"is_preprint":false},{"pmid":"27028637","id":"PMC_27028637","title":"Insights into the Structural Dynamics of Nucleocytoplasmic Transport of tRNA by Exportin-t.","date":"2016","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27028637","citation_count":5,"is_preprint":false},{"pmid":"21058036","id":"PMC_21058036","title":"Flexibility of the exportins Cse1p and Xpot depicted by elastic network model.","date":"2010","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/21058036","citation_count":2,"is_preprint":false},{"pmid":"41021161","id":"PMC_41021161","title":"Integrating single-cell and bulk RNA sequencing data establishes a cuproptosis-related gene predictive signature in breast cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41021161","citation_count":2,"is_preprint":false},{"pmid":"24013345","id":"PMC_24013345","title":"Characterization of export receptor exportins (XPOs) in the parasite Schistosoma mansoni.","date":"2013","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/24013345","citation_count":2,"is_preprint":false},{"pmid":"24334215","id":"PMC_24334215","title":"The intrinsic dynamics of Cse1p and Xpot elucidated by coarse-grained models.","date":"2013","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24334215","citation_count":1,"is_preprint":false},{"pmid":"40416714","id":"PMC_40416714","title":"Exportin-T Promotes Breast Cancer Progression via PI3K/AKT/mTOR Signaling Pathway.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40416714","citation_count":1,"is_preprint":false},{"pmid":"41438360","id":"PMC_41438360","title":"Inhibition of XPOT promotes breast cancer cell pyroptosis to suppress cancer progression.","date":"2025","source":"Central-European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41438360","citation_count":0,"is_preprint":false},{"pmid":"41465102","id":"PMC_41465102","title":"Surviving the Heat: Genetic Diversity and Adaptation in Sudanese Butana Cattle.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41465102","citation_count":0,"is_preprint":false},{"pmid":"41380350","id":"PMC_41380350","title":"Uncovering genomic traces of local adaptation and milk production traits in the Comisana Sheep, a Mediterranean dairy breed.","date":"2025","source":"Animal : an international journal of animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/41380350","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16508,"output_tokens":3217,"usd":0.04889,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10756,"output_tokens":3475,"usd":0.070328,"stage2_stop_reason":"end_turn"},"total_usd":0.119218,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Chemical and enzymatic footprinting, phosphate modification interference, Xenopus oocyte nuclear export assays with Xpo-t antibody blocking, mutant/precursor tRNA binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (footprinting, interference, in vivo oocyte export blockade, mutant tRNA analysis) in a single rigorous study\",\n      \"pmids\": [\"9857198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (3.2 Å and 3.1 Å resolution crystal structures)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures of both functional states with direct mechanistic interpretation, published in a high-rigor venue\",\n      \"pmids\": [\"19680239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays with peripherally localized nucleoporins, subcellular fractionation/localization, RanGTP-dependence assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding assays for two domains combined with localization data, single lab\",\n      \"pmids\": [\"12138183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays (co-IP of Xpo-t/RanGTP with tRNA-Rz), somatic cell export assays, Xenopus oocyte nuclear extract injection experiments\",\n      \"journal\": \"Biomacromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding and functional export assays in two cell systems, single lab\",\n      \"pmids\": [\"11777397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of Xpo-t in human fibroblasts, mTORC1 activity assays, autophagy assays, tRNA localization\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (mTORC1, autophagy), single lab, single study\",\n      \"pmids\": [\"20714220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic epistasis (overexpression suppressor assay), mRNA profiling, growth assays in S. pombe\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple phenotypic readouts (tRNA levels, transcriptomics, growth), single lab\",\n      \"pmids\": [\"22160596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Classical all-atom and accelerated molecular dynamics simulations based on published crystal structures\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation\",\n      \"pmids\": [\"27028637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA screening, proteomics (mass spectrometry), co-IP, subcellular fractionation, functional tonicity-response assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen plus proteomics plus direct interaction assays for novel NFAT5 cargo, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35635291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, CCK-8 proliferation assay, wound healing/migration assays, subcutaneous xenograft, flow cytometry, Western blot\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined in vitro and in vivo phenotypes and molecular readouts, single lab\",\n      \"pmids\": [\"30334580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, high-throughput tRNA sequencing, RNA-seq, protein mass spectrometry, codon preference analysis, cell cycle/cytokinesis assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (tRNA-seq, proteomics, functional assays) in a single study, single lab\",\n      \"pmids\": [\"37928256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, CCK-8, Transwell assay, Western blotting for PI3K/AKT/mTOR and CDK4/6 signaling components\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily KD + Western blot, no reconstitution or direct binding evidence for PI3K pathway connection\",\n      \"pmids\": [\"40416714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, CCK-8, TUNEL, Transwell, ELISA (IL-1β, IL-18), Western blot (GSDMD, NLRP3, ASC, caspase-1), pyroptosis inhibitor rescue\",\n      \"journal\": \"Central-European journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD + downstream readouts with inhibitor rescue, no direct mechanistic link between tRNA export and pyroptosis established\",\n      \"pmids\": [\"41438360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XPOT (Exportin-T) is a karyopherin-β family nuclear export receptor that wraps around mature, 5'- and 3'-end-processed tRNAs—contacting the acceptor and TΨC arms—cooperatively with RanGTP to form an export-competent complex; after transit through the NPC (facilitated by N-terminal interactions with Nup153/RanBP2 and C-terminal interactions with Nup214), RanGTP hydrolysis in the cytoplasm triggers a large conformational opening that releases tRNA cargo. Beyond canonical tRNA export, XPOT selectively exports subsets of tRNA isodecoders to control translation of specific proteins (e.g., TTC19) and thereby regulates cytokinesis, and it has been found to mediate tonicity-dependent nuclear export of the transcription factor NFAT5 in a process requiring RUVBL2 as a chaperone; nuclear accumulation of tRNAs caused by XPOT loss also suppresses mTORC1 and activates autophagy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. 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 [#0]. 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 [#1]. 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 [#2]. 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 [#9], and it mediates tonicity-dependent nuclear export of the transcription factor NFAT5 in a process requiring RUVBL2 as a chaperone [#7]. Loss of XPOT causes nuclear accumulation of tRNAs that suppresses mTORC1 activity and activates autophagy independently of nutritional status [#4]. XPOT depletion across multiple cancer cell models impairs proliferation and invasion and arrests cells in G0/G1 with downregulation of cyclins and CDKs [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"Footprinting, modification interference, and Xenopus oocyte nuclear export assays with antibody blocking and mutant/precursor tRNAs\",\n      \"pmids\": [\"9857198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the atomic basis of end recognition\",\n        \"The 'at least two mechanisms' discriminating pre-tRNAs were not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined how the export complex docks at and traverses the NPC, identifying separate Ran-dependent and Ran-independent nucleoporin contacts.\",\n      \"evidence\": \"In vitro binding assays with peripheral nucleoporins plus subcellular localization in a single lab\",\n      \"pmids\": [\"12138183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab in vitro binding without structural mapping of the interfaces\",\n        \"Functional contribution of each nucleoporin contact to net export rate not quantified\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the structural basis for cargo recognition and directional transport by capturing both the tRNA/RanGTP-bound and unbound states.\",\n      \"evidence\": \"X-ray crystallography of S. pombe Xpot at 3.2 Å (bound) and 3.1 Å (free)\",\n      \"pmids\": [\"19680239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Static snapshots do not reveal the release trajectory\",\n        \"Human XPOT structure not solved in this work\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected XPOT-controlled tRNA localization to nutrient signaling, showing tRNA export status itself modulates mTORC1 and autophagy.\",\n      \"evidence\": \"siRNA knockdown in human fibroblasts with mTORC1, autophagy, and tRNA localization readouts\",\n      \"pmids\": [\"20714220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular link between nuclear tRNA pool and mTORC1 not defined\",\n        \"Single study, single cell type\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed the XPOT ortholog upstream of a transcriptional nutritional-stress response, linking perturbed tRNA processing/export to amino acid metabolism gene control.\",\n      \"evidence\": \"Genetic epistasis (overexpression suppression), mRNA profiling, and growth assays in S. pombe\",\n      \"pmids\": [\"22160596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting nuclear tRNA levels to Atf1p/Pcr1p signaling unresolved\",\n        \"Conservation of this circuit in human cells not tested here\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Modeled the cargo-release transition, proposing how RanGTP hydrolysis propagates conformational changes through hinge regions to open the receptor.\",\n      \"evidence\": \"All-atom and accelerated molecular dynamics simulations on published crystal structures\",\n      \"pmids\": [\"27028637\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational only, no experimental validation of the proposed hinges\",\n        \"Predicted release intermediates not captured structurally\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked XPOT to cancer cell proliferation, showing depletion arrests cells in G0/G1 with broad cyclin/CDK downregulation.\",\n      \"evidence\": \"siRNA knockdown with proliferation, migration, xenograft, flow cytometry, and Western blot in HCC lines\",\n      \"pmids\": [\"30334580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not establish whether the cell-cycle effect is via tRNA export or another XPOT function\",\n        \"Direct molecular targets driving cyclin loss not identified\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-canonical XPOT function exporting the transcription factor NFAT5 under hypotonicity, requiring RUVBL2 as a chaperone.\",\n      \"evidence\": \"siRNA screening, proteomics, co-IP, fractionation, and tonicity-response assays\",\n      \"pmids\": [\"35635291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for protein (versus tRNA) cargo recognition unknown\",\n        \"RanGTP dependence of NFAT5 export not defined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated cargo-selective tRNA export, where XPOT preferentially exports specific isodecoders to control translation of defined proteins and thereby cytokinesis.\",\n      \"evidence\": \"siRNA knockdown with tRNA-seq, RNA-seq, mass spectrometry, codon analysis, and cytokinesis assays in TNBC cells\",\n      \"pmids\": [\"37928256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Basis for isodecoder selectivity by XPOT not mechanistically resolved\",\n        \"Generality of the TTC19/cytokinesis axis beyond TNBC untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended XPOT's pro-tumor role in breast cancer to PI3K/AKT/mTOR signaling and to pyroptosis suppression.\",\n      \"evidence\": \"siRNA knockdown with CCK-8, Transwell, Western blot for PI3K/AKT/mTOR and pyroptosis markers, and inhibitor rescue\",\n      \"pmids\": [\"40416714\", \"41438360\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct binding or reconstitution linking XPOT to PI3K/AKT/mTOR or pyroptosis machinery\",\n        \"Whether effects depend on tRNA export not established\",\n        \"Single-lab correlative Western-blot readouts\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model for isodecoder-selective or protein-cargo recognition\",\n        \"Causal chain from nuclear tRNA accumulation to mTORC1/autophagy undefined\",\n        \"Human XPOT structures in alternative cargo states lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAN\", \"NUP153\", \"RANBP2\", \"NUP214\", \"NFAT5\", \"RUVBL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}