{"gene":"XPO5","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2011,"finding":"XPO5 (exportin-5) directly binds Dicer mRNA and mediates its nuclear export; inhibition of XPO5 causes increased nuclear retention of Dicer mRNA and reduced Dicer protein levels. Overexpression of pre-miRNA or adenoviral VA1 RNA titrates XPO5 away from Dicer mRNA, reducing Dicer levels and enhancing viral replication.","method":"In vitro binding assays, cellular RNA immunoprecipitation, XPO5 inhibition/knockdown, overexpression of competing RNAs","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro and cellular RNA-IP, multiple orthogonal methods (in vitro assay + RIP + functional knockdown) in a single study","pmids":["21297638"],"is_preprint":false},{"year":2018,"finding":"ERK-induced phosphorylation of XPO5 at a Serine-Proline (pS-P) motif enables binding by Pin1's WW domain; Pin1 then catalyzes a conformational change in XPO5 that diminishes its ability to export pre-miRNAs from the nucleus, resulting in reduced mature miRNA levels and promoted hepatocellular carcinoma development.","method":"Co-IP (Pin1 WW domain binding to phospho-XPO5), shRNA knockdown of Pin1, in vitro and in vivo HCC models, pre-miRNA nuclear export assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain-specific interaction mapping, functional rescue with shRNA, in vitro and in vivo validation","pmids":["29445125"],"is_preprint":false},{"year":2020,"finding":"XPO5 pervasively binds double-stranded RNA regions in clustered primary miRNA precursors (pri-miRNAs such as mir-17~92 and mir-15b~16-2) and vault RNAs in a RanGTP-independent manner, and enhances DROSHA/DGCR8 microprocessor processing of these pri-miRNAs. Genetic deletion of XPO5 compromises biogenesis of most miRNAs and causes severe defects in mouse embryonic development and skin morphogenesis.","method":"Global XPO5-associated RNA profiling (CLIP-seq), genetic deletion (KO mice), pri-miRNA processing assays with DROSHA/DGCR8, RanGTP-independence demonstrated biochemically","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — global RNA binding profiling, genetic KO with multiple developmental phenotypes, in vitro processing assays, replicated across multiple miRNA clusters","pmids":["32296071"],"is_preprint":false},{"year":2022,"finding":"The phosphatase PP2A, specifically the B55β regulatory subunit-containing holoenzyme, dephosphorylates XPO5, reversing ERK-mediated phosphorylation; dephosphorylation favors XPO5 cytoplasmic distribution, promotes pre-miRNA export, and increases mature miRNA expression, leading to HCC inhibition in vitro and in vivo.","method":"Phosphatase identification assay, co-IP of PP2A subunits with XPO5, subcellular fractionation, in vitro and in vivo HCC models","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with regulatory subunit characterization, functional in vitro/in vivo validation, single lab","pmids":["35441157"],"is_preprint":false},{"year":2016,"finding":"XPO5 (exportin 5) interacts with NUP93 and SMAD4; mutations in NUP93 that cause steroid-resistant nephrotic syndrome abrogate the NUP93–SMAD4 interaction and interfere with BMP7-induced SMAD transcriptional reporter activity, placing XPO5 in a complex with NUP93 at the nuclear pore relevant to SMAD signaling in podocytes.","method":"Co-IP (XPO5–NUP93 interaction), SMAD transcriptional reporter assay, patient mutation analysis, NUP93 knockdown","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrated XPO5-NUP93 interaction; functional SMAD reporter assay; single study but multiple orthogonal methods","pmids":["26878725"],"is_preprint":false},{"year":2023,"finding":"Lipid kinase PIP5K1A interacts with XPO5 in the nucleus and blocks XPO5 binding to pre-let-7 miRNA, thereby reducing mature let-7 levels; this function of PIP5K1A is kinase-independent. In C. elegans, the ortholog PPK-1 functions in the lin-28/let-7 heterochronic pathway controlling seam cell developmental timing.","method":"Co-IP (PIP5K1A–XPO5 interaction in nucleus), pre-miRNA binding competition assay, C. elegans genetic pathway (lin-28/let-7 epistasis), kinase-dead mutant analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, competitive binding assay, genetic epistasis in C. elegans, kinase-independence by mutagenesis; single lab","pmids":["37655623"],"is_preprint":false},{"year":2025,"finding":"METTL1 interacts with XPO5 in the nucleus (validated by co-IP); genetic ablation of METTL1 redistributes XPO5 to the cytosol, accelerating pre-miRNA export and enhancing miRNA maturation. Mechanistically, METTL1 facilitates ERK-mediated phosphorylation of XPO5, promoting its nuclear retention; constitutive ERK activation restores nuclear XPO5 in METTL1-deficient cells. This function is independent of METTL1's canonical m7G methyltransferase activity.","method":"APEX2 proximity labeling coupled with LC-MS/MS (interactome), co-IP and western blot, METTL1 KO cells, subcellular fractionation, constitutively active ERK rescue experiment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics + Co-IP validation + KO rescue with ERK, multiple orthogonal methods; single lab, single study","pmids":["41591839"],"is_preprint":false},{"year":2024,"finding":"SARS-CoV-2 N protein induces autophagic degradation of XPO5 (along with Dicer, SRSF3, and hnRNPA3), thereby inhibiting miRNA biogenesis; XPO5 knockdown exacerbates N protein-induced pneumonia severity, while XPO5 overexpression decreases it.","method":"XPO5 knockdown and overexpression in lung cells/mice, autophagic degradation assay, N protein expression, in vivo pneumonia severity assessment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined cellular/in vivo phenotype; mechanism (autophagic degradation) demonstrated; single study","pmids":["39138195"],"is_preprint":false},{"year":2025,"finding":"YTHDC1 phase separation promotes nuclear export of m6A-modified lncRNA by forming a nuclear pore complex with SRSF3, ALYREF, and XPO5, facilitating translocation from nucleus to cytoplasm; XPO5 participates as a component of this export complex.","method":"Co-IP/complex assembly, phase separation assays, m6A modification analysis, nuclear export assays, knockdown of complex components","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — complex membership inferred from co-IP in a single study focused on lncRNA export; XPO5's specific mechanistic contribution to this complex is not individually resolved","pmids":["40221424"],"is_preprint":false},{"year":2025,"finding":"Melatonin inhibits ERK-mediated phosphorylation of XPO5, which promotes nuclear transport of pre-miR-590-5p (shown to bind XPO5 by RNA immunoprecipitation) and enhances chondrogenic differentiation of human bone marrow mesenchymal stem cells.","method":"RNA immunoprecipitation (XPO5–pre-miR-590-5p interaction), western blot for ERK/XPO5 phosphorylation, chondrogenic differentiation assay with MLT treatment","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP experiment demonstrating XPO5-pre-miRNA interaction, functional phenotype shown, but mechanistic resolution of XPO5's specific role is limited; single lab","pmids":["40549108"],"is_preprint":false}],"current_model":"XPO5 (exportin-5) is a nuclear export receptor that binds pre-miRNAs (and structured RNAs including vault RNAs) in both RanGTP-dependent and RanGTP-independent manners to facilitate their export to the cytoplasm; it also directly binds Dicer mRNA to support its nuclear export, enhances DROSHA/DGCR8-mediated processing of clustered pri-miRNAs in the nucleus, and its activity is regulated by ERK-mediated phosphorylation (which promotes nuclear retention via Pin1-catalyzed conformational change) and dephosphorylated by PP2A-B55β (which restores cytoplasmic distribution and pre-miRNA export), with additional regulatory inputs from METTL1 (facilitating ERK phosphorylation) and PIP5K1A (blocking pre-miRNA binding in a kinase-independent manner), and mutations in XPO5 or its interaction partner NUP93 disrupt SMAD signaling and cause steroid-resistant nephrotic syndrome."},"narrative":{"mechanistic_narrative":"XPO5 (exportin-5) is a nuclear export receptor central to microRNA biogenesis, acting at multiple steps from nuclear pri-miRNA processing to cytoplasmic delivery of pre-miRNAs [PMID:32296071]. It pervasively binds double-stranded regions of clustered primary miRNA precursors and structured RNAs such as vault RNAs in a RanGTP-independent manner and enhances DROSHA/DGCR8 microprocessor processing of these pri-miRNAs; genetic deletion compromises biogenesis of most miRNAs and causes severe defects in mouse embryonic development and skin morphogenesis [PMID:32296071]. Beyond pre-miRNA cargo, XPO5 directly binds and exports Dicer mRNA, so that competing structured RNAs that titrate XPO5 away from Dicer mRNA reduce Dicer protein levels [PMID:21297638]. XPO5 export activity is governed by a phosphorylation switch: ERK phosphorylation at a Ser-Pro motif licenses Pin1 WW-domain binding and a Pin1-catalyzed conformational change that retains XPO5 in the nucleus and diminishes pre-miRNA export, promoting hepatocellular carcinoma [PMID:29445125], while the PP2A-B55β holoenzyme dephosphorylates XPO5 to restore its cytoplasmic distribution, pre-miRNA export and mature miRNA levels, opposing HCC [PMID:35441157]. This switch is tuned by additional partners: METTL1 facilitates ERK-mediated phosphorylation to drive nuclear retention independently of its m7G methyltransferase activity [PMID:41591839], and the lipid kinase PIP5K1A binds XPO5 in the nucleus and blocks pre-let-7 binding in a kinase-independent manner [PMID:37655623]. XPO5 also interacts with NUP93 and SMAD4 at the nuclear pore, and NUP93 mutations causing steroid-resistant nephrotic syndrome disrupt the NUP93-SMAD4 interaction and BMP7-induced SMAD signaling in podocytes [PMID:26878725].","teleology":[{"year":2011,"claim":"Established that XPO5 cargo extends beyond pre-miRNAs to a protein-coding mRNA, linking XPO5 directly to Dicer abundance and explaining how competing structured RNAs can suppress the miRNA pathway.","evidence":"In vitro binding, cellular RNA-IP, and competition by pre-miRNA/VA1 RNA in XPO5-knockdown cells","pmids":["21297638"],"confidence":"High","gaps":["Does not define the cis-elements in Dicer mRNA recognized by XPO5","Does not establish whether other mRNAs are XPO5 cargo"]},{"year":2016,"claim":"Placed XPO5 in a nuclear-pore complex with NUP93 and SMAD4, connecting the export receptor to BMP7/SMAD signaling and a Mendelian kidney disease.","evidence":"Co-IP of XPO5-NUP93, SMAD transcriptional reporter, patient NUP93 mutation analysis in podocytes","pmids":["26878725"],"confidence":"Medium","gaps":["XPO5's own functional contribution within the NUP93-SMAD4 complex is not isolated","No XPO5 mutation directly tested for the nephrotic phenotype here"]},{"year":2018,"claim":"Defined the regulatory logic that switches XPO5 off, showing ERK phosphorylation plus Pin1 isomerization conformationally suppresses pre-miRNA export to drive tumorigenesis.","evidence":"Domain-mapped Co-IP of Pin1 WW with phospho-XPO5, Pin1 shRNA, export assays, HCC models in vitro and in vivo","pmids":["29445125"],"confidence":"High","gaps":["Structural basis of the Pin1-induced conformational change not resolved","Identity of the upstream stimulus activating ERK toward XPO5 not defined"]},{"year":2020,"claim":"Reframed XPO5 as a nuclear enhancer of microprocessor activity, not merely an exporter, by showing RanGTP-independent binding to clustered pri-miRNAs and vault RNAs and an essential developmental role.","evidence":"CLIP-seq RNA profiling, DROSHA/DGCR8 processing assays, and XPO5-KO mouse phenotyping","pmids":["32296071"],"confidence":"High","gaps":["Mechanism by which XPO5 stimulates DROSHA/DGCR8 processing not defined at atomic level","Relative contribution of nuclear processing vs export to the KO phenotype not separated"]},{"year":2022,"claim":"Identified the phosphatase arm of the XPO5 switch, showing PP2A-B55β reverses ERK phosphorylation to restore export and suppress HCC.","evidence":"Phosphatase identification, Co-IP of PP2A B55β with XPO5, fractionation, HCC models","pmids":["35441157"],"confidence":"Medium","gaps":["Single-lab characterization","Site specificity of dephosphorylation not mapped"]},{"year":2023,"claim":"Revealed a kinase-independent inhibitory partner, with nuclear PIP5K1A blocking XPO5's pre-let-7 binding and tying the interaction to the conserved lin-28/let-7 heterochronic pathway.","evidence":"Co-IP, pre-miRNA binding competition, kinase-dead mutant analysis, C. elegans lin-28/let-7 epistasis","pmids":["37655623"],"confidence":"Medium","gaps":["Structural basis for competition with pre-miRNA not resolved","Generality across pre-miRNAs beyond let-7 not established"]},{"year":2024,"claim":"Showed XPO5 is a target of viral pathway suppression, as SARS-CoV-2 N protein drives its autophagic degradation to inhibit miRNA biogenesis and worsen lung pathology.","evidence":"XPO5 knockdown/overexpression in lung cells and mice, autophagic degradation assay, in vivo pneumonia severity","pmids":["39138195"],"confidence":"Medium","gaps":["Autophagy receptor/adaptor targeting XPO5 not identified","Selectivity of N-protein for XPO5 vs co-degraded factors not dissected"]},{"year":2025,"claim":"Showed METTL1 controls the XPO5 phosphorylation switch independently of its methyltransferase activity by facilitating ERK-mediated phosphorylation and nuclear retention.","evidence":"APEX2 proximity labeling/LC-MS/MS, Co-IP, METTL1-KO fractionation, constitutively active ERK rescue","pmids":["41591839"],"confidence":"Medium","gaps":["How METTL1 promotes ERK activity toward XPO5 mechanistically unresolved","Single-study, single-lab finding"]},{"year":2025,"claim":"Extended XPO5 cargo to m6A-modified lncRNA export via a YTHDC1/SRSF3/ALYREF complex, though XPO5's individual contribution is not isolated.","evidence":"Co-IP/complex assembly, phase separation assays, m6A and nuclear export assays with component knockdowns","pmids":["40221424"],"confidence":"Low","gaps":["XPO5's specific mechanistic role in the complex not individually resolved","Inferred complex membership from Co-IP in a single study"]},{"year":null,"claim":"How XPO5's distinct activities — RanGTP-independent pri-miRNA processing enhancement versus RanGTP-coupled export of pre-miRNAs and mRNAs — are coordinated on a single receptor, and what structural states the phosphorylation/conformational switch toggles between, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of phospho- vs dephospho-XPO5 cargo states","Cargo selection rules across pre-miRNA, mRNA, and lncRNA not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,5,9]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["PIN1","NUP93","SMAD4","PP2A-B55Β","PIP5K1A","METTL1","YTHDC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HAV4","full_name":"Exportin-5","aliases":["Ran-binding protein 21"],"length_aa":1204,"mass_kda":136.3,"function":"Mediates the nuclear export of proteins bearing a double-stranded RNA binding domain (dsRBD) and double-stranded RNAs (cargos). XPO5 in the nucleus binds cooperatively to the RNA and to the GTPase Ran in its active GTP-bound form. Proteins containing dsRBDs can associate with this trimeric complex through the RNA. Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause disassembly of the complex and release of the cargo from the export receptor. XPO5 then returns to the nuclear compartment by diffusion through the nuclear pore complex, to 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. Overexpression may in some circumstances enhance RNA-mediated gene silencing (RNAi). Mediates nuclear export of isoform 5 of ADAR/ADAR1 in a RanGTP-dependent manner Mediates the nuclear export of micro-RNA precursors, which form short hairpins (PubMed:14631048, PubMed:14681208, PubMed:15613540). Also mediates the nuclear export of synthetic short hairpin RNAs used for RNA interference. In some circumstances can also mediate the nuclear export of deacylated and aminoacylated tRNAs. Specifically recognizes dsRNAs that lack a 5'-overhang in a sequence-independent manner, have only a short 3'-overhang, and that have a double-stranded length of at least 15 base-pairs (PubMed:19965479). Binding is dependent on Ran-GTP (PubMed:19965479) (Microbial infection) Mediates the nuclear export of adenovirus VA1 dsRNA","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HAV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/XPO5","classification":"Common Essential","n_dependent_lines":994,"n_total_lines":1208,"dependency_fraction":0.8228476821192053},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124571","cell_line_id":"CID001580","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001580","total_profiled":1310},"omim":[{"mim_id":"618964","title":"REQUIRED FOR MEIOTIC NUCLEAR DIVISION 5 HOMOLOG A; RMND5A","url":"https://www.omim.org/entry/618964"},{"mim_id":"616893","title":"NEPHROTIC SYNDROME, TYPE 13; NPHS13","url":"https://www.omim.org/entry/616893"},{"mim_id":"616892","title":"NEPHROTIC SYNDROME, TYPE 12; NPHS12","url":"https://www.omim.org/entry/616892"},{"mim_id":"614352","title":"NUCLEOPORIN, 205-KD; NUP205","url":"https://www.omim.org/entry/614352"},{"mim_id":"614351","title":"NUCLEOPORIN, 93-KD; NUP93","url":"https://www.omim.org/entry/614351"}],"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/XPO5"},"hgnc":{"alias_symbol":["KIAA1291"],"prev_symbol":[]},"alphafold":{"accession":"Q9HAV4","domains":[{"cath_id":"1.20.58","chopping":"660-819_831-866","consensus_level":"medium","plddt":89.9191,"start":660,"end":866},{"cath_id":"1.20.272","chopping":"1064-1174","consensus_level":"medium","plddt":86.3494,"start":1064,"end":1174}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAV4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAV4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAV4-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=XPO5","jax_strain_url":"https://www.jax.org/strain/search?query=XPO5"},"sequence":{"accession":"Q9HAV4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HAV4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HAV4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAV4"}},"corpus_meta":[{"pmid":"26878725","id":"PMC_26878725","title":"Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.","date":"2016","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26878725","citation_count":160,"is_preprint":false},{"pmid":"21297638","id":"PMC_21297638","title":"Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels.","date":"2011","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21297638","citation_count":81,"is_preprint":false},{"pmid":"21552306","id":"PMC_21552306","title":"Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis.","date":"2010","source":"International journal of molecular epidemiology and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21552306","citation_count":53,"is_preprint":false},{"pmid":"29445125","id":"PMC_29445125","title":"Pin1 impairs microRNA biogenesis by mediating conformation change of XPO5 in hepatocellular carcinoma.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29445125","citation_count":44,"is_preprint":false},{"pmid":"32296071","id":"PMC_32296071","title":"XPO5 promotes primary miRNA processing independently of RanGTP.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32296071","citation_count":37,"is_preprint":false},{"pmid":"23549446","id":"PMC_23549446","title":"Association of polymorphisms in microRNA machinery genes (DROSHA, DICER1, RAN, and XPO5) with risk of idiopathic primary ovarian insufficiency in Korean women.","date":"2013","source":"Menopause (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23549446","citation_count":27,"is_preprint":false},{"pmid":"23874110","id":"PMC_23874110","title":"A miR-SNP of the XPO5 gene is associated with advanced non-small-cell lung cancer.","date":"2013","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/23874110","citation_count":26,"is_preprint":false},{"pmid":"28383405","id":"PMC_28383405","title":"Association of microRNA-related gene XPO5 rs11077 polymorphism with susceptibility to thyroid cancer.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28383405","citation_count":23,"is_preprint":false},{"pmid":"24648983","id":"PMC_24648983","title":"A microRNA-related single nucleotide polymorphism of the XPO5 gene is associated with survival of small cell lung cancer patients.","date":"2013","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/24648983","citation_count":20,"is_preprint":false},{"pmid":"28300636","id":"PMC_28300636","title":"Perinatal protein malnutrition alters expression of miRNA biogenesis genes Xpo5 and Ago2 in mice brain.","date":"2017","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/28300636","citation_count":18,"is_preprint":false},{"pmid":"40221424","id":"PMC_40221424","title":"YTHDC1 phase separation drives the nuclear export of m6A-modified lncNONMMUT062668.2 through the transport complex SRSF3-ALYREF-XPO5 to aggravate pulmonary fibrosis.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40221424","citation_count":15,"is_preprint":false},{"pmid":"27000860","id":"PMC_27000860","title":"Downregulation and tumor-suppressive role of XPO5 in hepatocellular carcinoma.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27000860","citation_count":14,"is_preprint":false},{"pmid":"32127945","id":"PMC_32127945","title":"Association of microRNA biosynthesis genes XPO5 and RAN polymorphisms with cancer susceptibility: Bayesian hierarchical meta-analysis.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32127945","citation_count":11,"is_preprint":false},{"pmid":"35441157","id":"PMC_35441157","title":"Regulation of XPO5 phosphorylation by PP2A in hepatocellular carcinoma.","date":"2022","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/35441157","citation_count":11,"is_preprint":false},{"pmid":"37373948","id":"PMC_37373948","title":"Unleash Multifunctional Role of miRNA Biogenesis Gene Variants (XPO5*rs34324334 and RAN*rs14035) with Susceptibility to Hepatocellular Carcinoma.","date":"2023","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37373948","citation_count":9,"is_preprint":false},{"pmid":"31056154","id":"PMC_31056154","title":"Genetic variants in DICER1, DROSHA, RAN, and XPO5 genes and risk of pregnancy-induced hypertension.","date":"2019","source":"Pregnancy hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/31056154","citation_count":9,"is_preprint":false},{"pmid":"31185329","id":"PMC_31185329","title":"Influence of genetic polymorphisms in DICER and XPO5 genes on the risk of coronary artery disease and circulating levels of vascular miRNAs.","date":"2019","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/31185329","citation_count":8,"is_preprint":false},{"pmid":"39138195","id":"PMC_39138195","title":"SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39138195","citation_count":7,"is_preprint":false},{"pmid":"29699373","id":"PMC_29699373","title":"Evaluating the Oncogenic and Tumor Suppressor Role of XPO5 in Different Tissue Tumor Types.","date":"2018","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/29699373","citation_count":7,"is_preprint":false},{"pmid":"32770606","id":"PMC_32770606","title":"Analysis of microRNA processing machinery gene (DROSHA, DICER1, RAN, and XPO5) variants association with end-stage renal disease.","date":"2020","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/32770606","citation_count":5,"is_preprint":false},{"pmid":"32148964","id":"PMC_32148964","title":"Single-Nucleotide Polymorphisms in XPO5 are Associated with Noise-Induced Hearing Loss in a Chinese Population.","date":"2020","source":"Biochemistry research international","url":"https://pubmed.ncbi.nlm.nih.gov/32148964","citation_count":5,"is_preprint":false},{"pmid":"37655623","id":"PMC_37655623","title":"Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/37655623","citation_count":3,"is_preprint":false},{"pmid":"34328643","id":"PMC_34328643","title":"Effects of Knockdown of XPO5 by siRNA on the Biological Behavior of Head and Neck Cancer Cells.","date":"2021","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/34328643","citation_count":3,"is_preprint":false},{"pmid":"37507877","id":"PMC_37507877","title":"Altered MicroRNA Maturation in Ischemic Hearts: Implication of Hypoxia on XPO5 and DICER1 Dysregulation and RedoximiR State.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37507877","citation_count":3,"is_preprint":false},{"pmid":"31868332","id":"PMC_31868332","title":"Association between XPO5 rs11077 polymorphism and cancer susceptibility: a meta-analysis of 7284 cases and 8511 controls.","date":"2019","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31868332","citation_count":2,"is_preprint":false},{"pmid":"29683071","id":"PMC_29683071","title":"Frequency distribution of BLMH, XPO5 and HFE gene polymorphisms in the South Indian population and their association with Hodgkin Lymphoma.","date":"2018","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/29683071","citation_count":2,"is_preprint":false},{"pmid":"36371311","id":"PMC_36371311","title":"Mutation in XPO5 causes adult-onset autosomal dominant familial focal segmental glomerulosclerosis.","date":"2022","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36371311","citation_count":1,"is_preprint":false},{"pmid":"41591839","id":"PMC_41591839","title":"METTL1 interacts with XPO5 to modulate pre-miRNA export.","date":"2026","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/41591839","citation_count":1,"is_preprint":false},{"pmid":"37311119","id":"PMC_37311119","title":"Investigation of the association of the RAN (rs14035) and XPO5 (rs11077) polymorphisms with venous thromboembolism.","date":"2023","source":"Romanian journal of internal medicine = Revue roumaine de medecine interne","url":"https://pubmed.ncbi.nlm.nih.gov/37311119","citation_count":1,"is_preprint":false},{"pmid":"40657248","id":"PMC_40657248","title":"Tumor-derived exosomal lncRNA SNHG4 promotes triple-negative breast cancer progression by targeting XPO5.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40657248","citation_count":1,"is_preprint":false},{"pmid":"29912490","id":"PMC_29912490","title":"[The analysis of single nucleotide polymorphisms of the DGCR8 and XPO5 genes, and their association with the incidence of primary open angle glaucoma].","date":"2016","source":"Klinika oczna","url":"https://pubmed.ncbi.nlm.nih.gov/29912490","citation_count":1,"is_preprint":false},{"pmid":"41516223","id":"PMC_41516223","title":"XPO5 Polymorphism in Colon Cancer Patients: A Cross-Sectional Study.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41516223","citation_count":0,"is_preprint":false},{"pmid":"40549108","id":"PMC_40549108","title":"Melatonin-mediated Inhibition of XPO5 phosphorylation facilitates the chondrogenic differentiation of human bone marrow mesenchymal stem cells by regulating the transport of miR-590-5p.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40549108","citation_count":0,"is_preprint":false},{"pmid":"39596271","id":"PMC_39596271","title":"Relationship Between the Occurrence of Depression and DROSHA (rs6877842, rs10719) and XPO5 (rs11077) Single-Nucleotide Polymorphisms in the Polish Population: A Case-Control Study.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39596271","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19961,"output_tokens":2865,"usd":0.051429,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10183,"output_tokens":3472,"usd":0.068858,"stage2_stop_reason":"end_turn"},"total_usd":0.120287,"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\": 2011,\n      \"finding\": \"XPO5 (exportin-5) directly binds Dicer mRNA and mediates its nuclear export; inhibition of XPO5 causes increased nuclear retention of Dicer mRNA and reduced Dicer protein levels. Overexpression of pre-miRNA or adenoviral VA1 RNA titrates XPO5 away from Dicer mRNA, reducing Dicer levels and enhancing viral replication.\",\n      \"method\": \"In vitro binding assays, cellular RNA immunoprecipitation, XPO5 inhibition/knockdown, overexpression of competing RNAs\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro and cellular RNA-IP, multiple orthogonal methods (in vitro assay + RIP + functional knockdown) in a single study\",\n      \"pmids\": [\"21297638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ERK-induced phosphorylation of XPO5 at a Serine-Proline (pS-P) motif enables binding by Pin1's WW domain; Pin1 then catalyzes a conformational change in XPO5 that diminishes its ability to export pre-miRNAs from the nucleus, resulting in reduced mature miRNA levels and promoted hepatocellular carcinoma development.\",\n      \"method\": \"Co-IP (Pin1 WW domain binding to phospho-XPO5), shRNA knockdown of Pin1, in vitro and in vivo HCC models, pre-miRNA nuclear export assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain-specific interaction mapping, functional rescue with shRNA, in vitro and in vivo validation\",\n      \"pmids\": [\"29445125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"XPO5 pervasively binds double-stranded RNA regions in clustered primary miRNA precursors (pri-miRNAs such as mir-17~92 and mir-15b~16-2) and vault RNAs in a RanGTP-independent manner, and enhances DROSHA/DGCR8 microprocessor processing of these pri-miRNAs. Genetic deletion of XPO5 compromises biogenesis of most miRNAs and causes severe defects in mouse embryonic development and skin morphogenesis.\",\n      \"method\": \"Global XPO5-associated RNA profiling (CLIP-seq), genetic deletion (KO mice), pri-miRNA processing assays with DROSHA/DGCR8, RanGTP-independence demonstrated biochemically\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — global RNA binding profiling, genetic KO with multiple developmental phenotypes, in vitro processing assays, replicated across multiple miRNA clusters\",\n      \"pmids\": [\"32296071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The phosphatase PP2A, specifically the B55β regulatory subunit-containing holoenzyme, dephosphorylates XPO5, reversing ERK-mediated phosphorylation; dephosphorylation favors XPO5 cytoplasmic distribution, promotes pre-miRNA export, and increases mature miRNA expression, leading to HCC inhibition in vitro and in vivo.\",\n      \"method\": \"Phosphatase identification assay, co-IP of PP2A subunits with XPO5, subcellular fractionation, in vitro and in vivo HCC models\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with regulatory subunit characterization, functional in vitro/in vivo validation, single lab\",\n      \"pmids\": [\"35441157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"XPO5 (exportin 5) interacts with NUP93 and SMAD4; mutations in NUP93 that cause steroid-resistant nephrotic syndrome abrogate the NUP93–SMAD4 interaction and interfere with BMP7-induced SMAD transcriptional reporter activity, placing XPO5 in a complex with NUP93 at the nuclear pore relevant to SMAD signaling in podocytes.\",\n      \"method\": \"Co-IP (XPO5–NUP93 interaction), SMAD transcriptional reporter assay, patient mutation analysis, NUP93 knockdown\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrated XPO5-NUP93 interaction; functional SMAD reporter assay; single study but multiple orthogonal methods\",\n      \"pmids\": [\"26878725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Lipid kinase PIP5K1A interacts with XPO5 in the nucleus and blocks XPO5 binding to pre-let-7 miRNA, thereby reducing mature let-7 levels; this function of PIP5K1A is kinase-independent. In C. elegans, the ortholog PPK-1 functions in the lin-28/let-7 heterochronic pathway controlling seam cell developmental timing.\",\n      \"method\": \"Co-IP (PIP5K1A–XPO5 interaction in nucleus), pre-miRNA binding competition assay, C. elegans genetic pathway (lin-28/let-7 epistasis), kinase-dead mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, competitive binding assay, genetic epistasis in C. elegans, kinase-independence by mutagenesis; single lab\",\n      \"pmids\": [\"37655623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL1 interacts with XPO5 in the nucleus (validated by co-IP); genetic ablation of METTL1 redistributes XPO5 to the cytosol, accelerating pre-miRNA export and enhancing miRNA maturation. Mechanistically, METTL1 facilitates ERK-mediated phosphorylation of XPO5, promoting its nuclear retention; constitutive ERK activation restores nuclear XPO5 in METTL1-deficient cells. This function is independent of METTL1's canonical m7G methyltransferase activity.\",\n      \"method\": \"APEX2 proximity labeling coupled with LC-MS/MS (interactome), co-IP and western blot, METTL1 KO cells, subcellular fractionation, constitutively active ERK rescue experiment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics + Co-IP validation + KO rescue with ERK, multiple orthogonal methods; single lab, single study\",\n      \"pmids\": [\"41591839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SARS-CoV-2 N protein induces autophagic degradation of XPO5 (along with Dicer, SRSF3, and hnRNPA3), thereby inhibiting miRNA biogenesis; XPO5 knockdown exacerbates N protein-induced pneumonia severity, while XPO5 overexpression decreases it.\",\n      \"method\": \"XPO5 knockdown and overexpression in lung cells/mice, autophagic degradation assay, N protein expression, in vivo pneumonia severity assessment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined cellular/in vivo phenotype; mechanism (autophagic degradation) demonstrated; single study\",\n      \"pmids\": [\"39138195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDC1 phase separation promotes nuclear export of m6A-modified lncRNA by forming a nuclear pore complex with SRSF3, ALYREF, and XPO5, facilitating translocation from nucleus to cytoplasm; XPO5 participates as a component of this export complex.\",\n      \"method\": \"Co-IP/complex assembly, phase separation assays, m6A modification analysis, nuclear export assays, knockdown of complex components\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — complex membership inferred from co-IP in a single study focused on lncRNA export; XPO5's specific mechanistic contribution to this complex is not individually resolved\",\n      \"pmids\": [\"40221424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Melatonin inhibits ERK-mediated phosphorylation of XPO5, which promotes nuclear transport of pre-miR-590-5p (shown to bind XPO5 by RNA immunoprecipitation) and enhances chondrogenic differentiation of human bone marrow mesenchymal stem cells.\",\n      \"method\": \"RNA immunoprecipitation (XPO5–pre-miR-590-5p interaction), western blot for ERK/XPO5 phosphorylation, chondrogenic differentiation assay with MLT treatment\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP experiment demonstrating XPO5-pre-miRNA interaction, functional phenotype shown, but mechanistic resolution of XPO5's specific role is limited; single lab\",\n      \"pmids\": [\"40549108\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XPO5 (exportin-5) is a nuclear export receptor that binds pre-miRNAs (and structured RNAs including vault RNAs) in both RanGTP-dependent and RanGTP-independent manners to facilitate their export to the cytoplasm; it also directly binds Dicer mRNA to support its nuclear export, enhances DROSHA/DGCR8-mediated processing of clustered pri-miRNAs in the nucleus, and its activity is regulated by ERK-mediated phosphorylation (which promotes nuclear retention via Pin1-catalyzed conformational change) and dephosphorylated by PP2A-B55β (which restores cytoplasmic distribution and pre-miRNA export), with additional regulatory inputs from METTL1 (facilitating ERK phosphorylation) and PIP5K1A (blocking pre-miRNA binding in a kinase-independent manner), and mutations in XPO5 or its interaction partner NUP93 disrupt SMAD signaling and cause steroid-resistant nephrotic syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"XPO5 (exportin-5) is a nuclear export receptor central to microRNA biogenesis, acting at multiple steps from nuclear pri-miRNA processing to cytoplasmic delivery of pre-miRNAs [#2]. It pervasively binds double-stranded regions of clustered primary miRNA precursors and structured RNAs such as vault RNAs in a RanGTP-independent manner and enhances DROSHA/DGCR8 microprocessor processing of these pri-miRNAs; genetic deletion compromises biogenesis of most miRNAs and causes severe defects in mouse embryonic development and skin morphogenesis [#2]. Beyond pre-miRNA cargo, XPO5 directly binds and exports Dicer mRNA, so that competing structured RNAs that titrate XPO5 away from Dicer mRNA reduce Dicer protein levels [#0]. XPO5 export activity is governed by a phosphorylation switch: ERK phosphorylation at a Ser-Pro motif licenses Pin1 WW-domain binding and a Pin1-catalyzed conformational change that retains XPO5 in the nucleus and diminishes pre-miRNA export, promoting hepatocellular carcinoma [#1], while the PP2A-B55\\u03b2 holoenzyme dephosphorylates XPO5 to restore its cytoplasmic distribution, pre-miRNA export and mature miRNA levels, opposing HCC [#3]. This switch is tuned by additional partners: METTL1 facilitates ERK-mediated phosphorylation to drive nuclear retention independently of its m7G methyltransferase activity [#6], and the lipid kinase PIP5K1A binds XPO5 in the nucleus and blocks pre-let-7 binding in a kinase-independent manner [#5]. XPO5 also interacts with NUP93 and SMAD4 at the nuclear pore, and NUP93 mutations causing steroid-resistant nephrotic syndrome disrupt the NUP93-SMAD4 interaction and BMP7-induced SMAD signaling in podocytes [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that XPO5 cargo extends beyond pre-miRNAs to a protein-coding mRNA, linking XPO5 directly to Dicer abundance and explaining how competing structured RNAs can suppress the miRNA pathway.\",\n      \"evidence\": \"In vitro binding, cellular RNA-IP, and competition by pre-miRNA/VA1 RNA in XPO5-knockdown cells\",\n      \"pmids\": [\"21297638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the cis-elements in Dicer mRNA recognized by XPO5\", \"Does not establish whether other mRNAs are XPO5 cargo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed XPO5 in a nuclear-pore complex with NUP93 and SMAD4, connecting the export receptor to BMP7/SMAD signaling and a Mendelian kidney disease.\",\n      \"evidence\": \"Co-IP of XPO5-NUP93, SMAD transcriptional reporter, patient NUP93 mutation analysis in podocytes\",\n      \"pmids\": [\"26878725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"XPO5's own functional contribution within the NUP93-SMAD4 complex is not isolated\", \"No XPO5 mutation directly tested for the nephrotic phenotype here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the regulatory logic that switches XPO5 off, showing ERK phosphorylation plus Pin1 isomerization conformationally suppresses pre-miRNA export to drive tumorigenesis.\",\n      \"evidence\": \"Domain-mapped Co-IP of Pin1 WW with phospho-XPO5, Pin1 shRNA, export assays, HCC models in vitro and in vivo\",\n      \"pmids\": [\"29445125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Pin1-induced conformational change not resolved\", \"Identity of the upstream stimulus activating ERK toward XPO5 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reframed XPO5 as a nuclear enhancer of microprocessor activity, not merely an exporter, by showing RanGTP-independent binding to clustered pri-miRNAs and vault RNAs and an essential developmental role.\",\n      \"evidence\": \"CLIP-seq RNA profiling, DROSHA/DGCR8 processing assays, and XPO5-KO mouse phenotyping\",\n      \"pmids\": [\"32296071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which XPO5 stimulates DROSHA/DGCR8 processing not defined at atomic level\", \"Relative contribution of nuclear processing vs export to the KO phenotype not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the phosphatase arm of the XPO5 switch, showing PP2A-B55\\u03b2 reverses ERK phosphorylation to restore export and suppress HCC.\",\n      \"evidence\": \"Phosphatase identification, Co-IP of PP2A B55\\u03b2 with XPO5, fractionation, HCC models\",\n      \"pmids\": [\"35441157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab characterization\", \"Site specificity of dephosphorylation not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a kinase-independent inhibitory partner, with nuclear PIP5K1A blocking XPO5's pre-let-7 binding and tying the interaction to the conserved lin-28/let-7 heterochronic pathway.\",\n      \"evidence\": \"Co-IP, pre-miRNA binding competition, kinase-dead mutant analysis, C. elegans lin-28/let-7 epistasis\",\n      \"pmids\": [\"37655623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for competition with pre-miRNA not resolved\", \"Generality across pre-miRNAs beyond let-7 not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed XPO5 is a target of viral pathway suppression, as SARS-CoV-2 N protein drives its autophagic degradation to inhibit miRNA biogenesis and worsen lung pathology.\",\n      \"evidence\": \"XPO5 knockdown/overexpression in lung cells and mice, autophagic degradation assay, in vivo pneumonia severity\",\n      \"pmids\": [\"39138195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autophagy receptor/adaptor targeting XPO5 not identified\", \"Selectivity of N-protein for XPO5 vs co-degraded factors not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed METTL1 controls the XPO5 phosphorylation switch independently of its methyltransferase activity by facilitating ERK-mediated phosphorylation and nuclear retention.\",\n      \"evidence\": \"APEX2 proximity labeling/LC-MS/MS, Co-IP, METTL1-KO fractionation, constitutively active ERK rescue\",\n      \"pmids\": [\"41591839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How METTL1 promotes ERK activity toward XPO5 mechanistically unresolved\", \"Single-study, single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended XPO5 cargo to m6A-modified lncRNA export via a YTHDC1/SRSF3/ALYREF complex, though XPO5's individual contribution is not isolated.\",\n      \"evidence\": \"Co-IP/complex assembly, phase separation assays, m6A and nuclear export assays with component knockdowns\",\n      \"pmids\": [\"40221424\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"XPO5's specific mechanistic role in the complex not individually resolved\", \"Inferred complex membership from Co-IP in a single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How XPO5's distinct activities \\u2014 RanGTP-independent pri-miRNA processing enhancement versus RanGTP-coupled export of pre-miRNAs and mRNAs \\u2014 are coordinated on a single receptor, and what structural states the phosphorylation/conformational switch toggles between, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of phospho- vs dephospho-XPO5 cargo states\", \"Cargo selection rules across pre-miRNA, mRNA, and lncRNA not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 5, 9]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PIN1\", \"NUP93\", \"SMAD4\", \"PP2A-B55\\u03b2\", \"PIP5K1A\", \"METTL1\", \"YTHDC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}