{"gene":"KPNA3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"hSRP1α (KPNA3 alias) binds in vitro directly and specifically to substrates containing either a simple or bipartite NLS motif, promotes docking of import substrates to the nuclear envelope, and together with recombinant human Ran reconstitutes complete nuclear protein import in vitro, establishing it as a cytosolic receptor for NLS motifs.","method":"In vitro NLS-binding assay, nuclear envelope docking assay, in vitro nuclear import reconstitution with recombinant proteins","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of complete nuclear import with recombinant proteins, multiple orthogonal assays (binding, docking, transport)","pmids":["7754385"],"is_preprint":false},{"year":1996,"finding":"A short conserved amino-terminal domain of hSRP1α is necessary and sufficient for interaction with the p97 (importin β) subunit; fusion of this domain to a cytoplasmic reporter is sufficient to promote complete nuclear import, and addition of the domain alone inhibits import of NLS-containing proteins in vitro. Full-length hSRP1α can exit the nucleus, but the amino-terminal domain alone cannot, establishing hSRP1α as an adaptor tethering NLS substrates to the import machinery via its N-terminal p97-binding domain.","method":"Deletion mutagenesis, in vitro nuclear import inhibition assay, reporter fusion import assay, in vivo nuclear exit assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with in vitro reconstitution and in vivo localization, multiple orthogonal methods in one study","pmids":["8617227"],"is_preprint":false},{"year":1997,"finding":"hSRP1γ (KPNA3) can form a complex with importin β and mediates import of a BSA-NLS substrate in an in vitro nuclear import system, demonstrating its functional activity as an importin α adaptor.","method":"Complex formation assay, in vitro nuclear import assay with BSA-NLS substrate","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro import reconstitution and complex formation, single lab, two orthogonal methods","pmids":["9435235"],"is_preprint":false},{"year":1997,"finding":"KPNA3 (Qip1/hSrp1) interacts with DNA helicase Q1/RecQL via a putative NLS in Q1; unlike hSrp1, Qip1 and Rch1 but not hSrp1 interact with the Q1 NLS in two-hybrid assays, indicating isoform-specific substrate discrimination among importin α family members.","method":"Yeast two-hybrid screening, GST pulldown from human cell lysates","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GST pulldown confirmed by two-hybrid, single lab, two methods","pmids":["9168958"],"is_preprint":false},{"year":1997,"finding":"KPNA3 (hSRP1) binds proliferation-related nucleolar protein p120 through p120's NLS (amino acids 96–119) and requires the C-terminus of hSRP1 (amino acids 453–491); interaction confirmed by yeast two-hybrid and co-expression in Sf9 cells.","method":"Yeast two-hybrid screen, deletion mutagenesis, co-expression/co-immunoprecipitation in Sf9 insect cells","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus recombinant protein association assay, single lab, two orthogonal methods","pmids":["9211983"],"is_preprint":false},{"year":2015,"finding":"KPNA3 in Bombyx mori interacts directly with heat shock transcription factor (HSF) and transports it into the nucleus; KPNA3 knockdown eliminates the second HSP mRNA expression peak at 24 h after heat shock without reducing HSF protein levels, demonstrating that KPNA3-mediated nuclear import of HSF is required for the late heat shock response.","method":"Pull-down assay from tissue lysates, GST-pulldown with recombinant proteins, RNAi knockdown with mRNA quantification","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown with recombinant proteins plus functional KD phenotype, single lab, two orthogonal methods; note Bombyx mori ortholog","pmids":["26367326"],"is_preprint":false},{"year":2021,"finding":"KPNA3 variants associated with hereditary spastic paraplegia show altered expression levels, subcellular distribution, and protein interaction, implicating dysfunctional nucleocytoplasmic shuttling as a pathomechanism for HSP.","method":"Trio whole-exome sequencing, bioinformatics, cellular and biochemical assays measuring protein expression, subcellular localization, and protein interaction","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementary cellular and biochemical assays on patient-derived variants, single lab, multiple orthogonal methods","pmids":["34564892"],"is_preprint":false},{"year":2021,"finding":"The N-terminal domain (1–40 aa) of FAdV-4 Fiber-2 protein interacts with KPNA3/4; overexpression of KPNA3/4 enhances FAdV-4 replication, while knockout reduces it; deletion of residues 7–40 in Fiber-2 attenuates the virus, demonstrating KPNA3 assists nuclear import-dependent viral replication.","method":"Co-interaction assay, KPNA3/4 overexpression and CRISPR-Cas9 knockout, rescue of virus with Fiber-2 deletion mutant, in vitro and in vivo replication assays","journal":"Virulence","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus overexpression with functional viral replication readout, single lab, multiple orthogonal methods","pmids":["33616472"],"is_preprint":false},{"year":2023,"finding":"miR-26a inhibits nuclear translocation of NF-κB p65 by targeting KPNA3; KPNA3 mediates p65 nuclear import in OA chondrocytes, and p65 transcriptionally activates LOC727924, forming a p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop.","method":"miRNA inhibitor/mimic experiments, KPNA3 knockdown/overexpression, nuclear/cytoplasmic fractionation, luciferase reporter, in vivo DMM mouse model with immunostaining","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation-based nuclear translocation assay plus in vivo validation, single lab, multiple orthogonal methods","pmids":["37392568"],"is_preprint":false},{"year":2024,"finding":"KPNA3 specifically drives nuclear import of NPAT by binding its NLS, and simultaneously sterically blocks a C-terminal self-interaction facilitator (C-SIF) motif-dependent NPAT self-association, thereby suppressing aberrant cytoplasmic NPAT phase separation/condensation and enabling proper histone locus body (HLB) formation in the nucleus.","method":"Co-immunoprecipitation, in vitro nuclear import assay, phase separation/condensation assays, deletion and domain-mapping mutagenesis, live-cell imaging, structural modeling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of import, in vitro phase-separation assay, domain mutagenesis, and live imaging in a single rigorous study with multiple orthogonal methods","pmids":["39621428"],"is_preprint":false},{"year":2025,"finding":"KPNA3 mediates nuclear import of transcription factors TFEB and CREB in Schwann cells; SDF2L1 knockdown reduces KPNA3 expression, impairing TFEB and CREB nuclear accumulation and consequently suppressing autophagy and neurotrophin expression; KPNA3 overexpression rescues these deficits.","method":"Proteomics, KPNA3 knockdown/overexpression, nuclear/cytoplasmic fractionation, in vivo SDF2L1 KO mouse model","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation-based nuclear import assay plus in vivo rescue, single lab, multiple orthogonal methods","pmids":["40294738"],"is_preprint":false},{"year":2026,"finding":"KPNA3/importin α4 specifically governs Runx2 nuclear import; depletion of KPNA3 inhibits osteoblast differentiation. The polyQ repeat of Runx2 keeps the NLS accessible for KPNA3 binding; polyQ deletion causes folding of the N-terminus (blocking KPNA3 access) and leads to aberrant cytoplasmic Runx2 aggregation. KPNA3 also modulates Runx2 liquid-like condensate state.","method":"KPNA3 depletion (KO/KD), co-immunoprecipitation, nuclear import assays, structural modeling, condensation/phase-separation assays, osteoblast differentiation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including structural modeling, Co-IP, import assays, and functional differentiation readout in a single study","pmids":["41903133"],"is_preprint":false},{"year":2026,"finding":"KPNA3 knockdown in multiple myeloma cells inhibits ALDH2 transcription and downregulates hedgehog pathway activity; ivermectin binds directly to KPNA3, reduces KPNA3 protein levels, and promotes MM cell apoptosis.","method":"KPNA3 knockdown (in vitro and in vivo), drug-binding assay (ivermectin-KPNA3 direct binding), pathway activity measurements, apoptosis assays","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined pathway readout plus direct drug-binding assay, single lab, two orthogonal methods","pmids":["41813919"],"is_preprint":false}],"current_model":"KPNA3 (importin α4/hSRP1γ) is a cytosolic adaptor that directly recognizes classical NLS motifs on cargo proteins, forms a trimeric complex with importin β via its conserved N-terminal domain, and escorts diverse cargoes—including NPAT, Runx2, TFEB, CREB, NF-κB p65, HSF, and viral proteins—through the nuclear pore; beyond passive shuttling, KPNA3 can also suppress premature cytoplasmic phase separation of its cargoes (e.g., NPAT, Runx2) through steric hindrance of self-association domains, and its dysfunction causes hereditary spastic paraplegia and impairs tissue-specific nuclear transport events."},"narrative":{"mechanistic_narrative":"KPNA3 (importin α4/hSRP1γ) is a cytosolic adaptor of the classical nuclear import pathway that directly and specifically recognizes simple and bipartite nuclear localization signals (NLS) on cargo proteins and escorts them to the nuclear pore [PMID:7754385]. It functions as an adaptor by tethering NLS substrates to importin β (p97) through a short, conserved N-terminal domain that is necessary and sufficient for importin β binding, while a separate C-terminal region engages cargo NLS motifs [PMID:8617227, PMID:9211983]. Within the importin α family KPNA3 displays isoform-selective cargo discrimination, recognizing substrates such as the DNA helicase RecQL/Q1 that other family members do not [PMID:9168958]. Through this activity KPNA3 drives the nuclear import of a range of transcriptional and regulatory factors, including heat shock factor (HSF) in the late heat shock response [PMID:26367326], NF-κB p65 [PMID:37392568], TFEB and CREB to sustain autophagy and neurotrophin expression [PMID:40294738], and the osteoblast master regulator Runx2 [PMID:41903133]. Beyond passive shuttling, KPNA3 actively regulates the biophysical state of its cargo: by binding NPAT and Runx2 it sterically blocks self-association motifs, suppressing aberrant cytoplasmic phase separation and condensate formation while enabling proper nuclear assembly such as histone locus body formation [PMID:39621428, PMID:41903133]. KPNA3 is also exploited by viral proteins to support nuclear import-dependent replication [PMID:33616472]. Patient-derived KPNA3 variants causing hereditary spastic paraplegia alter its expression, localization, and interactions, establishing dysfunctional nucleocytoplasmic shuttling as a disease pathomechanism [PMID:34564892].","teleology":[{"year":1995,"claim":"Established that KPNA3 is a bona fide cytosolic NLS receptor, answering how NLS-bearing proteins are first recognized for nuclear delivery.","evidence":"In vitro NLS-binding, nuclear envelope docking, and reconstitution of complete import with recombinant Ran","pmids":["7754385"],"confidence":"High","gaps":["Did not define the importin β-binding interface","Cargo repertoire beyond model NLS substrates unaddressed"]},{"year":1996,"claim":"Defined KPNA3 as an adaptor by localizing importin β binding to a short N-terminal domain, explaining how NLS cargo is physically coupled to the import machinery.","evidence":"Deletion mutagenesis with in vitro import inhibition, reporter fusion import, and in vivo nuclear exit assays","pmids":["8617227"],"confidence":"High","gaps":["Did not map the cargo-binding region structurally","Regulation of adaptor cycling not addressed"]},{"year":1997,"claim":"Confirmed KPNA3/importin β complex formation drives generic NLS-substrate import and revealed isoform-specific cargo discrimination and a defined C-terminal cargo-binding region.","evidence":"In vitro import with BSA-NLS, complex-formation assays, yeast two-hybrid, GST pulldown, and deletion mapping for RecQL and p120","pmids":["9435235","9168958","9211983"],"confidence":"Medium","gaps":["Physiological relevance of RecQL and p120 import not tested in cells","Basis of isoform selectivity not structurally resolved"]},{"year":2015,"claim":"Linked KPNA3 to a specific physiological output by showing its import of HSF is required for the late heat shock response.","evidence":"Pull-down and GST-pulldown with recombinant proteins plus RNAi knockdown with HSP mRNA quantification (Bombyx mori ortholog)","pmids":["26367326"],"confidence":"Medium","gaps":["Demonstrated in insect ortholog, not human","Mechanism of timing-specific (late peak) regulation unclear"]},{"year":2021,"claim":"Connected KPNA3 dysfunction to human disease, establishing impaired nucleocytoplasmic shuttling as a cause of hereditary spastic paraplegia.","evidence":"Trio whole-exome sequencing with cellular/biochemical assays of variant expression, localization, and interaction","pmids":["34564892"],"confidence":"Medium","gaps":["Specific cargo whose mislocalization drives neurodegeneration not identified","Variant effects not modeled in neurons"]},{"year":2021,"claim":"Showed viral proteins hijack KPNA3 for replication, mapping a viral NLS interaction and demonstrating functional dependence on KPNA3.","evidence":"Co-interaction assay, CRISPR knockout and overexpression, and rescue with Fiber-2 deletion mutant in replication assays (FAdV-4)","pmids":["33616472"],"confidence":"Medium","gaps":["Redundancy with KPNA4 not fully separated","Structural basis of Fiber-2 NLS recognition unresolved"]},{"year":2024,"claim":"Revealed a moonlighting function beyond transport: KPNA3 sterically suppresses cytoplasmic cargo phase separation, answering how it ensures proper nuclear condensate assembly.","evidence":"Co-IP, in vitro import and phase-separation assays, domain mapping, live-cell imaging, and structural modeling of NPAT","pmids":["39621428"],"confidence":"High","gaps":["Generality across other condensate-forming cargoes initially untested","Quantitative thresholds for steric suppression undefined"]},{"year":2025,"claim":"Extended KPNA3 cargo physiology to TFEB and CREB, linking its import activity to autophagy and neurotrophin programs downstream of SDF2L1.","evidence":"Proteomics, knockdown/overexpression, nuclear/cytoplasmic fractionation, and SDF2L1 KO mouse rescue in Schwann cells","pmids":["40294738"],"confidence":"Medium","gaps":["Direct NLS binding to TFEB/CREB not biochemically dissected","Mechanism linking SDF2L1 to KPNA3 expression unclear"]},{"year":2026,"claim":"Generalized the dual transport/anti-aggregation role to Runx2, showing KPNA3 import and condensate control are required for osteoblast differentiation and depend on a polyQ-regulated NLS.","evidence":"KPNA3 depletion, Co-IP, import and phase-separation assays, structural modeling, and osteoblast differentiation readout","pmids":["41903133"],"confidence":"High","gaps":["In vivo skeletal consequences not tested","Interplay between polyQ length and NLS accessibility not fully quantified"]},{"year":2026,"claim":"Implicated KPNA3 in cancer signaling and identified it as a druggable target, with ivermectin binding KPNA3 to promote myeloma apoptosis.","evidence":"KPNA3 knockdown in vitro/in vivo, direct ivermectin-binding assay, hedgehog pathway and apoptosis readouts in multiple myeloma","pmids":["41813919"],"confidence":"Medium","gaps":["Mechanism linking KPNA3 to ALDH2 transcription unclear","Selectivity of ivermectin for KPNA3 over other importins not established"]},{"year":null,"claim":"How KPNA3 cargo selectivity and its anti-phase-separation activity are coordinated and regulated across tissues, and which cargo defects underlie its disease associations, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of isoform-specific NLS recognition","Regulation of the steric anti-condensation function unknown","Disease-causal cargo for HSP not pinpointed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,0,9]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[9,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,0]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,10,11]}],"complexes":["importin α/β heterodimer"],"partners":["KPNB1","NPAT","RUNX2","TFEB","CREB","RECQL","HSF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00505","full_name":"Importin subunit alpha-4","aliases":["Importin alpha Q2","Qip2","Karyopherin subunit alpha-3","SRP1-gamma"],"length_aa":521,"mass_kda":57.8,"function":"Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. Recognizes NLSs of influenza A virus nucleoprotein probably through ARM repeats 7-9","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O00505/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KPNA3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000102753","cell_line_id":"CID001560","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nuclear_membrane","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"DDX21","stoichiometry":10.0},{"gene":"KPNA4","stoichiometry":10.0},{"gene":"NOLC1","stoichiometry":10.0},{"gene":"RSL1D1","stoichiometry":10.0},{"gene":"KPNB1","stoichiometry":4.0},{"gene":"RANBP1","stoichiometry":4.0},{"gene":"SMARCA4","stoichiometry":4.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001560","total_profiled":1310},"omim":[{"mim_id":"620106","title":"SPASTIC PARAPLEGIA 88, AUTOSOMAL DOMINANT; SPG88","url":"https://www.omim.org/entry/620106"},{"mim_id":"602970","title":"KARYOPHERIN ALPHA-4; KPNA4","url":"https://www.omim.org/entry/602970"},{"mim_id":"601892","title":"KARYOPHERIN ALPHA-3; KPNA3","url":"https://www.omim.org/entry/601892"},{"mim_id":"601713","title":"GLIA MATURATION FACTOR, BETA; GMFB","url":"https://www.omim.org/entry/601713"},{"mim_id":"190232","title":"TRANSITION PROTEIN 2; TNP2","url":"https://www.omim.org/entry/190232"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":136.2},{"tissue":"tongue","ntpm":88.0}],"url":"https://www.proteinatlas.org/search/KPNA3"},"hgnc":{"alias_symbol":["SRP1gamma","SRP4","hSRP1","IPOA4"],"prev_symbol":[]},"alphafold":{"accession":"O00505","domains":[{"cath_id":"1.25.10.10","chopping":"70-198","consensus_level":"medium","plddt":94.4561,"start":70,"end":198},{"cath_id":"1.25.10.10","chopping":"218-314","consensus_level":"medium","plddt":95.2192,"start":218,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00505","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00505-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00505-F1-predicted_aligned_error_v6.png","plddt_mean":86.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KPNA3","jax_strain_url":"https://www.jax.org/strain/search?query=KPNA3"},"sequence":{"accession":"O00505","fasta_url":"https://rest.uniprot.org/uniprotkb/O00505.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00505/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00505"}},"corpus_meta":[{"pmid":"7754385","id":"PMC_7754385","title":"Identification of hSRP1 alpha as a functional receptor for nuclear localization sequences.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7754385","citation_count":320,"is_preprint":false},{"pmid":"8617227","id":"PMC_8617227","title":"The conserved amino-terminal domain of hSRP1 alpha is essential for nuclear protein import.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8617227","citation_count":227,"is_preprint":false},{"pmid":"30098595","id":"PMC_30098595","title":"LncRNA DLEU1 contributes to colorectal cancer progression via activation of KPNA3.","date":"2018","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30098595","citation_count":115,"is_preprint":false},{"pmid":"9435235","id":"PMC_9435235","title":"Cloning and characterization of hSRP1 gamma, a tissue-specific nuclear transport factor.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9435235","citation_count":97,"is_preprint":false},{"pmid":"9168958","id":"PMC_9168958","title":"Cloning of a cDNA encoding a novel importin-alpha homologue, Qip1: discrimination of Qip1 and Rch1 from hSrp1 by their ability to interact with DNA helicase Q1/RecQL.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9168958","citation_count":82,"is_preprint":false},{"pmid":"33585440","id":"PMC_33585440","title":"Exosomal Long Non-coding RNA HOTTIP Increases Resistance of Colorectal Cancer Cells to Mitomycin via Impairing MiR-214-Mediated Degradation of KPNA3.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33585440","citation_count":39,"is_preprint":false},{"pmid":"33616472","id":"PMC_33616472","title":"Domain in Fiber-2 interacted with KPNA3/4 significantly affects the replication and pathogenicity of the highly pathogenic FAdV-4.","date":"2021","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/33616472","citation_count":30,"is_preprint":false},{"pmid":"31417635","id":"PMC_31417635","title":"KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31417635","citation_count":27,"is_preprint":false},{"pmid":"37575080","id":"PMC_37575080","title":"SIRT1 promotes the progression and chemoresistance of colorectal cancer through the p53/miR-101/KPNA3 axis.","date":"2023","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37575080","citation_count":25,"is_preprint":false},{"pmid":"9154134","id":"PMC_9154134","title":"Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RCH1.","date":"1997","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9154134","citation_count":23,"is_preprint":false},{"pmid":"22960338","id":"PMC_22960338","title":"KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence.","date":"2012","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/22960338","citation_count":17,"is_preprint":false},{"pmid":"27626065","id":"PMC_27626065","title":"A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma.","date":"2016","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/27626065","citation_count":14,"is_preprint":false},{"pmid":"16644122","id":"PMC_16644122","title":"A combined effect of the KPNA3 and KPNB3 genes on susceptibility to schizophrenia.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/16644122","citation_count":12,"is_preprint":false},{"pmid":"34564892","id":"PMC_34564892","title":"Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.","date":"2021","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34564892","citation_count":11,"is_preprint":false},{"pmid":"35844217","id":"PMC_35844217","title":"Importin α3 (KPNA3) Deficiency Augments Effortful Reward-Seeking Behavior in Mice.","date":"2022","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35844217","citation_count":10,"is_preprint":false},{"pmid":"15882913","id":"PMC_15882913","title":"The KPNA3 gene may be a susceptibility candidate for schizophrenia.","date":"2005","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/15882913","citation_count":10,"is_preprint":false},{"pmid":"37392568","id":"PMC_37392568","title":"The p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop mediates vasoactive intestinal peptide effects on osteoarthritis chondrocytes.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37392568","citation_count":9,"is_preprint":false},{"pmid":"39621428","id":"PMC_39621428","title":"KPNA3 regulates histone locus body formation by modulating condensation and nuclear import of NPAT.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39621428","citation_count":6,"is_preprint":false},{"pmid":"32814091","id":"PMC_32814091","title":"C/EBPα-mediated transcriptional activation of miR-134-5p entails KPNA3 inhibition and modulates focal hypoxic-ischemic brain damage in neonatal rats.","date":"2020","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/32814091","citation_count":6,"is_preprint":false},{"pmid":"40294738","id":"PMC_40294738","title":"SDF2L1 downregulation mediates high glucose-caused Schwann cell dysfunction by inhibiting nuclear import of TFEB and CREB via KPNA3.","date":"2025","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40294738","citation_count":3,"is_preprint":false},{"pmid":"36593106","id":"PMC_36593106","title":"KPNA3 promotes epithelial-mesenchymal transition by regulating TGF-β and AKT signaling pathways in MDA-MB-231, a triple-negative breast cancer cell line.","date":"2023","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/36593106","citation_count":3,"is_preprint":false},{"pmid":"26367326","id":"PMC_26367326","title":"KPNA3-knockdown eliminates the second heat shock protein peak associated with the heat shock response of male silkworm pupae (Bombyx mori) by reducing heat shock factor transport into the nucleus.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26367326","citation_count":1,"is_preprint":false},{"pmid":"40565582","id":"PMC_40565582","title":"Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40565582","citation_count":1,"is_preprint":false},{"pmid":"41813919","id":"PMC_41813919","title":"The role of KPNA3 in multiple myeloma: implications for targeting nuclear import.","date":"2026","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/41813919","citation_count":0,"is_preprint":false},{"pmid":"9211983","id":"PMC_9211983","title":"Human proliferation-related protein p120 interacts with HSRP1.","date":"1997","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/9211983","citation_count":0,"is_preprint":false},{"pmid":"41903133","id":"PMC_41903133","title":"Polyglutamine homorepeat regulates Runx2 condensation and cellular localization in a KPNA3-dependent manner.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41903133","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14545,"output_tokens":3268,"usd":0.046328,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10818,"output_tokens":3378,"usd":0.06927,"stage2_stop_reason":"end_turn"},"total_usd":0.115598,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"hSRP1α (KPNA3 alias) binds in vitro directly and specifically to substrates containing either a simple or bipartite NLS motif, promotes docking of import substrates to the nuclear envelope, and together with recombinant human Ran reconstitutes complete nuclear protein import in vitro, establishing it as a cytosolic receptor for NLS motifs.\",\n      \"method\": \"In vitro NLS-binding assay, nuclear envelope docking assay, in vitro nuclear import reconstitution with recombinant proteins\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of complete nuclear import with recombinant proteins, multiple orthogonal assays (binding, docking, transport)\",\n      \"pmids\": [\"7754385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A short conserved amino-terminal domain of hSRP1α is necessary and sufficient for interaction with the p97 (importin β) subunit; fusion of this domain to a cytoplasmic reporter is sufficient to promote complete nuclear import, and addition of the domain alone inhibits import of NLS-containing proteins in vitro. Full-length hSRP1α can exit the nucleus, but the amino-terminal domain alone cannot, establishing hSRP1α as an adaptor tethering NLS substrates to the import machinery via its N-terminal p97-binding domain.\",\n      \"method\": \"Deletion mutagenesis, in vitro nuclear import inhibition assay, reporter fusion import assay, in vivo nuclear exit assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with in vitro reconstitution and in vivo localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"8617227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"hSRP1γ (KPNA3) can form a complex with importin β and mediates import of a BSA-NLS substrate in an in vitro nuclear import system, demonstrating its functional activity as an importin α adaptor.\",\n      \"method\": \"Complex formation assay, in vitro nuclear import assay with BSA-NLS substrate\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro import reconstitution and complex formation, single lab, two orthogonal methods\",\n      \"pmids\": [\"9435235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA3 (Qip1/hSrp1) interacts with DNA helicase Q1/RecQL via a putative NLS in Q1; unlike hSrp1, Qip1 and Rch1 but not hSrp1 interact with the Q1 NLS in two-hybrid assays, indicating isoform-specific substrate discrimination among importin α family members.\",\n      \"method\": \"Yeast two-hybrid screening, GST pulldown from human cell lysates\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GST pulldown confirmed by two-hybrid, single lab, two methods\",\n      \"pmids\": [\"9168958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA3 (hSRP1) binds proliferation-related nucleolar protein p120 through p120's NLS (amino acids 96–119) and requires the C-terminus of hSRP1 (amino acids 453–491); interaction confirmed by yeast two-hybrid and co-expression in Sf9 cells.\",\n      \"method\": \"Yeast two-hybrid screen, deletion mutagenesis, co-expression/co-immunoprecipitation in Sf9 insect cells\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus recombinant protein association assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"9211983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KPNA3 in Bombyx mori interacts directly with heat shock transcription factor (HSF) and transports it into the nucleus; KPNA3 knockdown eliminates the second HSP mRNA expression peak at 24 h after heat shock without reducing HSF protein levels, demonstrating that KPNA3-mediated nuclear import of HSF is required for the late heat shock response.\",\n      \"method\": \"Pull-down assay from tissue lysates, GST-pulldown with recombinant proteins, RNAi knockdown with mRNA quantification\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown with recombinant proteins plus functional KD phenotype, single lab, two orthogonal methods; note Bombyx mori ortholog\",\n      \"pmids\": [\"26367326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA3 variants associated with hereditary spastic paraplegia show altered expression levels, subcellular distribution, and protein interaction, implicating dysfunctional nucleocytoplasmic shuttling as a pathomechanism for HSP.\",\n      \"method\": \"Trio whole-exome sequencing, bioinformatics, cellular and biochemical assays measuring protein expression, subcellular localization, and protein interaction\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementary cellular and biochemical assays on patient-derived variants, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34564892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminal domain (1–40 aa) of FAdV-4 Fiber-2 protein interacts with KPNA3/4; overexpression of KPNA3/4 enhances FAdV-4 replication, while knockout reduces it; deletion of residues 7–40 in Fiber-2 attenuates the virus, demonstrating KPNA3 assists nuclear import-dependent viral replication.\",\n      \"method\": \"Co-interaction assay, KPNA3/4 overexpression and CRISPR-Cas9 knockout, rescue of virus with Fiber-2 deletion mutant, in vitro and in vivo replication assays\",\n      \"journal\": \"Virulence\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus overexpression with functional viral replication readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33616472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-26a inhibits nuclear translocation of NF-κB p65 by targeting KPNA3; KPNA3 mediates p65 nuclear import in OA chondrocytes, and p65 transcriptionally activates LOC727924, forming a p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop.\",\n      \"method\": \"miRNA inhibitor/mimic experiments, KPNA3 knockdown/overexpression, nuclear/cytoplasmic fractionation, luciferase reporter, in vivo DMM mouse model with immunostaining\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation-based nuclear translocation assay plus in vivo validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37392568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KPNA3 specifically drives nuclear import of NPAT by binding its NLS, and simultaneously sterically blocks a C-terminal self-interaction facilitator (C-SIF) motif-dependent NPAT self-association, thereby suppressing aberrant cytoplasmic NPAT phase separation/condensation and enabling proper histone locus body (HLB) formation in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, in vitro nuclear import assay, phase separation/condensation assays, deletion and domain-mapping mutagenesis, live-cell imaging, structural modeling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of import, in vitro phase-separation assay, domain mutagenesis, and live imaging in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"39621428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KPNA3 mediates nuclear import of transcription factors TFEB and CREB in Schwann cells; SDF2L1 knockdown reduces KPNA3 expression, impairing TFEB and CREB nuclear accumulation and consequently suppressing autophagy and neurotrophin expression; KPNA3 overexpression rescues these deficits.\",\n      \"method\": \"Proteomics, KPNA3 knockdown/overexpression, nuclear/cytoplasmic fractionation, in vivo SDF2L1 KO mouse model\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation-based nuclear import assay plus in vivo rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40294738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KPNA3/importin α4 specifically governs Runx2 nuclear import; depletion of KPNA3 inhibits osteoblast differentiation. The polyQ repeat of Runx2 keeps the NLS accessible for KPNA3 binding; polyQ deletion causes folding of the N-terminus (blocking KPNA3 access) and leads to aberrant cytoplasmic Runx2 aggregation. KPNA3 also modulates Runx2 liquid-like condensate state.\",\n      \"method\": \"KPNA3 depletion (KO/KD), co-immunoprecipitation, nuclear import assays, structural modeling, condensation/phase-separation assays, osteoblast differentiation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including structural modeling, Co-IP, import assays, and functional differentiation readout in a single study\",\n      \"pmids\": [\"41903133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KPNA3 knockdown in multiple myeloma cells inhibits ALDH2 transcription and downregulates hedgehog pathway activity; ivermectin binds directly to KPNA3, reduces KPNA3 protein levels, and promotes MM cell apoptosis.\",\n      \"method\": \"KPNA3 knockdown (in vitro and in vivo), drug-binding assay (ivermectin-KPNA3 direct binding), pathway activity measurements, apoptosis assays\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined pathway readout plus direct drug-binding assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"41813919\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KPNA3 (importin α4/hSRP1γ) is a cytosolic adaptor that directly recognizes classical NLS motifs on cargo proteins, forms a trimeric complex with importin β via its conserved N-terminal domain, and escorts diverse cargoes—including NPAT, Runx2, TFEB, CREB, NF-κB p65, HSF, and viral proteins—through the nuclear pore; beyond passive shuttling, KPNA3 can also suppress premature cytoplasmic phase separation of its cargoes (e.g., NPAT, Runx2) through steric hindrance of self-association domains, and its dysfunction causes hereditary spastic paraplegia and impairs tissue-specific nuclear transport events.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KPNA3 (importin α4/hSRP1γ) is a cytosolic adaptor of the classical nuclear import pathway that directly and specifically recognizes simple and bipartite nuclear localization signals (NLS) on cargo proteins and escorts them to the nuclear pore [#0]. It functions as an adaptor by tethering NLS substrates to importin β (p97) through a short, conserved N-terminal domain that is necessary and sufficient for importin β binding, while a separate C-terminal region engages cargo NLS motifs [#1, #4]. Within the importin α family KPNA3 displays isoform-selective cargo discrimination, recognizing substrates such as the DNA helicase RecQL/Q1 that other family members do not [#3]. Through this activity KPNA3 drives the nuclear import of a range of transcriptional and regulatory factors, including heat shock factor (HSF) in the late heat shock response [#5], NF-κB p65 [#8], TFEB and CREB to sustain autophagy and neurotrophin expression [#10], and the osteoblast master regulator Runx2 [#11]. Beyond passive shuttling, KPNA3 actively regulates the biophysical state of its cargo: by binding NPAT and Runx2 it sterically blocks self-association motifs, suppressing aberrant cytoplasmic phase separation and condensate formation while enabling proper nuclear assembly such as histone locus body formation [#9, #11]. KPNA3 is also exploited by viral proteins to support nuclear import-dependent replication [#7]. Patient-derived KPNA3 variants causing hereditary spastic paraplegia alter its expression, localization, and interactions, establishing dysfunctional nucleocytoplasmic shuttling as a disease pathomechanism [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that KPNA3 is a bona fide cytosolic NLS receptor, answering how NLS-bearing proteins are first recognized for nuclear delivery.\",\n      \"evidence\": \"In vitro NLS-binding, nuclear envelope docking, and reconstitution of complete import with recombinant Ran\",\n      \"pmids\": [\"7754385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the importin β-binding interface\", \"Cargo repertoire beyond model NLS substrates unaddressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined KPNA3 as an adaptor by localizing importin β binding to a short N-terminal domain, explaining how NLS cargo is physically coupled to the import machinery.\",\n      \"evidence\": \"Deletion mutagenesis with in vitro import inhibition, reporter fusion import, and in vivo nuclear exit assays\",\n      \"pmids\": [\"8617227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the cargo-binding region structurally\", \"Regulation of adaptor cycling not addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Confirmed KPNA3/importin β complex formation drives generic NLS-substrate import and revealed isoform-specific cargo discrimination and a defined C-terminal cargo-binding region.\",\n      \"evidence\": \"In vitro import with BSA-NLS, complex-formation assays, yeast two-hybrid, GST pulldown, and deletion mapping for RecQL and p120\",\n      \"pmids\": [\"9435235\", \"9168958\", \"9211983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of RecQL and p120 import not tested in cells\", \"Basis of isoform selectivity not structurally resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked KPNA3 to a specific physiological output by showing its import of HSF is required for the late heat shock response.\",\n      \"evidence\": \"Pull-down and GST-pulldown with recombinant proteins plus RNAi knockdown with HSP mRNA quantification (Bombyx mori ortholog)\",\n      \"pmids\": [\"26367326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in insect ortholog, not human\", \"Mechanism of timing-specific (late peak) regulation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected KPNA3 dysfunction to human disease, establishing impaired nucleocytoplasmic shuttling as a cause of hereditary spastic paraplegia.\",\n      \"evidence\": \"Trio whole-exome sequencing with cellular/biochemical assays of variant expression, localization, and interaction\",\n      \"pmids\": [\"34564892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargo whose mislocalization drives neurodegeneration not identified\", \"Variant effects not modeled in neurons\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed viral proteins hijack KPNA3 for replication, mapping a viral NLS interaction and demonstrating functional dependence on KPNA3.\",\n      \"evidence\": \"Co-interaction assay, CRISPR knockout and overexpression, and rescue with Fiber-2 deletion mutant in replication assays (FAdV-4)\",\n      \"pmids\": [\"33616472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy with KPNA4 not fully separated\", \"Structural basis of Fiber-2 NLS recognition unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a moonlighting function beyond transport: KPNA3 sterically suppresses cytoplasmic cargo phase separation, answering how it ensures proper nuclear condensate assembly.\",\n      \"evidence\": \"Co-IP, in vitro import and phase-separation assays, domain mapping, live-cell imaging, and structural modeling of NPAT\",\n      \"pmids\": [\"39621428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across other condensate-forming cargoes initially untested\", \"Quantitative thresholds for steric suppression undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended KPNA3 cargo physiology to TFEB and CREB, linking its import activity to autophagy and neurotrophin programs downstream of SDF2L1.\",\n      \"evidence\": \"Proteomics, knockdown/overexpression, nuclear/cytoplasmic fractionation, and SDF2L1 KO mouse rescue in Schwann cells\",\n      \"pmids\": [\"40294738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NLS binding to TFEB/CREB not biochemically dissected\", \"Mechanism linking SDF2L1 to KPNA3 expression unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Generalized the dual transport/anti-aggregation role to Runx2, showing KPNA3 import and condensate control are required for osteoblast differentiation and depend on a polyQ-regulated NLS.\",\n      \"evidence\": \"KPNA3 depletion, Co-IP, import and phase-separation assays, structural modeling, and osteoblast differentiation readout\",\n      \"pmids\": [\"41903133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo skeletal consequences not tested\", \"Interplay between polyQ length and NLS accessibility not fully quantified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated KPNA3 in cancer signaling and identified it as a druggable target, with ivermectin binding KPNA3 to promote myeloma apoptosis.\",\n      \"evidence\": \"KPNA3 knockdown in vitro/in vivo, direct ivermectin-binding assay, hedgehog pathway and apoptosis readouts in multiple myeloma\",\n      \"pmids\": [\"41813919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking KPNA3 to ALDH2 transcription unclear\", \"Selectivity of ivermectin for KPNA3 over other importins not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KPNA3 cargo selectivity and its anti-phase-separation activity are coordinated and regulated across tissues, and which cargo defects underlie its disease associations, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of isoform-specific NLS recognition\", \"Regulation of the steric anti-condensation function unknown\", \"Disease-causal cargo for HSP not pinpointed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 0, 9]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 10, 11]}\n    ],\n    \"complexes\": [\"importin α/β heterodimer\"],\n    \"partners\": [\"KPNB1\", \"NPAT\", \"Runx2\", \"TFEB\", \"CREB\", \"RECQL\", \"HSF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}