{"gene":"IPO13","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2010,"finding":"IPO13 (Importin 13) binds the nuclear localization sequences (NLS) flanking the ARX homeodomain to facilitate nuclear import of ARX. Missense mutations in either the N- or C-terminal NLS regions of the ARX homeodomain disrupt nuclear localization but do not abolish ARX-IPO13 binding; instead, IPO13 remains sequestered with mutant ARX even in the RanGTP-rich nuclear environment, preventing normal ARX nuclear distribution.","method":"Co-immunoprecipitation and immunofluorescence studies in vitro","journal":"PathoGenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and immunofluorescence, single lab, two orthogonal methods","pmids":["20148114"],"is_preprint":false},{"year":2017,"finding":"IPO13 mediates nuclear translocation of the glucocorticoid receptor (GR). RSV nonstructural protein 1 (NS1) competes with IPO13 for GR binding, reducing GR nuclear translocation and thereby suppressing GR-induced anti-inflammatory gene expression, accounting for glucocorticoid insensitivity during RSV infection.","method":"IPO13 expression knockdown in A549 cells and infected mouse lungs, GR nuclear translocation assay, competition binding assay between NS1 and IPO13 for GR","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (anti-inflammatory gene repression), single lab, multiple cellular and in vivo models","pmids":["28968829"],"is_preprint":false},{"year":2013,"finding":"IPO13 (Imp13) subcellular distribution is developmentally regulated in mouse brain: it is predominantly cytoplasmic in early embryonic neuronal cells and relocates to the nucleus at later developmental stages, suggesting dynamic regulation of its cargo transport activity during brain development.","method":"Immunohistochemical analysis of mouse embryonic brain sections at multiple developmental stages (E13.5, E15.5, E17.5, P0, adult) using a custom anti-imp13 polyclonal antibody","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment across multiple developmental stages, single lab, single method (IHC), but tied to mechanistic inference about cargo trafficking","pmids":["23605716"],"is_preprint":false},{"year":2018,"finding":"Loss of IPO13 function causes ocular coloboma, microphthalmia, and cataract. Morpholino-induced knockdown of ipo13 in zebrafish produced dose-dependent microphthalmia and coloboma phenotypes that were rescued by full-length ipo13 mRNA, establishing IPO13 as required for eye morphogenesis.","method":"Morpholino-oligonucleotide knockdown in zebrafish with mRNA rescue experiment; visual motor response and optokinetic response functional assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic readout and mRNA rescue, single lab, two orthogonal readouts (morphology + visual function)","pmids":["29700284"],"is_preprint":false},{"year":2022,"finding":"IPO13 is required for efficient neuronal differentiation of mouse embryonic stem cells (ESCs). IPO13-/- ESCs show reduced nuclear localization and transcriptional activity of import cargo Pax6, reduced expression of progenitor markers (Pax6, Nestin), impaired neuronal morphology, reduced neuronal marker expression, and altered glutamate response, establishing IPO13's role in neuronal differentiation in part through nuclear transport of Pax6.","method":"IPO13 knockout mouse ESC model with monolayer-based differentiation protocol; immunofluorescence for nuclear localization of Pax6; marker expression analysis; glutamate response assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and mechanistic cargo (Pax6) nuclear localization linkage, single lab, multiple orthogonal readouts","pmids":["35741036"],"is_preprint":false}],"current_model":"IPO13 is a bidirectional nuclear transport receptor (importin-β superfamily) that mediates nuclear import of cargo proteins including transcription factors ARX, Pax6, Pax3, and the glucocorticoid receptor; it facilitates ARX nuclear entry by binding NLS sequences flanking the ARX homeodomain (release of cargo in the nucleus requires RanGTP), is required for neuronal differentiation of embryonic stem cells (in part through Pax6 nuclear transport), and is essential for eye morphogenesis, while its subcellular localization shifts from cytoplasmic to nuclear during brain development in a stage-regulated manner."},"narrative":{"mechanistic_narrative":"IPO13 is a nuclear transport receptor that mediates the nuclear import of developmentally important transcription factors and steroid receptors, coupling cargo recognition in the cytoplasm to RanGTP-dependent release in the nucleus [PMID:20148114]. It recognizes nuclear localization sequences flanking the ARX homeodomain, and missense mutations in these NLS regions trap IPO13 with mutant ARX even in the RanGTP-rich nuclear environment, preventing normal ARX nuclear distribution [PMID:20148114]. Beyond ARX, IPO13 mediates nuclear translocation of the glucocorticoid receptor, and competition for this interaction by RSV nonstructural protein NS1 reduces GR nuclear entry and blunts glucocorticoid-induced anti-inflammatory gene expression [PMID:28968829]. Consistent with a role in cargo delivery during development, IPO13 is required for neuronal differentiation of embryonic stem cells in part through nuclear transport of Pax6 [PMID:35741036], and is essential for eye morphogenesis, with loss of function producing microphthalmia and coloboma [PMID:29700284]. Its own subcellular distribution is developmentally regulated, shifting from cytoplasmic in early embryonic neurons to nuclear at later stages [PMID:23605716].","teleology":[{"year":2010,"claim":"Established that IPO13 is the receptor that drives ARX nuclear import by binding NLS sequences flanking the homeodomain, and that disease-associated NLS mutations act by trapping cargo with the receptor rather than abolishing binding.","evidence":"Reciprocal Co-immunoprecipitation and immunofluorescence in vitro using wild-type and NLS-mutant ARX","pmids":["20148114"],"confidence":"Medium","gaps":["RanGTP-dependent release step inferred but not directly reconstituted","Binding affinity and structural basis of NLS recognition not defined"]},{"year":2013,"claim":"Showed that IPO13's own localization is dynamically regulated during brain development, implying its cargo transport activity is stage-dependent rather than constitutive.","evidence":"Immunohistochemistry of mouse embryonic brain across staged timepoints (E13.5 to adult)","pmids":["23605716"],"confidence":"Medium","gaps":["Single method (IHC) without functional readout","Mechanism controlling the cytoplasmic-to-nuclear shift unknown","Cargo specificity at each stage not determined"]},{"year":2017,"claim":"Extended IPO13's cargo repertoire to the glucocorticoid receptor and demonstrated a viral mechanism of glucocorticoid resistance through competitive inhibition of IPO13-GR binding.","evidence":"IPO13 knockdown in A549 cells and infected mouse lungs, GR nuclear translocation assays, and NS1/IPO13 competition binding","pmids":["28968829"],"confidence":"Medium","gaps":["GR NLS determinants recognized by IPO13 not mapped","Whether NS1 directly displaces IPO13 versus indirect effects not fully resolved"]},{"year":2018,"claim":"Demonstrated an essential organismal requirement for IPO13 in eye morphogenesis via a rescuable loss-of-function phenotype.","evidence":"Morpholino knockdown of ipo13 in zebrafish with full-length mRNA rescue plus visual motor and optokinetic functional assays","pmids":["29700284"],"confidence":"Medium","gaps":["Specific cargo(s) driving the ocular phenotype not identified","Morpholino-based knockdown not corroborated by a genetic mutant"]},{"year":2022,"claim":"Linked IPO13 to a defined cellular program—neuronal differentiation—mechanistically through nuclear import of Pax6.","evidence":"IPO13 knockout mouse ESC differentiation model with Pax6 nuclear localization, marker expression, and glutamate response assays","pmids":["35741036"],"confidence":"Medium","gaps":["Relative contribution of Pax6 versus other cargoes to the differentiation defect unquantified","Direct IPO13-Pax6 binding not biochemically characterized here"]},{"year":null,"claim":"The structural basis of IPO13 NLS recognition, its full cargo spectrum, and the mechanism regulating its developmental cytoplasmic-to-nuclear redistribution remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of IPO13-cargo complexes","RanGTP-dependent cargo release not directly reconstituted for any cargo","Mechanism driving stage-regulated IPO13 localization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["ARX","NR3C1","PAX6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94829","full_name":"Importin-13","aliases":["Karyopherin-13","Kap13","Ran-binding protein 13","RanBP13"],"length_aa":963,"mass_kda":108.2,"function":"Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin 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 the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. 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 (By similarity). Mediates the nuclear import of UBC9, the RBM8A/MAGOH complex, PAX6 and probably other members of the paired homeobox family. Also mediates nuclear export of eIF-1A, and the cytoplasmic release of eIF-1A is triggered by the loading of import substrates onto IPO13","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O94829/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IPO13","classification":"Common Essential","n_dependent_lines":1155,"n_total_lines":1208,"dependency_fraction":0.9561258278145696},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000117408","cell_line_id":"CID001552","localizations":[{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"CIAPIN1","stoichiometry":10.0},{"gene":"PDLIM7","stoichiometry":0.2},{"gene":"HK2","stoichiometry":0.2},{"gene":"MOCS2","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001552","total_profiled":1310},"omim":[{"mim_id":"620941","title":"SYNAPTOPODIN 2; SYNPO2","url":"https://www.omim.org/entry/620941"},{"mim_id":"610411","title":"IMPORTIN 13; IPO13","url":"https://www.omim.org/entry/610411"},{"mim_id":"300382","title":"ARISTALESS-RELATED HOMEOBOX, X-LINKED; ARX","url":"https://www.omim.org/entry/300382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":121.1}],"url":"https://www.proteinatlas.org/search/IPO13"},"hgnc":{"alias_symbol":["IMP13","KIAA0724","RANBP13"],"prev_symbol":[]},"alphafold":{"accession":"O94829","domains":[{"cath_id":"1.25.40","chopping":"281-499","consensus_level":"medium","plddt":93.4717,"start":281,"end":499}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94829","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94829-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94829-F1-predicted_aligned_error_v6.png","plddt_mean":90.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IPO13","jax_strain_url":"https://www.jax.org/strain/search?query=IPO13"},"sequence":{"accession":"O94829","fasta_url":"https://rest.uniprot.org/uniprotkb/O94829.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94829/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94829"}},"corpus_meta":[{"pmid":"16081918","id":"PMC_16081918","title":"Nosocomial outbreak caused by multidrug-resistant Pseudomonas aeruginosa producing IMP-13 metallo-beta-lactamase.","date":"2005","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16081918","citation_count":71,"is_preprint":false},{"pmid":"22992193","id":"PMC_22992193","title":"Occurrence of IMP-8, IMP-10, and IMP-13 metallo-β-lactamases located on class 1 integrons and other extended-spectrum β-lactamases in bacterial isolates from Tunisian rivers.","date":"2012","source":"Scandinavian journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22992193","citation_count":34,"is_preprint":false},{"pmid":"20148114","id":"PMC_20148114","title":"Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division.","date":"2010","source":"PathoGenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20148114","citation_count":33,"is_preprint":false},{"pmid":"29700284","id":"PMC_29700284","title":"Mutation of IPO13 causes recessive ocular coloboma, microphthalmia, and cataract.","date":"2018","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29700284","citation_count":22,"is_preprint":false},{"pmid":"28446596","id":"PMC_28446596","title":"Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1-3 family.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/28446596","citation_count":19,"is_preprint":false},{"pmid":"28968829","id":"PMC_28968829","title":"Respiratory Syncytial Virus Nonstructural Protein 1 Blocks Glucocorticoid Receptor Nuclear Translocation by Targeting IPO13 and May Account for Glucocorticoid Insensitivity.","date":"2017","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28968829","citation_count":15,"is_preprint":false},{"pmid":"32205343","id":"PMC_32205343","title":"Structure and Molecular Recognition Mechanism of IMP-13 Metallo-β-Lactamase.","date":"2020","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/32205343","citation_count":14,"is_preprint":false},{"pmid":"23605716","id":"PMC_23605716","title":"Expression and subcellular distribution of imp13 are regulated in brain development.","date":"2013","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/23605716","citation_count":13,"is_preprint":false},{"pmid":"38487887","id":"PMC_38487887","title":"Regional dissemination of NDM-1 producing Enterobacter hormaechei ST1740, with a subset of strains co-producing VIM-4 or IMP-13, France, 2019 to 2022.","date":"2024","source":"Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/38487887","citation_count":6,"is_preprint":false},{"pmid":"35434231","id":"PMC_35434231","title":"Transcriptomic profile dataset of embryonic stem cells (Wild-type and IPO13-Knock Out) with and without oxidative stress.","date":"2022","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/35434231","citation_count":3,"is_preprint":false},{"pmid":"35741036","id":"PMC_35741036","title":"Nuclear Transporter IPO13 Is Central to Efficient Neuronal Differentiation.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35741036","citation_count":3,"is_preprint":false},{"pmid":"39706477","id":"PMC_39706477","title":"Mobilization of an ICEclc-Like Element as a Potential Mechanism for the Spread of IMP-13 Carbapenemase in Pseudomonas aeruginosa.","date":"2024","source":"Journal of global antimicrobial resistance","url":"https://pubmed.ncbi.nlm.nih.gov/39706477","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8115,"output_tokens":1382,"usd":0.022537,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8156,"output_tokens":2054,"usd":0.046065,"stage2_stop_reason":"end_turn"},"total_usd":0.068602,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"IPO13 (Importin 13) binds the nuclear localization sequences (NLS) flanking the ARX homeodomain to facilitate nuclear import of ARX. Missense mutations in either the N- or C-terminal NLS regions of the ARX homeodomain disrupt nuclear localization but do not abolish ARX-IPO13 binding; instead, IPO13 remains sequestered with mutant ARX even in the RanGTP-rich nuclear environment, preventing normal ARX nuclear distribution.\",\n      \"method\": \"Co-immunoprecipitation and immunofluorescence studies in vitro\",\n      \"journal\": \"PathoGenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and immunofluorescence, single lab, two orthogonal methods\",\n      \"pmids\": [\"20148114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IPO13 mediates nuclear translocation of the glucocorticoid receptor (GR). RSV nonstructural protein 1 (NS1) competes with IPO13 for GR binding, reducing GR nuclear translocation and thereby suppressing GR-induced anti-inflammatory gene expression, accounting for glucocorticoid insensitivity during RSV infection.\",\n      \"method\": \"IPO13 expression knockdown in A549 cells and infected mouse lungs, GR nuclear translocation assay, competition binding assay between NS1 and IPO13 for GR\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (anti-inflammatory gene repression), single lab, multiple cellular and in vivo models\",\n      \"pmids\": [\"28968829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IPO13 (Imp13) subcellular distribution is developmentally regulated in mouse brain: it is predominantly cytoplasmic in early embryonic neuronal cells and relocates to the nucleus at later developmental stages, suggesting dynamic regulation of its cargo transport activity during brain development.\",\n      \"method\": \"Immunohistochemical analysis of mouse embryonic brain sections at multiple developmental stages (E13.5, E15.5, E17.5, P0, adult) using a custom anti-imp13 polyclonal antibody\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment across multiple developmental stages, single lab, single method (IHC), but tied to mechanistic inference about cargo trafficking\",\n      \"pmids\": [\"23605716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of IPO13 function causes ocular coloboma, microphthalmia, and cataract. Morpholino-induced knockdown of ipo13 in zebrafish produced dose-dependent microphthalmia and coloboma phenotypes that were rescued by full-length ipo13 mRNA, establishing IPO13 as required for eye morphogenesis.\",\n      \"method\": \"Morpholino-oligonucleotide knockdown in zebrafish with mRNA rescue experiment; visual motor response and optokinetic response functional assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic readout and mRNA rescue, single lab, two orthogonal readouts (morphology + visual function)\",\n      \"pmids\": [\"29700284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IPO13 is required for efficient neuronal differentiation of mouse embryonic stem cells (ESCs). IPO13-/- ESCs show reduced nuclear localization and transcriptional activity of import cargo Pax6, reduced expression of progenitor markers (Pax6, Nestin), impaired neuronal morphology, reduced neuronal marker expression, and altered glutamate response, establishing IPO13's role in neuronal differentiation in part through nuclear transport of Pax6.\",\n      \"method\": \"IPO13 knockout mouse ESC model with monolayer-based differentiation protocol; immunofluorescence for nuclear localization of Pax6; marker expression analysis; glutamate response assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and mechanistic cargo (Pax6) nuclear localization linkage, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"35741036\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IPO13 is a bidirectional nuclear transport receptor (importin-β superfamily) that mediates nuclear import of cargo proteins including transcription factors ARX, Pax6, Pax3, and the glucocorticoid receptor; it facilitates ARX nuclear entry by binding NLS sequences flanking the ARX homeodomain (release of cargo in the nucleus requires RanGTP), is required for neuronal differentiation of embryonic stem cells (in part through Pax6 nuclear transport), and is essential for eye morphogenesis, while its subcellular localization shifts from cytoplasmic to nuclear during brain development in a stage-regulated manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IPO13 is a nuclear transport receptor that mediates the nuclear import of developmentally important transcription factors and steroid receptors, coupling cargo recognition in the cytoplasm to RanGTP-dependent release in the nucleus [#0]. It recognizes nuclear localization sequences flanking the ARX homeodomain, and missense mutations in these NLS regions trap IPO13 with mutant ARX even in the RanGTP-rich nuclear environment, preventing normal ARX nuclear distribution [#0]. Beyond ARX, IPO13 mediates nuclear translocation of the glucocorticoid receptor, and competition for this interaction by RSV nonstructural protein NS1 reduces GR nuclear entry and blunts glucocorticoid-induced anti-inflammatory gene expression [#1]. Consistent with a role in cargo delivery during development, IPO13 is required for neuronal differentiation of embryonic stem cells in part through nuclear transport of Pax6 [#4], and is essential for eye morphogenesis, with loss of function producing microphthalmia and coloboma [#3]. Its own subcellular distribution is developmentally regulated, shifting from cytoplasmic in early embryonic neurons to nuclear at later stages [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that IPO13 is the receptor that drives ARX nuclear import by binding NLS sequences flanking the homeodomain, and that disease-associated NLS mutations act by trapping cargo with the receptor rather than abolishing binding.\",\n      \"evidence\": \"Reciprocal Co-immunoprecipitation and immunofluorescence in vitro using wild-type and NLS-mutant ARX\",\n      \"pmids\": [\"20148114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RanGTP-dependent release step inferred but not directly reconstituted\", \"Binding affinity and structural basis of NLS recognition not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that IPO13's own localization is dynamically regulated during brain development, implying its cargo transport activity is stage-dependent rather than constitutive.\",\n      \"evidence\": \"Immunohistochemistry of mouse embryonic brain across staged timepoints (E13.5 to adult)\",\n      \"pmids\": [\"23605716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (IHC) without functional readout\", \"Mechanism controlling the cytoplasmic-to-nuclear shift unknown\", \"Cargo specificity at each stage not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended IPO13's cargo repertoire to the glucocorticoid receptor and demonstrated a viral mechanism of glucocorticoid resistance through competitive inhibition of IPO13-GR binding.\",\n      \"evidence\": \"IPO13 knockdown in A549 cells and infected mouse lungs, GR nuclear translocation assays, and NS1/IPO13 competition binding\",\n      \"pmids\": [\"28968829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GR NLS determinants recognized by IPO13 not mapped\", \"Whether NS1 directly displaces IPO13 versus indirect effects not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated an essential organismal requirement for IPO13 in eye morphogenesis via a rescuable loss-of-function phenotype.\",\n      \"evidence\": \"Morpholino knockdown of ipo13 in zebrafish with full-length mRNA rescue plus visual motor and optokinetic functional assays\",\n      \"pmids\": [\"29700284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargo(s) driving the ocular phenotype not identified\", \"Morpholino-based knockdown not corroborated by a genetic mutant\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked IPO13 to a defined cellular program—neuronal differentiation—mechanistically through nuclear import of Pax6.\",\n      \"evidence\": \"IPO13 knockout mouse ESC differentiation model with Pax6 nuclear localization, marker expression, and glutamate response assays\",\n      \"pmids\": [\"35741036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of Pax6 versus other cargoes to the differentiation defect unquantified\", \"Direct IPO13-Pax6 binding not biochemically characterized here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of IPO13 NLS recognition, its full cargo spectrum, and the mechanism regulating its developmental cytoplasmic-to-nuclear redistribution remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of IPO13-cargo complexes\", \"RanGTP-dependent cargo release not directly reconstituted for any cargo\", \"Mechanism driving stage-regulated IPO13 localization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARX\", \"NR3C1\", \"PAX6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}