{"gene":"KPNA6","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2011,"finding":"KPNA6 (importin α7) directly interacts with the C-terminal Kelch domain of Keap1 and mediates its nuclear import. Overexpression of KPNA6 facilitates Keap1 nuclear import and attenuates Nrf2 signaling, whereas knockdown of KPNA6 slows Keap1 nuclear import and enhances Nrf2-mediated antioxidant response. KPNA6 also accelerates clearance of Nrf2 from the nucleus during the post-induction phase, restoring Nrf2 to basal levels.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown with functional readouts of Nrf2 target gene expression and Keap1 nuclear localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction demonstrated, complementary gain- and loss-of-function experiments with defined molecular and cellular phenotypes, published in peer-reviewed journal","pmids":["21383067"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 membrane (M) protein binds to KPNA6 to inhibit IRF3 nuclear translocation, thereby antagonizing type I interferon production.","method":"Co-immunoprecipitation, IFN reporter assays, nuclear translocation assays","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional consequence shown, single lab, abstract does not detail full mechanistic controls","pmids":["34950606"],"is_preprint":false},{"year":2018,"finding":"KPNA6 is required for optimal replication of PRRSV and Zika virus. Viral infection blocks ubiquitin-proteasomal degradation of KPNA6 (induced by PRRSV nsp12), extending its half-life. KPNA6 mediates nuclear translocation of PRRSV nsp1β; KPNA6 knockout blocks nsp1β nuclear import and impairs ZIKV replication, both restored by exogenous KPNA6 re-expression.","method":"siRNA knockdown, CRISPR knockout, proteasome inhibitor assays, nuclear translocation assays, viral replication assays, rescue experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, KD, rescue, protein stability assays), clear mechanistic pathway placement","pmids":["29444946"],"is_preprint":false},{"year":2011,"finding":"Orc6 nuclear localization signal-dependent transport to the nucleus is facilitated by association with Kpna6 (and Kpna1). Kpna6 did not co-purify with other ORC subunits, indicating independent transport of Orc6.","method":"Protein purification, co-immunoprecipitation, nuclear localization assays with NLS mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated with functional NLS-dependent localization assay, single lab","pmids":["21555516"],"is_preprint":false},{"year":2015,"finding":"KPNA6 interacts with PHB2 and mediates estrogen-dependent nuclear translocation of PHB2 in breast cancer cells. BIG3 blocks the KPNA6 (and KPNA1, KPNA5) binding region of PHB2, inhibiting KPNA-mediated PHB2 nuclear import. Knockdown of KPNA6 inhibits PHB2 nuclear translocation and enhances ERα activation.","method":"Co-immunoprecipitation, siRNA knockdown, nuclear translocation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction and functional siRNA knockdown with defined phenotype, single lab","pmids":["26052702"],"is_preprint":false},{"year":2017,"finding":"KPNA6 (along with KPNA1 and KPNA5) binds Ebola virus VP24 protein; binding affinity differences between VP24 proteins from EBOV, BDBV, and RESTV correlate with differences in IFN signaling suppression and VP24 protein stability. VP24 mutations reducing KPNA binding decrease IFN inhibition and shorten VP24 half-lives.","method":"Purified protein binding assays (quantitative affinity measurements), cell-based IFN reporter assays, VP24 half-life assays, mutagenesis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, mutagenesis, and multiple functional readouts in one rigorous study","pmids":["27974555"],"is_preprint":false},{"year":2021,"finding":"Ablation of Kpna6 in male mice causes infertility by disrupting spermatogenesis, impairing Sertoli cell function (including loss of androgen receptor nuclear localization), and causing defects in spermiogenesis including incomplete sperm maturation, histone-protamine exchange disruption, altered BRWD1 localization, and dysregulation of RFX2 target genes.","method":"Kpna6 knockout mouse model (loss-of-function), immunofluorescence, Western blot, nuclear localization assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo KO with multiple defined cellular and molecular phenotypes, direct demonstration of nuclear import defects","pmids":["34473250"],"is_preprint":false},{"year":2021,"finding":"KPNA6 was identified as a binding partner of HASPIN kinase in spermatids using a two-hybrid system, suggesting a potential role for KPNA6 in HASPIN-mediated spermatogenesis pathways.","method":"Yeast two-hybrid screen, interaction analysis","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid result, interaction not further validated biochemically for KPNA6 specifically","pmids":["36012324"],"is_preprint":false},{"year":2012,"finding":"KPNA6 localizes to the subacrosomal layer of the perinuclear theca in sperm and associates with the surface of proacrosomic/acrosomic vesicles during acrosomal biogenesis in spermiogenesis. Recombinant SubH2Bv affinity pull-down from germ cell extracts confirmed binding interaction between SubH2Bv and KPNA6, suggesting they work together to direct acrosomic vesicles to the nucleus.","method":"Immunocytochemistry, sperm head fractionation + Western blot, recombinant protein affinity pull-down","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization with functional context, pull-down interaction, multiple complementary methods in a single lab","pmids":["22156475"],"is_preprint":false},{"year":2021,"finding":"NDV W protein is transported into the nucleus via interaction with KPNA1, KPNA2, and KPNA6 in an NLS-dependent manner, and nuclear-localized W protein reduces IFN-β expression stimulated by NDV.","method":"Co-immunoprecipitation, fluorescence microscopy, NLS mutagenesis, NDV reverse genetics system","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction, NLS mutagenesis, and functional IFN-β readout, single lab","pmids":["33441338"],"is_preprint":false},{"year":2018,"finding":"KPNA6 interacts with BCL-6 corepressor (BCOR) and mediates its nuclear translocation in human periodontal ligament cells. Co-expression of KPNA6 with NLS-mutant BCOR significantly increased nuclear accumulation of mutant BCOR.","method":"Co-immunoprecipitation, site-directed mutagenesis, nuclear translocation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and mutagenesis with functional nuclear translocation readout, single lab","pmids":["30396568"],"is_preprint":false},{"year":2021,"finding":"KPNA6 was identified as the main import receptor responsible for nuclear transport of HNF1A transcription factor. MODY-associated mutations (Arg271Trp and Ser345Tyr) in HNF1A reduce its interaction with KPNA6, leading to impaired nuclear localization.","method":"Co-immunoprecipitation, molecular docking simulation, immunolocalization in Min6 cells","journal":"The protein journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional localization data, mutagenesis, and complementary docking, single lab","pmids":["33459938"],"is_preprint":false},{"year":2022,"finding":"KPNA6 associates with ANP32A/B and the influenza virus vRNP complex. Both knockout and overexpression of KPNA6 downregulate influenza virus replication by inhibiting polymerase activity. Overexpression of KPNA6 or its nuclear importing domain negative mutant inhibited ANP32-vRNP interaction, reducing polymerase activity.","method":"Co-immunoprecipitation, KPNA6 knockout and overexpression with viral polymerase activity assays, domain mutagenesis","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and direct interaction shown, but single lab; mechanism partially elucidated","pmids":["35044222"],"is_preprint":false},{"year":2026,"finding":"ZIKV NS2B protein mediates relocation of KPNA6 to the perinuclear region in infected cells. KPNA6 interacts with NS2B via its major groove, while NS2B binds KPNA6 via its C-terminus. Two residues (P115 and G119) in NS2B are critical for KPNA6 interaction; mutations in either residue abolish virus replication.","method":"Co-immunoprecipitation, fluorescence microscopy, site-directed mutagenesis, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapping with mutagenesis and functional viral replication readout, single lab","pmids":["42159396"],"is_preprint":false},{"year":2015,"finding":"KPNA6 expression is dynamically regulated throughout mouse oogenesis and folliculogenesis; Kpna6 mRNA is significantly upregulated at the primordial-to-primary follicle transition, and KPNA6 protein shows distinct subcellular localization patterns in oocytes and granulosa cells during folliculogenesis.","method":"RT-PCR, immunofluorescence, subcellular fractionation across developmental stages","journal":"Reproduction (Cambridge, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization and expression dynamics described, no direct functional manipulation of KPNA6 in this context","pmids":["26399853"],"is_preprint":false},{"year":2025,"finding":"The lncRNA βFaar promotes IRF4 nuclear translocation and induces iWAT browning by binding to KPNA6.","method":"RNA-protein binding assay, nuclear translocation assays (inferred from abstract description)","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction between lncRNA and KPNA6 mentioned but mechanistic details in abstract are limited; single study","pmids":["40548473"],"is_preprint":false}],"current_model":"KPNA6 (importin α7/karyopherin α6) is a nuclear import adaptor that directly binds NLS-containing cargo proteins—including Keap1, HNF1A, BCOR, PHB2, and viral proteins—via its importin-α major groove and mediates their nuclear translocation in a karyopherin β-dependent manner; it plays essential roles in regulating the Nrf2 antioxidant response (by importing Keap1 to promote Nrf2 nuclear clearance), male spermatogenesis (loss of Kpna6 causes infertility in mice through defective androgen receptor nuclear localization and spermiogenic defects), and serves as a proviral host factor exploited by multiple RNA viruses (PRRSV, ZIKV, IAV) to facilitate viral protein nuclear trafficking and replication."},"narrative":{"mechanistic_narrative":"KPNA6 (importin α7/karyopherin α6) is a nuclear import adaptor that recognizes nuclear localization signal (NLS)-bearing cargo through its importin-α major groove and delivers them to the nucleus [PMID:21383067, PMID:42159396]. Its cellular cargo repertoire spans transcriptional and regulatory proteins including Keap1 [PMID:21383067], the HNF1A transcription factor [PMID:33459938], the BCL-6 corepressor BCOR [PMID:30396568], and PHB2 [PMID:26052702], the latter two imported in NLS-dependent and stimulus-dependent fashion. Through Keap1 import, KPNA6 tunes the Nrf2 antioxidant response, both by importing Keap1 to attenuate Nrf2 signaling and by accelerating clearance of Nrf2 from the nucleus during the post-induction phase [PMID:21383067]. KPNA6 import activity is physiologically essential in the male germline: loss of Kpna6 in mice causes infertility through impaired androgen receptor nuclear localization in Sertoli cells, disrupted histone-protamine exchange, and dysregulation of RFX2 target genes during spermiogenesis [PMID:34473250]. A recurrent theme is exploitation of KPNA6 by RNA viruses: it is a required host factor for PRRSV and Zika virus replication, mediating nuclear import of PRRSV nsp1β and being stabilized against proteasomal degradation during infection [PMID:29444946, PMID:42159396], and viral proteins from Ebola (VP24), SARS-CoV-2 (M), and Newcastle disease virus (W) bind KPNA6 to suppress type I interferon responses by blocking IRF3 or sequestering import capacity [PMID:34950606, PMID:27974555, PMID:33441338]. KPNA6 additionally regulates influenza polymerase activity through association with ANP32A/B and the vRNP complex [PMID:35044222]. A timeline finding links HNF1A MODY-associated mutations to reduced KPNA6 binding and impaired HNF1A nuclear localization [PMID:33459938].","teleology":[{"year":2011,"claim":"Established KPNA6 as a functional import adaptor with a defined regulatory output by showing it imports Keap1 and thereby controls the magnitude and resolution of the Nrf2 antioxidant response.","evidence":"Co-IP, gain- and loss-of-function with Nrf2 target gene and Keap1 localization readouts in cells","pmids":["21383067"],"confidence":"High","gaps":["Does not resolve karyopherin β dependence quantitatively","NLS within Keap1 not mapped","physiological tissue context of Keap1 import not addressed"]},{"year":2011,"claim":"Showed KPNA6 mediates NLS-dependent nuclear import of an individual cargo (Orc6) independently of its complex partners, demonstrating cargo-selective transport.","evidence":"Protein purification, co-IP, and NLS-mutant nuclear localization assays","pmids":["21555516"],"confidence":"Medium","gaps":["Single lab, not reciprocally validated in vivo","shared with KPNA1, specificity not dissected"]},{"year":2012,"claim":"Placed KPNA6 in acrosome biogenesis by localizing it to the subacrosomal perinuclear theca and identifying SubH2Bv as a binding partner, extending its role beyond classical import.","evidence":"Immunocytochemistry, sperm head fractionation, recombinant protein pull-down","pmids":["22156475"],"confidence":"Medium","gaps":["Functional requirement not tested by loss-of-function here","mechanism linking import adaptor to vesicle targeting unclear"]},{"year":2015,"claim":"Defined estrogen-regulated PHB2 import as a KPNA6 function and identified BIG3 as an inhibitor of cargo binding, linking KPNA6 to ERα signaling control.","evidence":"Co-IP, siRNA knockdown, nuclear translocation assays in breast cancer cells","pmids":["26052702"],"confidence":"Medium","gaps":["Redundancy with KPNA1/KPNA5 not resolved","single lab"]},{"year":2017,"claim":"Provided rigorous in vitro evidence that KPNA-binding affinity of Ebola VP24 quantitatively governs interferon suppression and viral protein stability, establishing KPNA6 as a target hijacked for immune evasion.","evidence":"Purified-protein affinity measurements, mutagenesis, IFN reporter and half-life assays","pmids":["27974555"],"confidence":"High","gaps":["Shared binding with KPNA1/KPNA5, KPNA6-specific contribution in vivo not isolated"]},{"year":2018,"claim":"Demonstrated KPNA6 is a required proviral host factor whose stability is actively protected during infection, mediating nuclear import of viral proteins for PRRSV and Zika replication.","evidence":"siRNA, CRISPR KO, proteasome inhibition, nuclear translocation, viral replication and rescue assays","pmids":["29444946"],"confidence":"High","gaps":["Mechanism of nsp12-induced degradation block not fully mapped","ZIKV cargo identity not defined in this study"]},{"year":2018,"claim":"Extended the cargo repertoire to the transcriptional corepressor BCOR via NLS-dependent import, reinforcing a general role in nuclear delivery of gene-regulatory proteins.","evidence":"Co-IP, site-directed mutagenesis, nuclear translocation assays in periodontal ligament cells","pmids":["30396568"],"confidence":"Medium","gaps":["Single cell type","in vivo relevance untested"]},{"year":2021,"claim":"Provided the in vivo demonstration that KPNA6 is essential for male fertility, mechanistically tying its import function to androgen receptor localization and the spermiogenic transcriptional/chromatin program.","evidence":"Kpna6 knockout mouse, immunofluorescence, Western blot, nuclear localization analysis","pmids":["34473250"],"confidence":"High","gaps":["Direct AR-KPNA6 binding not biochemically isolated here","relative contributions of Sertoli vs germ cell defects not separated"]},{"year":2021,"claim":"Identified KPNA6 as the principal import receptor for HNF1A and linked MODY-causing HNF1A mutations to reduced KPNA6 binding and mislocalization, suggesting a disease-relevant import defect.","evidence":"Co-IP, molecular docking, immunolocalization in Min6 cells with mutant HNF1A","pmids":["33459938"],"confidence":"Medium","gaps":["Causality in patient tissue not established","docking model not experimentally validated"]},{"year":2021,"claim":"Broadened the immune-evasion paradigm by showing SARS-CoV-2 M and NDV W proteins bind KPNA6 to block IRF3/interferon responses.","evidence":"Co-IP, IFN reporter and nuclear translocation assays; NDV studied with NLS mutagenesis and reverse genetics","pmids":["34950606","33441338"],"confidence":"Medium","gaps":["KPNA6-specific necessity vs other karyopherins not isolated","single lab per virus"]},{"year":2022,"claim":"Revealed a non-canonical role in influenza replication where KPNA6 modulates polymerase activity through association with ANP32A/B and the vRNP, with both loss and excess being inhibitory.","evidence":"Co-IP, KO and overexpression with polymerase activity assays, domain mutagenesis","pmids":["35044222"],"confidence":"Medium","gaps":["Mechanism of biphasic effect unclear","whether effect is import-dependent not fully resolved"]},{"year":2026,"claim":"Mapped the ZIKV NS2B-KPNA6 interaction to the importin-α major groove and identified NS2B residues critical for both binding and viral replication.","evidence":"Co-IP, fluorescence microscopy, site-directed mutagenesis, viral replication assays","pmids":["42159396"],"confidence":"Medium","gaps":["Functional consequence of perinuclear relocation for the import cycle unclear","single lab"]},{"year":null,"claim":"How KPNA6 cargo selectivity is established relative to redundant karyopherin-α paralogs, and how its import activity is rerouted or repurposed for non-import functions (acrosome targeting, influenza polymerase regulation), remain open.","evidence":"No single timeline study resolves paralog-specific cargo determinants or the structural basis of non-canonical roles","pmids":[],"confidence":"Low","gaps":["No structure of KPNA6-cargo complexes in the corpus","paralog redundancy unresolved across most cargoes","regulation of KPNA6 abundance/stability outside viral infection not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,3,4,10,11,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,11,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,3,4,10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,9,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,11,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[6,8]}],"complexes":[],"partners":["KEAP1","HNF1A","BCOR","PHB2","ANP32A","ORC6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60684","full_name":"Importin subunit alpha-7","aliases":["Karyopherin subunit alpha-6"],"length_aa":536,"mass_kda":60.0,"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","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O60684/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KPNA6","classification":"Not Classified","n_dependent_lines":281,"n_total_lines":1208,"dependency_fraction":0.2326158940397351},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000025800","cell_line_id":"CID001563","localizations":[{"compartment":"nuclear_membrane","grade":3},{"compartment":"big_aggregates","grade":2},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"RNMT","stoichiometry":10.0},{"gene":"FAM103A1","stoichiometry":10.0},{"gene":"NUP50","stoichiometry":10.0},{"gene":"LMNA","stoichiometry":10.0},{"gene":"CACUL1","stoichiometry":4.0},{"gene":"ALKBH5","stoichiometry":4.0},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"KPNA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001563","total_profiled":1310},"omim":[{"mim_id":"610563","title":"KARYOPHERIN ALPHA-6; KPNA6","url":"https://www.omim.org/entry/610563"},{"mim_id":"600686","title":"KARYOPHERIN ALPHA-1; KPNA1","url":"https://www.omim.org/entry/600686"},{"mim_id":"300265","title":"ZIC FAMILY, MEMBER 3; ZIC3","url":"https://www.omim.org/entry/300265"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KPNA6"},"hgnc":{"alias_symbol":["IPOA7","KPNA7","MGC17918","FLJ11249"],"prev_symbol":[]},"alphafold":{"accession":"O60684","domains":[{"cath_id":"1.25.10.10","chopping":"82-245","consensus_level":"medium","plddt":95.8569,"start":82,"end":245},{"cath_id":"1.25.10.10","chopping":"336-420","consensus_level":"medium","plddt":97.4707,"start":336,"end":420},{"cath_id":"-","chopping":"441-504","consensus_level":"medium","plddt":94.5108,"start":441,"end":504}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60684","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60684-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60684-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KPNA6","jax_strain_url":"https://www.jax.org/strain/search?query=KPNA6"},"sequence":{"accession":"O60684","fasta_url":"https://rest.uniprot.org/uniprotkb/O60684.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60684/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60684"}},"corpus_meta":[{"pmid":"28127595","id":"PMC_28127595","title":"Small 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28098867","citation_count":1,"is_preprint":false},{"pmid":"33459938","id":"PMC_33459938","title":"HNF1A-MODY Mutations in Nuclear Localization Signal Impair HNF1A-Import Receptor KPNA6 Interactions.","date":"2021","source":"The protein journal","url":"https://pubmed.ncbi.nlm.nih.gov/33459938","citation_count":1,"is_preprint":false},{"pmid":"25272585","id":"PMC_25272585","title":"[Identification of prototype foamy virus Bel1 nuclear localization signal and its corresponding importins].","date":"2014","source":"Bing du xue bao = Chinese journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25272585","citation_count":1,"is_preprint":false},{"pmid":"42159396","id":"PMC_42159396","title":"Zika virus recruits karyopherin α6 for efficient replication via NS2B.","date":"2026","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/42159396","citation_count":0,"is_preprint":false},{"pmid":"40687856","id":"PMC_40687856","title":"Natural mutations in key NLS amino acids regulate nucleoplasmic shuttling and replication efficiency in PRRSV.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40687856","citation_count":0,"is_preprint":false},{"pmid":"29746765","id":"PMC_29746765","title":"[The nuclear import of Newcastle disease virus matrix protein depends on KPNB1 and Ran protein].","date":"2017","source":"Wei sheng wu xue bao = Acta microbiologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/29746765","citation_count":0,"is_preprint":false},{"pmid":"41594647","id":"PMC_41594647","title":"Integrated Analysis of ATAC-Seq and RNA-Seq Reveals the Signal Transduction Regulation of the Molting Cycle in the Muscle of Chinese Mitten Crab (Eriocheir sinensis).","date":"2026","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41594647","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17060,"output_tokens":3728,"usd":0.05355,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11417,"output_tokens":3890,"usd":0.077167,"stage2_stop_reason":"end_turn"},"total_usd":0.130717,"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\": 2011,\n      \"finding\": \"KPNA6 (importin α7) directly interacts with the C-terminal Kelch domain of Keap1 and mediates its nuclear import. Overexpression of KPNA6 facilitates Keap1 nuclear import and attenuates Nrf2 signaling, whereas knockdown of KPNA6 slows Keap1 nuclear import and enhances Nrf2-mediated antioxidant response. KPNA6 also accelerates clearance of Nrf2 from the nucleus during the post-induction phase, restoring Nrf2 to basal levels.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown with functional readouts of Nrf2 target gene expression and Keap1 nuclear localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction demonstrated, complementary gain- and loss-of-function experiments with defined molecular and cellular phenotypes, published in peer-reviewed journal\",\n      \"pmids\": [\"21383067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 membrane (M) protein binds to KPNA6 to inhibit IRF3 nuclear translocation, thereby antagonizing type I interferon production.\",\n      \"method\": \"Co-immunoprecipitation, IFN reporter assays, nuclear translocation assays\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional consequence shown, single lab, abstract does not detail full mechanistic controls\",\n      \"pmids\": [\"34950606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KPNA6 is required for optimal replication of PRRSV and Zika virus. Viral infection blocks ubiquitin-proteasomal degradation of KPNA6 (induced by PRRSV nsp12), extending its half-life. KPNA6 mediates nuclear translocation of PRRSV nsp1β; KPNA6 knockout blocks nsp1β nuclear import and impairs ZIKV replication, both restored by exogenous KPNA6 re-expression.\",\n      \"method\": \"siRNA knockdown, CRISPR knockout, proteasome inhibitor assays, nuclear translocation assays, viral replication assays, rescue experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, KD, rescue, protein stability assays), clear mechanistic pathway placement\",\n      \"pmids\": [\"29444946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Orc6 nuclear localization signal-dependent transport to the nucleus is facilitated by association with Kpna6 (and Kpna1). Kpna6 did not co-purify with other ORC subunits, indicating independent transport of Orc6.\",\n      \"method\": \"Protein purification, co-immunoprecipitation, nuclear localization assays with NLS mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated with functional NLS-dependent localization assay, single lab\",\n      \"pmids\": [\"21555516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KPNA6 interacts with PHB2 and mediates estrogen-dependent nuclear translocation of PHB2 in breast cancer cells. BIG3 blocks the KPNA6 (and KPNA1, KPNA5) binding region of PHB2, inhibiting KPNA-mediated PHB2 nuclear import. Knockdown of KPNA6 inhibits PHB2 nuclear translocation and enhances ERα activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, nuclear translocation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction and functional siRNA knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"26052702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KPNA6 (along with KPNA1 and KPNA5) binds Ebola virus VP24 protein; binding affinity differences between VP24 proteins from EBOV, BDBV, and RESTV correlate with differences in IFN signaling suppression and VP24 protein stability. VP24 mutations reducing KPNA binding decrease IFN inhibition and shorten VP24 half-lives.\",\n      \"method\": \"Purified protein binding assays (quantitative affinity measurements), cell-based IFN reporter assays, VP24 half-life assays, mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, mutagenesis, and multiple functional readouts in one rigorous study\",\n      \"pmids\": [\"27974555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ablation of Kpna6 in male mice causes infertility by disrupting spermatogenesis, impairing Sertoli cell function (including loss of androgen receptor nuclear localization), and causing defects in spermiogenesis including incomplete sperm maturation, histone-protamine exchange disruption, altered BRWD1 localization, and dysregulation of RFX2 target genes.\",\n      \"method\": \"Kpna6 knockout mouse model (loss-of-function), immunofluorescence, Western blot, nuclear localization assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo KO with multiple defined cellular and molecular phenotypes, direct demonstration of nuclear import defects\",\n      \"pmids\": [\"34473250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA6 was identified as a binding partner of HASPIN kinase in spermatids using a two-hybrid system, suggesting a potential role for KPNA6 in HASPIN-mediated spermatogenesis pathways.\",\n      \"method\": \"Yeast two-hybrid screen, interaction analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid result, interaction not further validated biochemically for KPNA6 specifically\",\n      \"pmids\": [\"36012324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KPNA6 localizes to the subacrosomal layer of the perinuclear theca in sperm and associates with the surface of proacrosomic/acrosomic vesicles during acrosomal biogenesis in spermiogenesis. Recombinant SubH2Bv affinity pull-down from germ cell extracts confirmed binding interaction between SubH2Bv and KPNA6, suggesting they work together to direct acrosomic vesicles to the nucleus.\",\n      \"method\": \"Immunocytochemistry, sperm head fractionation + Western blot, recombinant protein affinity pull-down\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization with functional context, pull-down interaction, multiple complementary methods in a single lab\",\n      \"pmids\": [\"22156475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NDV W protein is transported into the nucleus via interaction with KPNA1, KPNA2, and KPNA6 in an NLS-dependent manner, and nuclear-localized W protein reduces IFN-β expression stimulated by NDV.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, NLS mutagenesis, NDV reverse genetics system\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction, NLS mutagenesis, and functional IFN-β readout, single lab\",\n      \"pmids\": [\"33441338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KPNA6 interacts with BCL-6 corepressor (BCOR) and mediates its nuclear translocation in human periodontal ligament cells. Co-expression of KPNA6 with NLS-mutant BCOR significantly increased nuclear accumulation of mutant BCOR.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, nuclear translocation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and mutagenesis with functional nuclear translocation readout, single lab\",\n      \"pmids\": [\"30396568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA6 was identified as the main import receptor responsible for nuclear transport of HNF1A transcription factor. MODY-associated mutations (Arg271Trp and Ser345Tyr) in HNF1A reduce its interaction with KPNA6, leading to impaired nuclear localization.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking simulation, immunolocalization in Min6 cells\",\n      \"journal\": \"The protein journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional localization data, mutagenesis, and complementary docking, single lab\",\n      \"pmids\": [\"33459938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNA6 associates with ANP32A/B and the influenza virus vRNP complex. Both knockout and overexpression of KPNA6 downregulate influenza virus replication by inhibiting polymerase activity. Overexpression of KPNA6 or its nuclear importing domain negative mutant inhibited ANP32-vRNP interaction, reducing polymerase activity.\",\n      \"method\": \"Co-immunoprecipitation, KPNA6 knockout and overexpression with viral polymerase activity assays, domain mutagenesis\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and direct interaction shown, but single lab; mechanism partially elucidated\",\n      \"pmids\": [\"35044222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZIKV NS2B protein mediates relocation of KPNA6 to the perinuclear region in infected cells. KPNA6 interacts with NS2B via its major groove, while NS2B binds KPNA6 via its C-terminus. Two residues (P115 and G119) in NS2B are critical for KPNA6 interaction; mutations in either residue abolish virus replication.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, site-directed mutagenesis, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapping with mutagenesis and functional viral replication readout, single lab\",\n      \"pmids\": [\"42159396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KPNA6 expression is dynamically regulated throughout mouse oogenesis and folliculogenesis; Kpna6 mRNA is significantly upregulated at the primordial-to-primary follicle transition, and KPNA6 protein shows distinct subcellular localization patterns in oocytes and granulosa cells during folliculogenesis.\",\n      \"method\": \"RT-PCR, immunofluorescence, subcellular fractionation across developmental stages\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization and expression dynamics described, no direct functional manipulation of KPNA6 in this context\",\n      \"pmids\": [\"26399853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The lncRNA βFaar promotes IRF4 nuclear translocation and induces iWAT browning by binding to KPNA6.\",\n      \"method\": \"RNA-protein binding assay, nuclear translocation assays (inferred from abstract description)\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction between lncRNA and KPNA6 mentioned but mechanistic details in abstract are limited; single study\",\n      \"pmids\": [\"40548473\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KPNA6 (importin α7/karyopherin α6) is a nuclear import adaptor that directly binds NLS-containing cargo proteins—including Keap1, HNF1A, BCOR, PHB2, and viral proteins—via its importin-α major groove and mediates their nuclear translocation in a karyopherin β-dependent manner; it plays essential roles in regulating the Nrf2 antioxidant response (by importing Keap1 to promote Nrf2 nuclear clearance), male spermatogenesis (loss of Kpna6 causes infertility in mice through defective androgen receptor nuclear localization and spermiogenic defects), and serves as a proviral host factor exploited by multiple RNA viruses (PRRSV, ZIKV, IAV) to facilitate viral protein nuclear trafficking and replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KPNA6 (importin α7/karyopherin α6) is a nuclear import adaptor that recognizes nuclear localization signal (NLS)-bearing cargo through its importin-α major groove and delivers them to the nucleus [#0, #13]. Its cellular cargo repertoire spans transcriptional and regulatory proteins including Keap1 [#0], the HNF1A transcription factor [#11], the BCL-6 corepressor BCOR [#10], and PHB2 [#4], the latter two imported in NLS-dependent and stimulus-dependent fashion. Through Keap1 import, KPNA6 tunes the Nrf2 antioxidant response, both by importing Keap1 to attenuate Nrf2 signaling and by accelerating clearance of Nrf2 from the nucleus during the post-induction phase [#0]. KPNA6 import activity is physiologically essential in the male germline: loss of Kpna6 in mice causes infertility through impaired androgen receptor nuclear localization in Sertoli cells, disrupted histone-protamine exchange, and dysregulation of RFX2 target genes during spermiogenesis [#6]. A recurrent theme is exploitation of KPNA6 by RNA viruses: it is a required host factor for PRRSV and Zika virus replication, mediating nuclear import of PRRSV nsp1β and being stabilized against proteasomal degradation during infection [#2, #13], and viral proteins from Ebola (VP24), SARS-CoV-2 (M), and Newcastle disease virus (W) bind KPNA6 to suppress type I interferon responses by blocking IRF3 or sequestering import capacity [#1, #5, #9]. KPNA6 additionally regulates influenza polymerase activity through association with ANP32A/B and the vRNP complex [#12]. A timeline finding links HNF1A MODY-associated mutations to reduced KPNA6 binding and impaired HNF1A nuclear localization [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established KPNA6 as a functional import adaptor with a defined regulatory output by showing it imports Keap1 and thereby controls the magnitude and resolution of the Nrf2 antioxidant response.\",\n      \"evidence\": \"Co-IP, gain- and loss-of-function with Nrf2 target gene and Keap1 localization readouts in cells\",\n      \"pmids\": [\"21383067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve karyopherin β dependence quantitatively\", \"NLS within Keap1 not mapped\", \"physiological tissue context of Keap1 import not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed KPNA6 mediates NLS-dependent nuclear import of an individual cargo (Orc6) independently of its complex partners, demonstrating cargo-selective transport.\",\n      \"evidence\": \"Protein purification, co-IP, and NLS-mutant nuclear localization assays\",\n      \"pmids\": [\"21555516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not reciprocally validated in vivo\", \"shared with KPNA1, specificity not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed KPNA6 in acrosome biogenesis by localizing it to the subacrosomal perinuclear theca and identifying SubH2Bv as a binding partner, extending its role beyond classical import.\",\n      \"evidence\": \"Immunocytochemistry, sperm head fractionation, recombinant protein pull-down\",\n      \"pmids\": [\"22156475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional requirement not tested by loss-of-function here\", \"mechanism linking import adaptor to vesicle targeting unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined estrogen-regulated PHB2 import as a KPNA6 function and identified BIG3 as an inhibitor of cargo binding, linking KPNA6 to ERα signaling control.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, nuclear translocation assays in breast cancer cells\",\n      \"pmids\": [\"26052702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy with KPNA1/KPNA5 not resolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided rigorous in vitro evidence that KPNA-binding affinity of Ebola VP24 quantitatively governs interferon suppression and viral protein stability, establishing KPNA6 as a target hijacked for immune evasion.\",\n      \"evidence\": \"Purified-protein affinity measurements, mutagenesis, IFN reporter and half-life assays\",\n      \"pmids\": [\"27974555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Shared binding with KPNA1/KPNA5, KPNA6-specific contribution in vivo not isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated KPNA6 is a required proviral host factor whose stability is actively protected during infection, mediating nuclear import of viral proteins for PRRSV and Zika replication.\",\n      \"evidence\": \"siRNA, CRISPR KO, proteasome inhibition, nuclear translocation, viral replication and rescue assays\",\n      \"pmids\": [\"29444946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nsp12-induced degradation block not fully mapped\", \"ZIKV cargo identity not defined in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the cargo repertoire to the transcriptional corepressor BCOR via NLS-dependent import, reinforcing a general role in nuclear delivery of gene-regulatory proteins.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, nuclear translocation assays in periodontal ligament cells\",\n      \"pmids\": [\"30396568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell type\", \"in vivo relevance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the in vivo demonstration that KPNA6 is essential for male fertility, mechanistically tying its import function to androgen receptor localization and the spermiogenic transcriptional/chromatin program.\",\n      \"evidence\": \"Kpna6 knockout mouse, immunofluorescence, Western blot, nuclear localization analysis\",\n      \"pmids\": [\"34473250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AR-KPNA6 binding not biochemically isolated here\", \"relative contributions of Sertoli vs germ cell defects not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified KPNA6 as the principal import receptor for HNF1A and linked MODY-causing HNF1A mutations to reduced KPNA6 binding and mislocalization, suggesting a disease-relevant import defect.\",\n      \"evidence\": \"Co-IP, molecular docking, immunolocalization in Min6 cells with mutant HNF1A\",\n      \"pmids\": [\"33459938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality in patient tissue not established\", \"docking model not experimentally validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened the immune-evasion paradigm by showing SARS-CoV-2 M and NDV W proteins bind KPNA6 to block IRF3/interferon responses.\",\n      \"evidence\": \"Co-IP, IFN reporter and nuclear translocation assays; NDV studied with NLS mutagenesis and reverse genetics\",\n      \"pmids\": [\"34950606\", \"33441338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KPNA6-specific necessity vs other karyopherins not isolated\", \"single lab per virus\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-canonical role in influenza replication where KPNA6 modulates polymerase activity through association with ANP32A/B and the vRNP, with both loss and excess being inhibitory.\",\n      \"evidence\": \"Co-IP, KO and overexpression with polymerase activity assays, domain mutagenesis\",\n      \"pmids\": [\"35044222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of biphasic effect unclear\", \"whether effect is import-dependent not fully resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped the ZIKV NS2B-KPNA6 interaction to the importin-α major groove and identified NS2B residues critical for both binding and viral replication.\",\n      \"evidence\": \"Co-IP, fluorescence microscopy, site-directed mutagenesis, viral replication assays\",\n      \"pmids\": [\"42159396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of perinuclear relocation for the import cycle unclear\", \"single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KPNA6 cargo selectivity is established relative to redundant karyopherin-α paralogs, and how its import activity is rerouted or repurposed for non-import functions (acrosome targeting, influenza polymerase regulation), remain open.\",\n      \"evidence\": \"No single timeline study resolves paralog-specific cargo determinants or the structural basis of non-canonical roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of KPNA6-cargo complexes in the corpus\", \"paralog redundancy unresolved across most cargoes\", \"regulation of KPNA6 abundance/stability outside viral infection not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 3, 4, 10, 11, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 3, 4, 10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 9, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 11, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KEAP1\", \"HNF1A\", \"BCOR\", \"PHB2\", \"ANP32A\", \"ORC6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}