{"gene":"KPNA1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"KPNA1 (NPI-1/human SRP1 homolog) directly binds influenza A virus nucleoprotein (NP); GST-NPI-1 fusion protein co-precipitated partially purified NP from solution, and anti-NPI-1 sera co-immunoprecipitated NP from infected MDBK cells, demonstrating the interaction in infected cells.","method":"GST pulldown assay and reciprocal co-immunoprecipitation from virus-infected cells","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in infected cells plus GST pulldown reconstitution, replicated across multiple methods in same study","pmids":["7831767"],"is_preprint":false},{"year":1997,"finding":"KPNA1 (NPI-1) binds the influenza NP at a nonconventional NLS motif (SxGTKRSYxxM); alanine scanning mutagenesis identified this motif as required for NPI-1 binding and demonstrated it possesses functional NLS activity in HeLa cells.","method":"Yeast two-hybrid mutational (alanine-scanning) analysis and NLS-fusion protein nuclear localization assay in HeLa cells","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with functional NLS assay, two complementary approaches in same study","pmids":["9032315"],"is_preprint":false},{"year":1994,"finding":"Human KPNA1 (SRP1 homolog) physically interacts with the V(D)J recombination protein RAG-1; the interaction was confirmed by co-immunoprecipitation after co-transfection, and deletion analysis mapped the RAG-1-interacting region to four ARM repeats of KPNA1 and the N-terminal region of RAG-1.","method":"Yeast two-hybrid, co-immunoprecipitation after co-transfection in 293T cells, deletion analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP in mammalian cells plus domain mapping","pmids":["8052633"],"is_preprint":false},{"year":2007,"finding":"Ebola virus VP24 binds within the PY-STAT1-binding region located in the C-terminus of KPNA1, competitively inhibiting PY-STAT1 interaction with KPNA1 (and also KPNA5/karyopherin α5 and KPNA6/karyopherin α6, which together form the NPI-1 subfamily); this blocks IFN-induced nuclear accumulation of PY-STAT1 and IFN-stimulated gene expression.","method":"Mutational analysis of KPNA1, co-immunoprecipitation with endogenous and overexpressed proteins, IFN-stimulated gene expression assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutational mapping, interaction with endogenous proteins confirmed, functional readout (gene expression inhibition), multiple VP24 variants tested","pmids":["17928350"],"is_preprint":false},{"year":2000,"finding":"KPNA1 (karyopherin α1/NPI-1/hSRP1) interacts with EBV nuclear antigen 1 (EBNA-1); the interaction was confirmed in vitro by GST-fusion pulldown and by co-immunoprecipitation of endogenous EBNA-1 from B cell (Raji) extracts, demonstrating that EBNA-1 can use KPNA1 (as well as karyopherin α2) for nuclear import.","method":"GST pulldown, co-immunoprecipitation from B cell extracts, yeast two-hybrid","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by GST pulldown and Co-IP with endogenous proteins from B cells","pmids":["10612665"],"is_preprint":false},{"year":2006,"finding":"KPNA1 (NPI-1/importin α5) functions as the nuclear import adaptor for EBV EBNA-1; phosphorylation of Ser385 in the EBNA-1 NLS increases binding affinity of EBNA-1 to KPNA1 and accelerates nuclear import rate, while phosphorylation of Ser383 and Ser386 reduces nuclear import. Lys379 and Arg380 are essential for the EBNA-1 NLS function via KPNA1.","method":"Microinjection of NLS peptide-BSA conjugates, GFP-EBNA-1 transfection with Ser-to-Ala substitutions, in vitro binding assays with phospho-NLS peptides and different importin α isoforms","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — microinjection functional assay, mutagenesis, direct binding comparison among importin α isoforms; multiple orthogonal methods","pmids":["16439554"],"is_preprint":false},{"year":2011,"finding":"KPNA1 (NPI-1) selectively mediates nuclear import of HIV-1 Vpr (full-length) but not Rch1 or Qip1; Vpr preferentially binds the ninth ARM repeat of KPNA1, and CAS (exportin for importin α) releases Vpr from the Vpr/NPI-1 complex but not from Rch1 or Qip1. CAS knockdown greatly reduced NPI-1-mediated nuclear import of Vpr.","method":"Digitonin-permeabilized cell nuclear import assay, surface plasmon resonance binding assay, CAS siRNA knockdown","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstituted in vitro nuclear import, quantitative SPR binding, siRNA knockdown with functional rescue; multiple orthogonal methods","pmids":["22110766"],"is_preprint":false},{"year":2022,"finding":"PEDV nsp7 interacts with the DNA-binding domain of STAT1, competitively sequestering the KPNA1–STAT1 interaction and thereby blocking KPNA1-mediated nuclear translocation of STAT1/STAT2 (ISGF3 complex) without affecting STAT1 phosphorylation levels or ISGF3 assembly.","method":"Co-immunoprecipitation, nuclear translocation assays, IFN-stimulated gene expression assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mechanistic follow-up (nuclear translocation assay, gene expression readout), single lab","pmids":["35442061"],"is_preprint":false},{"year":2008,"finding":"KPNA1 (NPI-1 subfamily, importin α5) is localized to the cytoplasm under basal conditions in HeLa cells, but accumulates in the nucleus in response to oxidative stress (H2O2 treatment), as determined by immunofluorescence with a monoclonal antibody that recognizes the ARM motif of importin α5/NPI-1.","method":"Immunofluorescence microscopy with monospecific monoclonal antibody; epitope mapping by recombinant deletion mutants","journal":"Hybridoma","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single immunofluorescence experiment, no functional consequence directly tested for KPNA1 itself","pmids":["18707546"],"is_preprint":false},{"year":2016,"finding":"KPNA1 (importin α5) binds the NLS motif (215PRQKRPR221) of prototype foamy virus transactivator Bel1 and mediates its nuclear import; demonstrated by GST pulldown and in vitro nuclear import assay. NOTE: The original paper (PMID 27277550) was subsequently retracted (PMID 28098867) due to irreproducible results and contamination issues.","method":"GST pulldown assay, in vitro nuclear import assay — RETRACTED","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, subsequently retracted due to irreproducibility and cell contamination","pmids":["27277550","28098867"],"is_preprint":false},{"year":2021,"finding":"Kpna1 (mouse importin α1/KPNA1) knockout in mice produces behavioral phenotypes including decreased anxiety-like behavior, short-term memory deficits, impaired sensorimotor gating (prepulse inhibition), and altered plasma corticosterone and cytokine (LIX/CXCL5) levels, establishing a role for KPNA1 in neuropsychiatric-relevant behaviors and neuroendocrine signaling.","method":"Kpna1 knockout mouse behavioral battery (elevated plus maze, novel object recognition, prepulse inhibition, inhibitory avoidance, forced swim test); plasma hormone/cytokine measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple defined behavioral and biochemical phenotypic readouts; single lab","pmids":["34767585"],"is_preprint":false},{"year":2025,"finding":"KPNA1 in neuronal axons largely does not form a complex with importin β1 (IPOB1) under steady-state conditions; axonal KPNA1 shows relatively stationary mobility and bidirectional motility, and partly co-migrates with endosome/lysosome-associated factors, indicating axonal transport dependent on endosomes. A schizophrenia-associated truncation mutant (KPNA1-E448X) was predominantly nuclear and absent from axons; restoring a nuclear export signal (NES) to the mutant rescued its axonal localization and dynamics.","method":"Live-cell fluorescence imaging of KPNA1-GFP in neurons, co-migration analysis with endosome/lysosome markers, nuclear import complex analysis, NES rescue experiment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging of axonal dynamics, mutagenesis rescue, multiple fluorescent markers; single lab, single study","pmids":["40010609"],"is_preprint":false}],"current_model":"KPNA1 (importin α5/NPI-1) is a nuclear localization signal (NLS) receptor/adaptor that binds NLS-containing cargo proteins (including influenza NP, EBV EBNA-1, RAG-1, HIV-1 Vpr, and phosphorylated STAT1) via its ARM-repeat domain and mediates their import into the nucleus; viral proteins (Ebola VP24, PEDV nsp7, SVV 3Cpro) exploit this pathway by competing with PY-STAT1 for KPNA1 binding to suppress IFN signaling, while CAS regulates KPNA1 recycling after cargo release; beyond classical nucleocytoplasmic transport, KPNA1 also functions in neuronal axons where it associates with endosomal transport machinery and its loss produces neuropsychiatric-related behavioral deficits in mice."},"narrative":{"mechanistic_narrative":"KPNA1 (importin α5/NPI-1/hSRP1) is a nuclear localization signal (NLS) receptor that recognizes NLS-bearing cargo through its ARM-repeat domain and adapts them to the classical nuclear import pathway [PMID:8052633, PMID:16439554]. It engages a broad range of cargo, including the V(D)J recombinase RAG-1 via four of its ARM repeats [PMID:8052633], EBV nuclear antigen EBNA-1—whose import KPNA1 accelerates upon phosphorylation of Ser385 within the EBNA-1 NLS [PMID:16439554]—influenza A nucleoprotein through a nonconventional NLS motif [PMID:7831767, PMID:9032315], and HIV-1 Vpr, which binds selectively to the ninth ARM repeat in a manner that distinguishes KPNA1 from other importin α isoforms [PMID:22110766]. After cargo delivery, the exportin CAS releases cargo such as Vpr from KPNA1 to recycle the adaptor [PMID:22110766]. A C-terminal region of KPNA1 binds phosphorylated STAT1 (PY-STAT1), and this interferon-signaling node is a recurrent target of viral antagonism: Ebola VP24 occupies the PY-STAT1-binding region to competitively block PY-STAT1 import and ISG expression [PMID:17928350], while PEDV nsp7 sequesters the STAT1 DNA-binding domain to disrupt KPNA1-mediated nuclear translocation of the ISGF3 complex without altering STAT1 phosphorylation [PMID:35442061]. Beyond classical transport, KPNA1 has a neuronal role: its knockout in mice produces neuropsychiatric-relevant behavioral and neuroendocrine phenotypes [PMID:34767585], and in axons KPNA1 co-migrates with endosome/lysosome-associated factors rather than forming a steady-state importin β1 complex, with a schizophrenia-associated E448X truncation mislocalizing to the nucleus and losing axonal targeting unless a nuclear export signal is restored [PMID:40010609].","teleology":[{"year":1994,"claim":"Established that human KPNA1 physically engages an endogenous nuclear protein, RAG-1, and mapped the interaction to specific ARM repeats, defining KPNA1 as an NLS-cargo adaptor with a discrete cargo-binding surface.","evidence":"Yeast two-hybrid, Co-IP after co-transfection in 293T cells, and deletion mapping","pmids":["8052633"],"confidence":"High","gaps":["Did not establish import kinetics or dependence on importin β","Functional consequence for V(D)J recombination not tested"]},{"year":1995,"claim":"Showed KPNA1 directly binds a viral cargo (influenza NP) in infected cells, demonstrating that pathogens recruit KPNA1 for nuclear access.","evidence":"GST pulldown and reciprocal Co-IP from virus-infected MDBK cells","pmids":["7831767"],"confidence":"High","gaps":["NLS motif within NP not yet defined","Import efficiency relative to other importin α isoforms unknown"]},{"year":1997,"claim":"Defined the nonconventional NLS motif on influenza NP recognized by KPNA1, refining the cargo-recognition specificity of the adaptor.","evidence":"Yeast two-hybrid alanine-scanning mutagenesis and NLS-fusion nuclear localization assay in HeLa cells","pmids":["9032315"],"confidence":"High","gaps":["Structural basis of nonconventional NLS recognition not resolved","Did not address which ARM repeats bind this motif"]},{"year":2000,"claim":"Extended KPNA1 cargo repertoire to EBV EBNA-1 using endogenous protein from B cells, showing redundancy with karyopherin α2.","evidence":"GST pulldown, Co-IP of endogenous EBNA-1 from Raji B cell extracts, yeast two-hybrid","pmids":["10612665"],"confidence":"High","gaps":["Did not quantify isoform preference","Phospho-regulation of the NLS not yet examined"]},{"year":2006,"claim":"Demonstrated that NLS phosphorylation tunes KPNA1 binding affinity and import rate, establishing post-translational control of cargo selection.","evidence":"Microinjection of NLS peptide-BSA conjugates, GFP-EBNA-1 Ser-to-Ala mutants, and in vitro binding with phospho-NLS peptides across importin α isoforms","pmids":["16439554"],"confidence":"High","gaps":["Kinase responsible for Ser385 phosphorylation not identified","Generality of phospho-tuning to other cargo not tested"]},{"year":2007,"claim":"Identified the C-terminal PY-STAT1-binding region of KPNA1 as the node targeted by Ebola VP24 to block interferon signaling, linking KPNA1 to innate immune nuclear import.","evidence":"KPNA1 mutational mapping, Co-IP of endogenous/overexpressed proteins, and ISG expression assays","pmids":["17928350"],"confidence":"High","gaps":["Did not resolve VP24 binding stoichiometry or structure","Contribution of KPNA5/KPNA6 redundancy in vivo unquantified"]},{"year":2008,"claim":"Showed KPNA1 itself relocalizes from cytoplasm to nucleus under oxidative stress, indicating its distribution is stimulus-regulated.","evidence":"Immunofluorescence with a monospecific monoclonal antibody in H2O2-treated HeLa cells","pmids":["18707546"],"confidence":"Medium","gaps":["Single immunofluorescence experiment without functional consequence for KPNA1","Mechanism driving stress-induced relocalization unknown"]},{"year":2011,"claim":"Reconstituted isoform-selective import of HIV-1 Vpr through the ninth ARM repeat of KPNA1 and showed CAS-dependent cargo release, mechanistically connecting cargo binding to recycling.","evidence":"Digitonin-permeabilized cell import assay, surface plasmon resonance, and CAS siRNA knockdown with functional rescue","pmids":["22110766"],"confidence":"High","gaps":["Structural basis for ninth-ARM-repeat selectivity not solved","Whether CAS regulates release of all KPNA1 cargo not addressed"]},{"year":2021,"claim":"Revealed a physiological role for KPNA1 beyond transport biochemistry, with knockout mice showing neuropsychiatric-relevant behavioral and neuroendocrine deficits.","evidence":"Kpna1 knockout mouse behavioral battery plus plasma hormone/cytokine measurement","pmids":["34767585"],"confidence":"Medium","gaps":["Molecular cargo underlying behavioral phenotypes not identified","Single lab; cell-type-specific contributions unresolved"]},{"year":2022,"claim":"Defined a distinct viral strategy in which PEDV nsp7 sequesters the STAT1 DNA-binding domain to disrupt KPNA1-mediated ISGF3 import without affecting STAT1 phosphorylation, separating import blockade from upstream signaling.","evidence":"Co-IP, nuclear translocation assays, and ISG expression assays","pmids":["35442061"],"confidence":"Medium","gaps":["Single lab without reciprocal structural confirmation","Quantitative effect on KPNA1 occupancy not measured"]},{"year":2025,"claim":"Characterized a non-canonical axonal function of KPNA1 dependent on endosomal transport rather than steady-state importin β1 complexing, and showed a schizophrenia-associated truncation mislocalizes by losing nuclear export.","evidence":"Live-cell imaging of KPNA1-GFP in neurons, co-migration with endosome/lysosome markers, import complex analysis, and NES rescue of the E448X mutant","pmids":["40010609"],"confidence":"Medium","gaps":["Axonal cargo carried by KPNA1 not identified","Link between axonal mislocalization and disease phenotype not functionally proven","Single study"]},{"year":null,"claim":"The endogenous physiological cargo of KPNA1 that drive its neuronal and neuroendocrine functions, and the structural basis of its isoform-selective cargo recognition, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No native neuronal cargo identified for axonal KPNA1","No high-resolution structure of KPNA1 with cargo or viral antagonists","Relative in vivo contribution of NPI-1 subfamily redundancy unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7]}],"complexes":[],"partners":["STAT1","RAG1","CSE1L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52294","full_name":"Importin subunit alpha-5","aliases":["Karyopherin subunit alpha-1","Nucleoprotein interactor 1","NPI-1","RAG cohort protein 2","SRP1-beta"],"length_aa":538,"mass_kda":60.2,"function":"Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1 (PubMed:27713473, PubMed:7892216, PubMed:8692858). Binds specifically and directly to substrates containing either a simple or bipartite NLS motif (PubMed:27713473, PubMed:7892216, PubMed:8692858). 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 (PubMed:27713473, PubMed:7892216). 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 (PubMed:7892216). 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 (PubMed:7892216). Mediator of PR-DUB complex component BAP1 nuclear import; acts redundantly with KPNA2 and Transportin-1/TNPO1 (PubMed:35446349) (Microbial infection) In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P52294/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KPNA1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000114030","cell_line_id":"CID001558","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"nuclear_membrane","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"NUP50","stoichiometry":10.0},{"gene":"ANP32A","stoichiometry":10.0},{"gene":"HDAC2","stoichiometry":4.0},{"gene":"KPNB1","stoichiometry":4.0},{"gene":"NOP58","stoichiometry":4.0},{"gene":"CSE1L","stoichiometry":0.2},{"gene":"CSNK2A1","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001558","total_profiled":1310},"omim":[{"mim_id":"615820","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 8; DCAF8","url":"https://www.omim.org/entry/615820"},{"mim_id":"610563","title":"KARYOPHERIN ALPHA-6; KPNA6","url":"https://www.omim.org/entry/610563"},{"mim_id":"604545","title":"KARYOPHERIN ALPHA-5; KPNA5","url":"https://www.omim.org/entry/604545"},{"mim_id":"602970","title":"KARYOPHERIN ALPHA-4; KPNA4","url":"https://www.omim.org/entry/602970"},{"mim_id":"602424","title":"DOUBLESEX- AND MAB3-RELATED TRANSCRIPTION FACTOR 1; DMRT1","url":"https://www.omim.org/entry/602424"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KPNA1"},"hgnc":{"alias_symbol":["SRP1","RCH2","NPI-1","IPOA5"],"prev_symbol":[]},"alphafold":{"accession":"P52294","domains":[{"cath_id":"1.25.10.10","chopping":"29-54_86-253","consensus_level":"medium","plddt":90.499,"start":29,"end":253},{"cath_id":"1.25.10.10","chopping":"424-506","consensus_level":"medium","plddt":95.2184,"start":424,"end":506}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52294","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52294-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52294-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KPNA1","jax_strain_url":"https://www.jax.org/strain/search?query=KPNA1"},"sequence":{"accession":"P52294","fasta_url":"https://rest.uniprot.org/uniprotkb/P52294.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52294/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52294"}},"corpus_meta":[{"pmid":"17928350","id":"PMC_17928350","title":"Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17928350","citation_count":215,"is_preprint":false},{"pmid":"9032315","id":"PMC_9032315","title":"The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal.","date":"1997","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9032315","citation_count":211,"is_preprint":false},{"pmid":"1448093","id":"PMC_1448093","title":"Cloning and characterization of SRP1, a suppressor of temperature-sensitive RNA polymerase I mutations, in Saccharomyces cerevisiae.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1448093","citation_count":180,"is_preprint":false},{"pmid":"8052633","id":"PMC_8052633","title":"RAG-1 interacts with the repeated amino acid motif of the human homologue of the yeast protein SRP1.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8052633","citation_count":171,"is_preprint":false},{"pmid":"7831767","id":"PMC_7831767","title":"NPI-1, the human homolog of SRP-1, interacts with influenza virus nucleoprotein.","date":"1995","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/7831767","citation_count":140,"is_preprint":false},{"pmid":"8631802","id":"PMC_8631802","title":"The nuclear localization signal of lymphoid enhancer factor-1 is recognized by two differentially expressed Srp1-nuclear localization sequence receptor proteins.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8631802","citation_count":94,"is_preprint":false},{"pmid":"7565597","id":"PMC_7565597","title":"Yeast Srp1, a nuclear protein related to Drosophila and mouse pendulin, is required for normal migration, division, and integrity of nuclei during mitosis.","date":"1995","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/7565597","citation_count":52,"is_preprint":false},{"pmid":"16439554","id":"PMC_16439554","title":"Nuclear import of Epstein-Barr virus nuclear antigen 1 mediated by NPI-1 (Importin alpha5) is up- and down-regulated by phosphorylation of the nuclear localization signal for which Lys379 and Arg380 are essential.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16439554","citation_count":48,"is_preprint":false},{"pmid":"3139887","id":"PMC_3139887","title":"Yeast gene SRP1 (serine-rich protein). Intragenic repeat structure and identification of a family of SRP1-related DNA sequences.","date":"1988","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3139887","citation_count":39,"is_preprint":false},{"pmid":"9421507","id":"PMC_9421507","title":"Identification and characterization of srp1, a gene of fission yeast encoding a RNA binding domain and a RS domain typical of SR splicing factors.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9421507","citation_count":37,"is_preprint":false},{"pmid":"7761467","id":"PMC_7761467","title":"Isolation of a yeast protein kinase that is activated by the protein encoded by SRP1 (Srp1p) and phosphorylates Srp1p complexed with nuclear localization signal peptides.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7761467","citation_count":35,"is_preprint":false},{"pmid":"28848534","id":"PMC_28848534","title":"Mechanisms of Chromium and Uranium Toxicity in Pseudomonas stutzeri RCH2 Grown under Anaerobic Nitrate-Reducing Conditions.","date":"2017","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28848534","citation_count":28,"is_preprint":false},{"pmid":"10612665","id":"PMC_10612665","title":"Epstein-barr virus nuclear antigen-1 binds to nuclear transporter karyopherin alpha1/NPI-1 in addition to karyopherin alpha2/Rch1.","date":"2000","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/10612665","citation_count":28,"is_preprint":false},{"pmid":"35442061","id":"PMC_35442061","title":"Porcine Epidemic Diarrhea Virus nsp7 Inhibits Interferon-Induced JAK-STAT Signaling through Sequestering the Interaction between KPNA1 and STAT1.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/35442061","citation_count":27,"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":"11115121","id":"PMC_11115121","title":"A Rox1-independent hypoxic pathway in yeast. Antagonistic action of the repressor Ord1 and activator Yap1 for hypoxic expression of the SRP1/TIR1 gene.","date":"2000","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11115121","citation_count":21,"is_preprint":false},{"pmid":"37819133","id":"PMC_37819133","title":"Seneca Valley virus 3Cpro antagonizes type I interferon response by targeting STAT1-STAT2-IRF9 and KPNA1 signals.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37819133","citation_count":19,"is_preprint":false},{"pmid":"22110766","id":"PMC_22110766","title":"Nuclear exportin receptor CAS regulates the NPI-1-mediated nuclear import of HIV-1 Vpr.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22110766","citation_count":19,"is_preprint":false},{"pmid":"23425335","id":"PMC_23425335","title":"Investigation of rare variants in LRP1, KPNA1, ALS2CL and ZNF480 genes in schizophrenia patients reflects genetic heterogeneity of the disease.","date":"2013","source":"Behavioral and brain functions : BBF","url":"https://pubmed.ncbi.nlm.nih.gov/23425335","citation_count":18,"is_preprint":false},{"pmid":"25274630","id":"PMC_25274630","title":"Yeast importin-α (Srp1) performs distinct roles in the import of nuclear proteins and in targeting proteasomes to the nucleus.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25274630","citation_count":16,"is_preprint":false},{"pmid":"24338021","id":"PMC_24338021","title":"Nuclear import factor Srp1 and its associated protein Sts1 couple ribosome-bound nascent polypeptides to proteasomes for cotranslational degradation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24338021","citation_count":14,"is_preprint":false},{"pmid":"34767585","id":"PMC_34767585","title":"Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34767585","citation_count":13,"is_preprint":false},{"pmid":"28194258","id":"PMC_28194258","title":"Complete genome sequence of Pseudomonas stutzeri strain RCH2 isolated from a Hexavalent Chromium [Cr(VI)] contaminated site.","date":"2017","source":"Standards in genomic sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28194258","citation_count":10,"is_preprint":false},{"pmid":"10724483","id":"PMC_10724483","title":"At acidic pH, the diminished hypoxic expression of the SRP1/TIR1 yeast gene depends on the GPA2-cAMP and HOG pathways.","date":"2000","source":"Research in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10724483","citation_count":8,"is_preprint":false},{"pmid":"2839375","id":"PMC_2839375","title":"Gene cloning from yeast chromosome-specific mini-library. Isolation of the SRP1-related DNA sequence located on chromosome XV.","date":"1988","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2839375","citation_count":6,"is_preprint":false},{"pmid":"18707546","id":"PMC_18707546","title":"Generation and characterization of a monoclonal antibody against NPI-1 subfamily of importin alpha.","date":"2008","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/18707546","citation_count":6,"is_preprint":false},{"pmid":"38336912","id":"PMC_38336912","title":"A Kpna1-deficient psychotropic drug-induced schizophrenia model mouse for studying gene-environment interactions.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38336912","citation_count":2,"is_preprint":false},{"pmid":"11427966","id":"PMC_11427966","title":"At acidic pH, the GPA2-cAMP pathway is necessary to counteract the ORD1-mediated repression of the hypoxic SRP1/TIR1 yeast gene.","date":"2001","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11427966","citation_count":2,"is_preprint":false},{"pmid":"27277550","id":"PMC_27277550","title":"Nuclear import of prototype foamy virus transactivator Bel1 is mediated by KPNA1, KPNA6 and KPNA7.","date":"2016","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27277550","citation_count":1,"is_preprint":false},{"pmid":"28098867","id":"PMC_28098867","title":"[Retracted] Nuclear import of prototype foamy virus transactivator Bel1 is mediated by KPNA1, KPNA6 and KPNA7.","date":"2017","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28098867","citation_count":1,"is_preprint":false},{"pmid":"40010609","id":"PMC_40010609","title":"Direct observation of importin α family member KPNA1 in axonal transport with or without a schizophrenia-related mutation.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40010609","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.25.640171","title":"New Insights into nuclear import and nucleolar localization of yeast RNA exosome subunits","date":"2025-03-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.25.640171","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17634,"output_tokens":3231,"usd":0.050683,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10676,"output_tokens":3671,"usd":0.072578,"stage2_stop_reason":"end_turn"},"total_usd":0.123261,"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\": \"KPNA1 (NPI-1/human SRP1 homolog) directly binds influenza A virus nucleoprotein (NP); GST-NPI-1 fusion protein co-precipitated partially purified NP from solution, and anti-NPI-1 sera co-immunoprecipitated NP from infected MDBK cells, demonstrating the interaction in infected cells.\",\n      \"method\": \"GST pulldown assay and reciprocal co-immunoprecipitation from virus-infected cells\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in infected cells plus GST pulldown reconstitution, replicated across multiple methods in same study\",\n      \"pmids\": [\"7831767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA1 (NPI-1) binds the influenza NP at a nonconventional NLS motif (SxGTKRSYxxM); alanine scanning mutagenesis identified this motif as required for NPI-1 binding and demonstrated it possesses functional NLS activity in HeLa cells.\",\n      \"method\": \"Yeast two-hybrid mutational (alanine-scanning) analysis and NLS-fusion protein nuclear localization assay in HeLa cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with functional NLS assay, two complementary approaches in same study\",\n      \"pmids\": [\"9032315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Human KPNA1 (SRP1 homolog) physically interacts with the V(D)J recombination protein RAG-1; the interaction was confirmed by co-immunoprecipitation after co-transfection, and deletion analysis mapped the RAG-1-interacting region to four ARM repeats of KPNA1 and the N-terminal region of RAG-1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation after co-transfection in 293T cells, deletion analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP in mammalian cells plus domain mapping\",\n      \"pmids\": [\"8052633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ebola virus VP24 binds within the PY-STAT1-binding region located in the C-terminus of KPNA1, competitively inhibiting PY-STAT1 interaction with KPNA1 (and also KPNA5/karyopherin α5 and KPNA6/karyopherin α6, which together form the NPI-1 subfamily); this blocks IFN-induced nuclear accumulation of PY-STAT1 and IFN-stimulated gene expression.\",\n      \"method\": \"Mutational analysis of KPNA1, co-immunoprecipitation with endogenous and overexpressed proteins, IFN-stimulated gene expression assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutational mapping, interaction with endogenous proteins confirmed, functional readout (gene expression inhibition), multiple VP24 variants tested\",\n      \"pmids\": [\"17928350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KPNA1 (karyopherin α1/NPI-1/hSRP1) interacts with EBV nuclear antigen 1 (EBNA-1); the interaction was confirmed in vitro by GST-fusion pulldown and by co-immunoprecipitation of endogenous EBNA-1 from B cell (Raji) extracts, demonstrating that EBNA-1 can use KPNA1 (as well as karyopherin α2) for nuclear import.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation from B cell extracts, yeast two-hybrid\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by GST pulldown and Co-IP with endogenous proteins from B cells\",\n      \"pmids\": [\"10612665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KPNA1 (NPI-1/importin α5) functions as the nuclear import adaptor for EBV EBNA-1; phosphorylation of Ser385 in the EBNA-1 NLS increases binding affinity of EBNA-1 to KPNA1 and accelerates nuclear import rate, while phosphorylation of Ser383 and Ser386 reduces nuclear import. Lys379 and Arg380 are essential for the EBNA-1 NLS function via KPNA1.\",\n      \"method\": \"Microinjection of NLS peptide-BSA conjugates, GFP-EBNA-1 transfection with Ser-to-Ala substitutions, in vitro binding assays with phospho-NLS peptides and different importin α isoforms\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — microinjection functional assay, mutagenesis, direct binding comparison among importin α isoforms; multiple orthogonal methods\",\n      \"pmids\": [\"16439554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KPNA1 (NPI-1) selectively mediates nuclear import of HIV-1 Vpr (full-length) but not Rch1 or Qip1; Vpr preferentially binds the ninth ARM repeat of KPNA1, and CAS (exportin for importin α) releases Vpr from the Vpr/NPI-1 complex but not from Rch1 or Qip1. CAS knockdown greatly reduced NPI-1-mediated nuclear import of Vpr.\",\n      \"method\": \"Digitonin-permeabilized cell nuclear import assay, surface plasmon resonance binding assay, CAS siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted in vitro nuclear import, quantitative SPR binding, siRNA knockdown with functional rescue; multiple orthogonal methods\",\n      \"pmids\": [\"22110766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PEDV nsp7 interacts with the DNA-binding domain of STAT1, competitively sequestering the KPNA1–STAT1 interaction and thereby blocking KPNA1-mediated nuclear translocation of STAT1/STAT2 (ISGF3 complex) without affecting STAT1 phosphorylation levels or ISGF3 assembly.\",\n      \"method\": \"Co-immunoprecipitation, nuclear translocation assays, IFN-stimulated gene expression assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mechanistic follow-up (nuclear translocation assay, gene expression readout), single lab\",\n      \"pmids\": [\"35442061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KPNA1 (NPI-1 subfamily, importin α5) is localized to the cytoplasm under basal conditions in HeLa cells, but accumulates in the nucleus in response to oxidative stress (H2O2 treatment), as determined by immunofluorescence with a monoclonal antibody that recognizes the ARM motif of importin α5/NPI-1.\",\n      \"method\": \"Immunofluorescence microscopy with monospecific monoclonal antibody; epitope mapping by recombinant deletion mutants\",\n      \"journal\": \"Hybridoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunofluorescence experiment, no functional consequence directly tested for KPNA1 itself\",\n      \"pmids\": [\"18707546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KPNA1 (importin α5) binds the NLS motif (215PRQKRPR221) of prototype foamy virus transactivator Bel1 and mediates its nuclear import; demonstrated by GST pulldown and in vitro nuclear import assay. NOTE: The original paper (PMID 27277550) was subsequently retracted (PMID 28098867) due to irreproducible results and contamination issues.\",\n      \"method\": \"GST pulldown assay, in vitro nuclear import assay — RETRACTED\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, subsequently retracted due to irreproducibility and cell contamination\",\n      \"pmids\": [\"27277550\", \"28098867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Kpna1 (mouse importin α1/KPNA1) knockout in mice produces behavioral phenotypes including decreased anxiety-like behavior, short-term memory deficits, impaired sensorimotor gating (prepulse inhibition), and altered plasma corticosterone and cytokine (LIX/CXCL5) levels, establishing a role for KPNA1 in neuropsychiatric-relevant behaviors and neuroendocrine signaling.\",\n      \"method\": \"Kpna1 knockout mouse behavioral battery (elevated plus maze, novel object recognition, prepulse inhibition, inhibitory avoidance, forced swim test); plasma hormone/cytokine measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple defined behavioral and biochemical phenotypic readouts; single lab\",\n      \"pmids\": [\"34767585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KPNA1 in neuronal axons largely does not form a complex with importin β1 (IPOB1) under steady-state conditions; axonal KPNA1 shows relatively stationary mobility and bidirectional motility, and partly co-migrates with endosome/lysosome-associated factors, indicating axonal transport dependent on endosomes. A schizophrenia-associated truncation mutant (KPNA1-E448X) was predominantly nuclear and absent from axons; restoring a nuclear export signal (NES) to the mutant rescued its axonal localization and dynamics.\",\n      \"method\": \"Live-cell fluorescence imaging of KPNA1-GFP in neurons, co-migration analysis with endosome/lysosome markers, nuclear import complex analysis, NES rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging of axonal dynamics, mutagenesis rescue, multiple fluorescent markers; single lab, single study\",\n      \"pmids\": [\"40010609\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KPNA1 (importin α5/NPI-1) is a nuclear localization signal (NLS) receptor/adaptor that binds NLS-containing cargo proteins (including influenza NP, EBV EBNA-1, RAG-1, HIV-1 Vpr, and phosphorylated STAT1) via its ARM-repeat domain and mediates their import into the nucleus; viral proteins (Ebola VP24, PEDV nsp7, SVV 3Cpro) exploit this pathway by competing with PY-STAT1 for KPNA1 binding to suppress IFN signaling, while CAS regulates KPNA1 recycling after cargo release; beyond classical nucleocytoplasmic transport, KPNA1 also functions in neuronal axons where it associates with endosomal transport machinery and its loss produces neuropsychiatric-related behavioral deficits in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KPNA1 (importin α5/NPI-1/hSRP1) is a nuclear localization signal (NLS) receptor that recognizes NLS-bearing cargo through its ARM-repeat domain and adapts them to the classical nuclear import pathway [#2, #5]. It engages a broad range of cargo, including the V(D)J recombinase RAG-1 via four of its ARM repeats [#2], EBV nuclear antigen EBNA-1—whose import KPNA1 accelerates upon phosphorylation of Ser385 within the EBNA-1 NLS [#5]—influenza A nucleoprotein through a nonconventional NLS motif [#0, #1], and HIV-1 Vpr, which binds selectively to the ninth ARM repeat in a manner that distinguishes KPNA1 from other importin α isoforms [#6]. After cargo delivery, the exportin CAS releases cargo such as Vpr from KPNA1 to recycle the adaptor [#6]. A C-terminal region of KPNA1 binds phosphorylated STAT1 (PY-STAT1), and this interferon-signaling node is a recurrent target of viral antagonism: Ebola VP24 occupies the PY-STAT1-binding region to competitively block PY-STAT1 import and ISG expression [#3], while PEDV nsp7 sequesters the STAT1 DNA-binding domain to disrupt KPNA1-mediated nuclear translocation of the ISGF3 complex without altering STAT1 phosphorylation [#7]. Beyond classical transport, KPNA1 has a neuronal role: its knockout in mice produces neuropsychiatric-relevant behavioral and neuroendocrine phenotypes [#10], and in axons KPNA1 co-migrates with endosome/lysosome-associated factors rather than forming a steady-state importin β1 complex, with a schizophrenia-associated E448X truncation mislocalizing to the nucleus and losing axonal targeting unless a nuclear export signal is restored [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that human KPNA1 physically engages an endogenous nuclear protein, RAG-1, and mapped the interaction to specific ARM repeats, defining KPNA1 as an NLS-cargo adaptor with a discrete cargo-binding surface.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP after co-transfection in 293T cells, and deletion mapping\",\n      \"pmids\": [\"8052633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish import kinetics or dependence on importin β\", \"Functional consequence for V(D)J recombination not tested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed KPNA1 directly binds a viral cargo (influenza NP) in infected cells, demonstrating that pathogens recruit KPNA1 for nuclear access.\",\n      \"evidence\": \"GST pulldown and reciprocal Co-IP from virus-infected MDBK cells\",\n      \"pmids\": [\"7831767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NLS motif within NP not yet defined\", \"Import efficiency relative to other importin α isoforms unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the nonconventional NLS motif on influenza NP recognized by KPNA1, refining the cargo-recognition specificity of the adaptor.\",\n      \"evidence\": \"Yeast two-hybrid alanine-scanning mutagenesis and NLS-fusion nuclear localization assay in HeLa cells\",\n      \"pmids\": [\"9032315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of nonconventional NLS recognition not resolved\", \"Did not address which ARM repeats bind this motif\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extended KPNA1 cargo repertoire to EBV EBNA-1 using endogenous protein from B cells, showing redundancy with karyopherin α2.\",\n      \"evidence\": \"GST pulldown, Co-IP of endogenous EBNA-1 from Raji B cell extracts, yeast two-hybrid\",\n      \"pmids\": [\"10612665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify isoform preference\", \"Phospho-regulation of the NLS not yet examined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that NLS phosphorylation tunes KPNA1 binding affinity and import rate, establishing post-translational control of cargo selection.\",\n      \"evidence\": \"Microinjection of NLS peptide-BSA conjugates, GFP-EBNA-1 Ser-to-Ala mutants, and in vitro binding with phospho-NLS peptides across importin α isoforms\",\n      \"pmids\": [\"16439554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser385 phosphorylation not identified\", \"Generality of phospho-tuning to other cargo not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the C-terminal PY-STAT1-binding region of KPNA1 as the node targeted by Ebola VP24 to block interferon signaling, linking KPNA1 to innate immune nuclear import.\",\n      \"evidence\": \"KPNA1 mutational mapping, Co-IP of endogenous/overexpressed proteins, and ISG expression assays\",\n      \"pmids\": [\"17928350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve VP24 binding stoichiometry or structure\", \"Contribution of KPNA5/KPNA6 redundancy in vivo unquantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed KPNA1 itself relocalizes from cytoplasm to nucleus under oxidative stress, indicating its distribution is stimulus-regulated.\",\n      \"evidence\": \"Immunofluorescence with a monospecific monoclonal antibody in H2O2-treated HeLa cells\",\n      \"pmids\": [\"18707546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single immunofluorescence experiment without functional consequence for KPNA1\", \"Mechanism driving stress-induced relocalization unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstituted isoform-selective import of HIV-1 Vpr through the ninth ARM repeat of KPNA1 and showed CAS-dependent cargo release, mechanistically connecting cargo binding to recycling.\",\n      \"evidence\": \"Digitonin-permeabilized cell import assay, surface plasmon resonance, and CAS siRNA knockdown with functional rescue\",\n      \"pmids\": [\"22110766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ninth-ARM-repeat selectivity not solved\", \"Whether CAS regulates release of all KPNA1 cargo not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a physiological role for KPNA1 beyond transport biochemistry, with knockout mice showing neuropsychiatric-relevant behavioral and neuroendocrine deficits.\",\n      \"evidence\": \"Kpna1 knockout mouse behavioral battery plus plasma hormone/cytokine measurement\",\n      \"pmids\": [\"34767585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo underlying behavioral phenotypes not identified\", \"Single lab; cell-type-specific contributions unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a distinct viral strategy in which PEDV nsp7 sequesters the STAT1 DNA-binding domain to disrupt KPNA1-mediated ISGF3 import without affecting STAT1 phosphorylation, separating import blockade from upstream signaling.\",\n      \"evidence\": \"Co-IP, nuclear translocation assays, and ISG expression assays\",\n      \"pmids\": [\"35442061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal structural confirmation\", \"Quantitative effect on KPNA1 occupancy not measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized a non-canonical axonal function of KPNA1 dependent on endosomal transport rather than steady-state importin β1 complexing, and showed a schizophrenia-associated truncation mislocalizes by losing nuclear export.\",\n      \"evidence\": \"Live-cell imaging of KPNA1-GFP in neurons, co-migration with endosome/lysosome markers, import complex analysis, and NES rescue of the E448X mutant\",\n      \"pmids\": [\"40010609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Axonal cargo carried by KPNA1 not identified\", \"Link between axonal mislocalization and disease phenotype not functionally proven\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological cargo of KPNA1 that drive its neuronal and neuroendocrine functions, and the structural basis of its isoform-selective cargo recognition, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No native neuronal cargo identified for axonal KPNA1\", \"No high-resolution structure of KPNA1 with cargo or viral antagonists\", \"Relative in vivo contribution of NPI-1 subfamily redundancy unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT1\", \"RAG1\", \"CSE1L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}