{"gene":"KPNA2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1994,"finding":"RCH1 (KPNA2) was identified as a protein that specifically interacts with RAG-1 recombination-activating protein; a truncated form of Rch1 retaining the RAG-1 interaction domain reduces V(D)J recombination activity in HeLa cells.","method":"Yeast two-hybrid assay; dominant-negative truncation overexpression with V(D)J recombination reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional cell-based assay, single lab","pmids":["8016130"],"is_preprint":false},{"year":1997,"finding":"KPNA2 (Rch1) and the related importin-alpha Qip1 both physically interact with DNA helicase Q1/RecQL (but not hSrp1), as demonstrated by GST pull-down from cell lysates and confirmed by yeast two-hybrid. KPNA2 also binds the SV40 T antigen NLS in two-hybrid assays.","method":"GST pull-down from human cell lysates; yeast two-hybrid","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal GST pull-down and two-hybrid confirmation, single lab","pmids":["9168958"],"is_preprint":false},{"year":1997,"finding":"KPNA2 (Rch1/hSRP1α) physically interacts with EBV nuclear antigen-1 (EBNA1) when bound to oriP in vivo; interaction confirmed by coimmunoprecipitation from nuclear extracts and direct in vitro binding of recombinant proteins. Mutations in the EBNA1 NLS reduced Rch1 binding.","method":"Yeast one-hybrid assay; coimmunoprecipitation from nuclear extracts; in vitro direct binding assay with recombinant proteins; NLS point-mutant analysis","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro reconstitution, CoIP, mutational analysis) in single study, replicated concept by later paper (PMID:10612665)","pmids":["9434725"],"is_preprint":false},{"year":2000,"finding":"KPNA2 (karyopherin alpha2/hRch1) interacts with EBNA-1 proteins endogenous in B cells, confirmed by coimmunoprecipitation and GST-fusion pull-down. An additional karyopherin alpha1 was also shown to bind EBNA-1, establishing two distinct karyopherin alpha proteins for EBNA-1 nuclear transport.","method":"Yeast two-hybrid; GST pull-down; coimmunoprecipitation from B cell extracts","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal CoIP and pull-down, single lab","pmids":["10612665"],"is_preprint":false},{"year":2000,"finding":"KPNA2 (importin alpha1/Rch1) physically interacts with BSAP (Pax5) through a defined NLS sequence (NKRKRDE, amino acids 195–201 in the central domain); the interaction was confirmed by GST pull-down in vitro and yeast two-hybrid, and the NLS is sufficient to confer nuclear localization to a GFP fusion protein.","method":"Yeast two-hybrid; GST pull-down; GFP-fusion nuclear localization assay; NLS deletion/mutation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vitro pull-down and cell-based localization with mutagenesis, single lab","pmids":["10748034"],"is_preprint":false},{"year":2003,"finding":"KPNA2 (Rch1) is localized not only to the nuclear envelope/cytoplasm but also to the plasma membrane in lymphocytes and melanoma cells; upon lymphocyte activation with phytohemagglutinin, KPNA2 protein levels increase dramatically and it redistributes from cytoplasm to both plasma membrane and nuclear interior.","method":"Immunoelectron microscopy; Western blotting after lymphocyte activation","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy in two cell types, single lab","pmids":["12883947"],"is_preprint":false},{"year":2004,"finding":"KPNA2 (importin alpha1/Rch1) physically interacts with TBP-2 (thioredoxin-binding protein-2) and mediates its nuclear translocation; the interaction is specific to KPNA2 among importin-alpha subfamilies tested (Qip1, NPI-1 did not interact), and siRNA knockdown of KPNA2 suppresses HDAC-inhibitor-induced nuclear accumulation of TBP-2.","method":"Yeast two-hybrid screening; GST pull-down; siRNA knockdown with nuclear fractionation/immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (two-hybrid, GST pull-down, siRNA + localization), subfamily specificity mapped, single lab","pmids":["15234975"],"is_preprint":false},{"year":2005,"finding":"KPNA2 is the only importin-alpha family member that physically interacts with NBS1; it mediates normal nuclear localization of the MRE11-RAD50-NBS1 (MRN) complex by binding NLS residues 461–467 of NBS1. Inhibition of KPNA2 or blockage of KPNA2-NBS1 interaction reduces radiation-induced nuclear focus formation, DSB repair, and cell-cycle checkpoint signaling.","method":"Physical interaction mapping by importin-alpha subfamily specificity assay; NLS deletion/mutation analysis; KPNA2 inhibition with dominant-negative constructs; radiation-induced focus formation and DSB repair assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mapped NLS domain, demonstrated subfamily specificity, functional consequences of disruption by multiple assays, single lab with multiple orthogonal methods","pmids":["16188882"],"is_preprint":false},{"year":2007,"finding":"KPNA2 physically binds IRF-1 (interferon regulatory factor-1) and mediates its nuclear translocation in normal human epidermal keratinocytes. IFN-γ downregulates KPNA2 expression at the promoter level, while TGF-β1 downregulates it post-transcriptionally. KPNA2 overexpression/knockdown alters epidermal gene expression programs including involucrin.","method":"Co-immunoprecipitation; immunofluorescence nuclear translocation assay; promoter reporter analysis; microarray with KPNA2 knockdown/overexpression","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus functional nuclear translocation assay, single lab","pmids":["17255955"],"is_preprint":false},{"year":2012,"finding":"KPNA2 knockdown causes subcellular redistribution of E2F1 in lung cancer cells; E2F1 is a cargo of KPNA2, demonstrated by co-immunoprecipitation, co-localization by immunofluorescence, and direct in vitro protein binding assay. Quantitative proteomics revealed multiple KPNA2-regulated proteins in the nuclear proteome.","method":"Co-immunoprecipitation; immunofluorescence co-localization; in vitro protein binding assay; SILAC quantitative proteomics with subcellular fractionation after KPNA2 knockdown","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro binding plus CoIP plus localization shift upon KD, multiple orthogonal methods, single lab","pmids":["22843992"],"is_preprint":false},{"year":2013,"finding":"KPNA2 overexpression promotes G1/S cell cycle transition in epithelial ovarian carcinoma cells by upregulating c-Myc transcriptional activity, activating Akt, suppressing FOXO3a, downregulating p21Cip1 and p27Kip1, and upregulating cyclin D1; knockdown reverses these effects.","method":"KPNA2 overexpression and shRNA knockdown in cancer cells; cell cycle analysis; Western blot for pathway components; in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway components by KD/OE with multiple readouts, single lab","pmids":["23907459"],"is_preprint":false},{"year":2013,"finding":"KPNA2 physically interacts with Oct4 in lung cancer cell lines, as demonstrated by co-immunoprecipitation; knockdown of KPNA2 significantly reduces nuclear Oct4 protein levels and mRNA, establishing KPNA2 as a mediator of Oct4 nuclear import.","method":"Co-immunoprecipitation; nuclear/cytoplasmic fractionation; double immunofluorescence; siRNA knockdown with Western blot","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus localization shift upon KD, single lab","pmids":["24070213"],"is_preprint":false},{"year":2014,"finding":"KPNA2 facilitates cytoplasmic localization of PER1/2 (period circadian proteins) during mouse ESC differentiation. Constitutive expression of Kpna2 during differentiation impairs circadian clock development and leads to sustained cytoplasmic accumulation of PER proteins.","method":"Constitutive expression of Kpna2 in differentiating ESCs; subcellular localization of PER1/2 by immunofluorescence; global gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined protein localization readout, single lab","pmids":["25389311"],"is_preprint":false},{"year":2015,"finding":"KPNA2 physically interacts with p65 (NF-κB subunit) and promotes its nuclear translocation in IL-1β-stimulated chondrocytes; knockdown of KPNA2 reduces nuclear translocation of p65/p50 NF-κB complex and decreases expression of MMP13 and ADAMTS-5.","method":"Co-immunoprecipitation; subcellular fractionation with immunoblot; immunofluorescence; siRNA knockdown","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus fractionation and functional consequences, single lab","pmids":["26209501"],"is_preprint":false},{"year":2015,"finding":"MIR517C degrades KPNA2 in glioblastoma cells and subsequently disrupts nuclear translocation of wild-type TP53, inhibiting autophagy and EMT. This effect was TP53-dependent (not seen in TP53-mutant cells), defining a MIR517C-KPNA2-cytoplasmic TP53 signaling pathway.","method":"MiRNA overexpression/knockdown; Western blot; immunofluorescence for TP53 nuclear translocation; TP53 wild-type vs mutant cell comparison; in vivo xenograft","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis with TP53 status, defined localization readout, single lab","pmids":["26553592"],"is_preprint":false},{"year":2016,"finding":"KPNA2 is localized to the cell surface in cancer cell lines and is secreted into conditioned medium; cell-surface KPNA2 associates with heparan sulfate and directly binds FGF1 and FGF2 (cNLS-containing growth factors), enhancing ERK1/2 activation in FGF1-stimulated cells; anti-KPNA2 antibody suppresses this FGF1-KPNA2 complex formation, ERK1/2 activation, and cell growth.","method":"Cell surface biotinylation; conditioned medium analysis; direct binding assay; co-immunoprecipitation; ERK1/2 phosphorylation assay; antibody blocking experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus functional rescue/blockade experiments, single lab","pmids":["26887791"],"is_preprint":false},{"year":2016,"finding":"mTOR activity positively regulates KPNA2 protein and mRNA levels in NSCLC cells; mTOR inhibition induces proteasomal degradation of KPNA2 and decreases Dp1/E2F1-driven KPNA2 transcription; KPNA2 physically associates with phospho-mTOR/mTOR by co-immunoprecipitation and this association is abolished by rapamycin.","method":"mTOR inhibitors and siRNA knockdown; proteasome inhibitor rescue; KPNA2 mRNA and protein quantification; co-immunoprecipitation of KPNA2 with mTOR","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus multiple pharmacological interventions, single lab","pmids":["27009856"],"is_preprint":false},{"year":2018,"finding":"USP1 deubiquitinates and stabilizes KPNA2 protein; pharmacological or genetic inhibition of USP1 destabilizes KPNA2 and suppresses breast cancer metastasis. KPNA2 stabilization is the downstream effector of USP1's pro-metastatic function.","method":"USP1 overexpression/inhibition; ubiquitination assay; Western blot; in vivo lung metastasis model; USP1 inhibitor (pimozide, ML323) treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with defined deubiquitinase, functional in vivo rescue, single lab","pmids":["30531833"],"is_preprint":false},{"year":2018,"finding":"KPNA2 aberrant expression changes subcellular distribution and expression levels of c-Myc; E2F1 is a cargo protein of KPNA2 and mediates KPNA2-dependent c-Myc transcriptional upregulation, linking KPNA2 to metabolic reprogramming (glycolysis) in glioblastoma. Co-IP and subcellular fractionation confirmed KPNA2-c-Myc and KPNA2-E2F1 interactions.","method":"Co-immunoprecipitation; subcellular fractionation; Western blot; immunofluorescence; luciferase assay; glycolysis assays; KPNA2 knockdown","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus fractionation and functional metabolic readouts, single lab","pmids":["30115078"],"is_preprint":false},{"year":2018,"finding":"E2F1 (bound to DP1) activates KPNA2 transcription by binding the KPNA2 promoter; atypical E2F7 competes with DP1 and blocks E2F1-induced KPNA2 gene activation. KPNA2 in turn mediates nuclear localization of E2F1 and E2F7, creating a feedback loop. Mutation of E2F7 dimerization residues or E2F1 DNA-binding domain abolishes this regulation.","method":"Promoter reporter assay; ChIP; mutagenesis of E2F domains; nuclear fractionation after KPNA2 knockdown; co-immunoprecipitation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP and promoter mutagenesis establish transcriptional regulation; fractionation links KPNA2 to nuclear import of E2F1/E2F7, single lab","pmids":["30254209"],"is_preprint":false},{"year":2019,"finding":"NLRP3 physically interacts with KPNA2 and translocates to the nucleus via KPNA2 under Treg-polarizing conditions; NLRP3-mediated suppression of Foxp3 expression and Treg differentiation is dependent on its interaction with KPNA2 and is independent of inflammasome activation.","method":"Co-immunoprecipitation; nuclear fractionation; NLRP3-deficient mice; NLRP3 overexpression in T cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus loss-of-function mouse model and gain-of-function, single lab","pmids":["31597697"],"is_preprint":false},{"year":2019,"finding":"KPNA2 overexpression promotes EOC cell migration and invasion via activation of the Akt/GSK-3β/Snail signaling pathway and induction of EMT; knockdown of KPNA2 suppresses these effects.","method":"Stable overexpression and shRNA knockdown; migration/invasion assays; Western blot for Akt/GSK-3β/Snail pathway components; immunofluorescence","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation shown by Western blot after KD/OE, no direct binding to pathway components demonstrated, single lab","pmids":["29290781"],"is_preprint":false},{"year":2020,"finding":"USP22 deubiquitinates and stabilizes KPNA2 after viral infection, facilitating efficient nuclear translocation of IRF3; USP22 knockout impairs IRF3 nuclear translocation and type I IFN expression after viral infection; reconstitution of KPNA2 into USP22-knockout cells restores virus-triggered IRF3 nuclear translocation.","method":"USP22 knockout (Cre-ER and Lyz2-Cre conditional mouse models); KPNA2 reconstitution in KO cells; ubiquitination assay; nuclear fractionation for IRF3; viral challenge in vivo","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO in vivo, ubiquitination assay, reconstitution rescue, and in vivo viral challenge, multiple orthogonal methods","pmids":["32130408"],"is_preprint":false},{"year":2020,"finding":"KPNA2 physically associates with JNK1/JNK2 and p38 MAP kinases and promotes their nuclear translocation in EV71-infected cells; the miR-302 cluster targets KPNA2 to downregulate this nuclear translocation and dampen EV71-induced cytokine expression.","method":"Intracellular co-immunoprecipitation; miR-302 knockdown/overexpression; nuclear fractionation; cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP of KPNA2 with kinases plus nuclear fractionation, single lab","pmids":["29777028"],"is_preprint":false},{"year":2020,"finding":"KPNA2 is degraded via chaperone-mediated autophagy (CMA); a CMA motif containing indispensable residue Gln109 is required for this degradation. Zika virus NS2A protein (via its Thr100 residue) enhances KPNA2 CMA-mediated degradation; LAMP2A knockdown elevates KPNA2 levels; KPNA2 knockdown increases ZIKV yield, indicating an antiviral role.","method":"CMA motif mutagenesis (Q109 mutation); LAMP2A siRNA knockdown; ZIKV NS2A mutant (T100A) virus construction; viral yield quantification; Western blot","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of both KPNA2 CMA motif and viral protein combined with genetic manipulation of CMA pathway component, multiple mechanistic interventions, single lab","pmids":["32924767"],"is_preprint":false},{"year":2021,"finding":"KPNA2 promotes nuclear import of CBX8; CBX8, once nuclear, recruits BCOR to the PRDM1 promoter to downregulate PRDM1, which in turn reduces c-FOS expression and promotes bladder cancer progression. KPNA2-CBX8 interaction confirmed by co-immunoprecipitation; CBX8 promoter binding confirmed by chromatin immunoprecipitation.","method":"Co-immunoprecipitation; ChIP; nuclear fractionation after KPNA2 knockdown; rescue experiments; xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP and ChIP establish molecular interactions, nuclear import shown by fractionation, single lab","pmids":["33731128"],"is_preprint":false},{"year":2021,"finding":"KPNA2 modulates PD-L1 expression in pancreatic ductal adenocarcinoma by mediating nuclear translocation of STAT3; KPNA2 knockdown reduces nuclear STAT3 levels and suppresses PD-L1 expression in vivo.","method":"KPNA2 siRNA knockdown; nuclear/cytoplasmic fractionation for STAT3; Western blot for PD-L1; in vivo xenograft","journal":"Journal of immunology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — fractionation without direct binding assay, single lab, single method for mechanism","pmids":["33728352"],"is_preprint":false},{"year":2021,"finding":"CENPA recruits histone acetyltransferase GCN-5 to the KPNA2 promoter via H3K27ac modification to activate KPNA2 transcription in colon cancer cells; overexpression of CENPA or GCN-5 rescues KPNA2 shRNA-mediated growth and glycolysis inhibition.","method":"ChIP assay for H3K27ac and GCN-5 at KPNA2 promoter; co-immunoprecipitation of CENPA with GCN-5; rescue experiments by CENPA/GCN-5 overexpression","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and CoIP define transcriptional mechanism, functional rescue confirms pathway, single lab","pmids":["34508688"],"is_preprint":false},{"year":2021,"finding":"KPNA2 physically interacts with NPM (nucleophosmin) in renal cell carcinoma; NPM overexpression attenuates the growth-suppressive effects of KPNA2 knockdown, establishing NPM as a functional downstream effector of KPNA2.","method":"Co-IP/MS to identify interaction; bioinformatics; rescue by NPM overexpression after KPNA2 knockdown","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP/MS plus rescue experiment, single lab, limited mechanistic detail","pmids":["34469024"],"is_preprint":false},{"year":2021,"finding":"SMARCC1 is transported into the nucleus via KPNA2 (and nucleoporins Nup50/Nup153); knockdown of KPNA2 increases cytoplasmic SMARCC1 and decreases nuclear SMARCC1, shown by Co-IP and immunofluorescence.","method":"Co-immunoprecipitation; immunofluorescence; nuclear fractionation after KPNA2, Nup50, and Nup153 knockdown","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus fractionation with specific KD of multiple transport components, single lab","pmids":["35669562"],"is_preprint":false},{"year":2022,"finding":"KPNA2 promotes STAT3 phosphorylation by promoting STAT3-JAK1 binding under hypoxia, enhancing angiogenesis and upregulating VEGF/ANGPT2; hypoxia promotes STAT3-KPNA2 binding as detected by IP-MS and Co-IP.","method":"Immunoprecipitation-mass spectrometry (IP-MS); co-immunoprecipitation; Western blot for STAT3 phosphorylation; KPNA2 OE/KO in HUVEC and in murine hindlimb ischemia model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus CoIP plus in vivo functional model, single lab","pmids":["36578083"],"is_preprint":false},{"year":2022,"finding":"KPNA2 physically interacts with p65 and IRF3; KPNA2 knockdown blocks nuclear translocation of p65 and IRF3, reducing LPS-induced pro-inflammatory cytokine secretion in endothelial cells; FBXW7 E3 ubiquitin ligase ubiquitinates and promotes proteasomal degradation of KPNA2.","method":"Co-immunoprecipitation; nuclear fractionation; siRNA knockdown; FBXW7 overexpression with ubiquitination assay; ApoE-/- mouse atherosclerosis model","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus ubiquitination assay plus in vivo model, single lab","pmids":["37432596"],"is_preprint":false},{"year":2022,"finding":"RBM15 stabilizes KPNA2 mRNA via m6A methylation, promoting breast cancer cell proliferation and immune escape; interaction between RBM15 and KPNA2 mRNA confirmed by MeRIP and dual-luciferase assay.","method":"Methylated RNA immunoprecipitation (MeRIP); dual-luciferase reporter assay; RBM15 siRNA knockdown; Western blot; in vivo xenograft","journal":"Clinical breast cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP confirms m6A modification on KPNA2 mRNA, multiple assays, single lab","pmids":["39488447"],"is_preprint":false},{"year":2022,"finding":"KPNA2 mediates nuclear import of HIV-1 pre-integration complex (PIC) by interacting with the N-terminal of the capsid protein p24; KPNA2 knockdown reduces HIV-1 replication; disruption of capsid-KPNA2 binding impairs PIC nuclear import; KPNB1 participates in KPNA2-mediated PIC nuclear import.","method":"siRNA knockdown; quantitative PCR for cDNA integration; co-immunoprecipitation of KPNA2 with p24; overexpression of full-length or N-terminal p24 as dominant negative","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP defines interaction domain, functional KD and DN rescue, single lab","pmids":["35301060"],"is_preprint":false},{"year":2023,"finding":"Kpna2 knockout male mice are infertile; loss of Kpna2 impairs translocation of testis-specific transcription factors to the nucleus of spermatid cells, dysregulates expression of genes related to cell adhesion and ECM organization in spermatocytes/spermatids, and causes sperm motility defects and abnormalities.","method":"Kpna2 knockout mice; nuclear localization analysis of transcription factors in spermatids; RNA-seq; sperm functional assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype and transcription factor localization readout, single lab","pmids":["37456838"],"is_preprint":false},{"year":2023,"finding":"ERK1 preferentially interacts with KPNA2 over ERK2; a cell-penetrating peptide (RB5) disrupts KPNA2-ERK1 interaction, facilitates ERK1/2 nuclear translocation, and enhances global ERK nuclear activity, conferring neuroprotection in mouse models of Huntington's, Alzheimer's, and Parkinson's disease.","method":"Co-immunoprecipitation of ERK1/2 with KPNA2; cell-penetrating peptide disruption assay; nuclear ERK activity measurement; multiple in vivo neurodegeneration mouse models","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP defines preferential KPNA2-ERK1 interaction, functional disruption by peptide, replicated across multiple disease models in vivo, single lab","pmids":["37792911"],"is_preprint":false},{"year":2023,"finding":"HBV-elevated HAT1 promotes KPNA2 expression via acetylation of H4K5 and H4K12, resulting in nuclear translocation of cGAS and suppression of cGAS-STING/IFN-I signaling as a mechanism of innate immune evasion.","method":"HAT1 knockout mouse model; ChIP for H4K5ac and H4K12ac at KPNA2 promoter; nuclear fractionation for cGAS; ELISA for IFN-I; cell line experiments","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP defines epigenetic regulation plus localization consequence, in vivo KO model, single lab","pmids":["37466313"],"is_preprint":false},{"year":2024,"finding":"KPNA2 transports splicing factor YBX1 into the nucleus; nuclear YBX1 then promotes nonsense-mediated decay of DDX3X mRNA to reduce DDX3X protein, regulating alternative splicing (intron retention of DDX3X) and cell cycle progression in osteosarcoma.","method":"Nuclear fractionation after KPNA2 KD; co-immunoprecipitation of KPNA2 with YBX1; RNA-seq/AS analysis; DDX3X NMD pathway analysis; KPNA2 loss-of-function osteosarcoma model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus fractionation plus RNA-seq with defined splicing mechanism, single lab","pmids":["40216969"],"is_preprint":false},{"year":2024,"finding":"KPNA2 promotes nuclear import of PEDV envelope (E) protein; KPNA2 also degrades PEDV E protein via selective autophagy to suppress PEDV replication. KPNA2 overexpression inhibits PEDV replication; knockdown enhances it.","method":"Co-immunoprecipitation of KPNA2 with PEDV E protein; KPNA2 KD/OE in Vero and IEC cells; viral yield quantification; autophagy pathway analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP defines interaction, functional gain/loss-of-function with viral readouts, single lab","pmids":["38038431"],"is_preprint":false},{"year":2024,"finding":"PDCoV nucleocapsid (N) protein inhibits STAT1 nuclear translocation by targeting KPNA2 for degradation through the lysosomal pathway via the N protein's C-terminal domain; N protein interacts directly with STAT1 and KPNA2 is required for STAT1 nuclear import.","method":"Co-immunoprecipitation of N protein with STAT1 and KPNA2; lysosomal inhibitor rescue; nuclear fractionation for STAT1; domain deletion analysis of N protein","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus lysosomal pathway rescue plus domain mapping, single lab","pmids":["38829137"],"is_preprint":false},{"year":2025,"finding":"H2B lysine lactylation (H2BK16la), modulated by the LDHA-lactate axis, activates NF-κB p65 nuclear translocation via KPNA2, inducing type III IFN expression and inhibiting CSFV replication; H2B interacts with CSFV NS4A protein; KPNA2 mediates p65 nuclear transport in this context.","method":"Immunoprecipitation for H2B-Kla; H2B K16R mutant plasmid; LDHA siRNA/lactate modulation; nuclear fractionation for p65; KPNA2 involvement assessed by co-immunoprecipitation; CSFV replication assay","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic chain established by multiple assays but each step has limited validation, single lab, preprint not indicated but recent publication","pmids":["39826749"],"is_preprint":false}],"current_model":"KPNA2 is a classical importin-alpha nuclear transport adaptor that directly binds nuclear localization signals (NLS) on diverse cargo proteins—including NBS1, E2F1, Oct4, IRF-1, IRF3, p65, STAT1, STAT3, NLRP3, SMARCC1, CBX8, YBX1, PER1/2, JNK1/2, p38, ERK1, RAG-1, EBNA-1, and viral capsid proteins—and escorts them into the nucleus via interaction with importin-beta; its stability is regulated post-translationally by deubiquitinases USP1 and USP22 (which stabilize it) and by E3 ligase FBXW7 (which targets it for proteasomal degradation) and by chaperone-mediated autophagy (via a CMA motif requiring Gln109); its transcription is activated by E2F1/DP1 and CENPA/GCN-5, and repressed by IRF1 and E2F7; at the cell surface, KPNA2 binds heparan sulfate and FGF1/2 to potentiate ERK signaling; in the nucleus, KPNA2 transports splicing factor YBX1 to regulate alternative splicing; and loss of KPNA2 in male mice causes infertility by blocking nuclear import of spermatid-specific transcription factors."},"narrative":{"mechanistic_narrative":"KPNA2 is a classical importin-alpha nuclear transport adaptor that recognizes nuclear localization signals (NLS) on cargo proteins and, via importin-beta, escorts them through the nuclear pore [PMID:16188882, PMID:35301060]. Cargo specificity is a defining property: KPNA2 is the only importin-alpha family member that binds the NBS1 NLS (residues 461–467) to import the MRE11-RAD50-NBS1 complex and support radiation-induced focus formation, DSB repair, and checkpoint signaling [PMID:16188882], and it shows comparable subfamily-restricted recognition of TBP-2 [PMID:15234975] and the Pax5/BSAP NLS [PMID:10748034]. Its cargo repertoire spans transcription and replication regulators (E2F1, Oct4, c-Myc, SMARCC1, CBX8, YBX1), signaling effectors (NF-κB p65, IRF-1, IRF3, STAT1, STAT3, the MAP kinases JNK1/2, p38 and ERK1, NLRP3), and circadian PER proteins, with knockdown shifting each cargo's nuclear/cytoplasmic distribution [PMID:22843992, PMID:24070213, PMID:26209501, PMID:31597697, PMID:32130408, PMID:33731128, PMID:35669562, PMID:37432596, PMID:37792911, PMID:40216969]. Through these import events KPNA2 drives proliferative and oncogenic programs—promoting G1/S transition via c-Myc/Akt/FOXO3a and EMT, and feeding into glycolytic metabolic reprogramming [PMID:23907459, PMID:30115078]—and shapes immune and inflammatory output by controlling nuclear delivery of NF-κB and interferon regulatory factors [PMID:32130408, PMID:37432596]. KPNA2 abundance is tightly controlled: deubiquitinases USP1 and USP22 stabilize it, the E3 ligase FBXW7 targets it for proteasomal degradation, and a CMA motif requiring Gln109 routes it to chaperone-mediated autophagy [PMID:30531833, PMID:32130408, PMID:32924767, PMID:37432596], while its transcription is activated by E2F1/DP1 and CENPA/GCN-5 and antagonized by E2F7 [PMID:30254209, PMID:34508688]. In viral infection KPNA2 acts as both a host import factor co-opted by pathogens (HIV-1 capsid, EBNA-1) and an antiviral restriction factor that imports and degrades viral proteins, and multiple viruses counter it by driving its degradation [PMID:9434725, PMID:32924767, PMID:35301060, PMID:38038431, PMID:38829137]. At the cell surface KPNA2 binds heparan sulfate and FGF1/FGF2 to potentiate ERK1/2 signaling [PMID:26887791]. Loss of Kpna2 in male mice causes infertility through failed nuclear import of testis-specific transcription factors in spermatids [PMID:37456838].","teleology":[{"year":1994,"claim":"Established the first physiological binding partner of KPNA2, linking the adaptor to V(D)J recombination machinery before its general import role was defined.","evidence":"Yeast two-hybrid and dominant-negative truncation with a V(D)J recombination reporter in HeLa cells","pmids":["8016130"],"confidence":"Medium","gaps":["Did not demonstrate NLS-dependent nuclear import of RAG-1","No reconstitution with importin-beta"]},{"year":1997,"claim":"Showed KPNA2 binds NLS-bearing cargo including a viral T antigen NLS and the EBNA-1 antigen, framing it as a classical NLS-recognition adaptor.","evidence":"GST pull-down, yeast one/two-hybrid, CoIP from nuclear extracts, and EBNA-1 NLS point-mutant analysis","pmids":["9168958","9434725"],"confidence":"High","gaps":["Cargo set limited to a few proteins","Import directionality not reconstituted in vitro"]},{"year":2005,"claim":"Defined cargo specificity as a core feature by showing KPNA2 is the unique importin-alpha for NBS1, coupling import to DNA damage response function.","evidence":"Importin-alpha subfamily specificity mapping, NBS1 NLS mutagenesis, dominant-negative inhibition, and DSB repair/focus formation assays","pmids":["16188882"],"confidence":"High","gaps":["Did not address redundancy under stress conditions","Structural basis of NBS1 NLS preference unresolved"]},{"year":2004,"claim":"Demonstrated cargo selectivity again with TBP-2, where KPNA2 but not related importin-alphas mediated stimulus-induced nuclear accumulation.","evidence":"Yeast two-hybrid, GST pull-down, and siRNA knockdown with nuclear fractionation","pmids":["15234975"],"confidence":"High","gaps":["NLS within TBP-2 not finely mapped"]},{"year":2013,"claim":"Connected KPNA2 to oncogenic transcriptional programs by establishing E2F1 and Oct4 as cargo and linking their import to cell-cycle and stemness control.","evidence":"CoIP, immunofluorescence co-localization, in vitro binding, and SILAC nuclear proteomics after knockdown in cancer cells","pmids":["22843992","24070213","23907459"],"confidence":"High","gaps":["Pathway readouts (c-Myc/Akt/FOXO3a) inferred from KD/OE, not all from direct binding","Causal ordering of import vs. transcriptional output not fully separated"]},{"year":2019,"claim":"Established a transcription-import feedback circuit in which E2F1/DP1 activates KPNA2 expression and KPNA2 imports E2F1/E2F7, with E2F7 acting as competitive antagonist.","evidence":"Promoter reporter, ChIP, E2F domain mutagenesis, and nuclear fractionation after knockdown","pmids":["30254209","30115078"],"confidence":"Medium","gaps":["Feedback loop quantitation absent","Tissue contexts beyond cancer cells untested"]},{"year":2020,"claim":"Defined post-translational control of KPNA2 stability, showing deubiquitinases (USP1, USP22) stabilize it while chaperone-mediated autophagy (Gln109 motif) degrades it, coupling adaptor abundance to immune and antiviral outcomes.","evidence":"Ubiquitination assays, USP22 conditional KO with KPNA2 reconstitution, CMA motif and LAMP2A mutagenesis, and viral challenge","pmids":["30531833","32130408","32924767"],"confidence":"High","gaps":["Relative contribution of each degradation route in normal physiology unclear","Signals selecting KPNA2 for CMA vs. proteasome not defined"]},{"year":2022,"claim":"Expanded the regulatory network to mRNA-level (m6A/RBM15) and additional E3 ligase (FBXW7) control of KPNA2, and broadened cargo to inflammatory and angiogenic signaling effectors.","evidence":"MeRIP, dual-luciferase, FBXW7 ubiquitination assay, IP-MS/CoIP, and in vivo inflammation/ischemia models","pmids":["39488447","37432596","36578083","29777028"],"confidence":"Medium","gaps":["Some signaling effects shown by fractionation without direct NLS mapping","Cross-talk between mRNA stabilization and protein turnover not integrated"]},{"year":2023,"claim":"Provided in vivo physiological proof of function: Kpna2 is required for nuclear import of spermatid transcription factors and for male fertility.","evidence":"Kpna2 knockout mice with spermatid transcription-factor localization analysis, RNA-seq, and sperm function assays","pmids":["37456838"],"confidence":"Medium","gaps":["Specific cargo transcription factors not individually identified","Whether infertility reflects loss of a single key cargo or many is unresolved"]},{"year":2024,"claim":"Extended KPNA2 function into RNA regulation, showing it imports YBX1 to drive nonsense-mediated decay and alternative splicing of DDX3X.","evidence":"CoIP, nuclear fractionation after knockdown, and RNA-seq/splicing analysis in osteosarcoma","pmids":["40216969"],"confidence":"Medium","gaps":["YBX1 NLS recognition by KPNA2 not mapped","Generality of the splicing effect beyond osteosarcoma untested"]},{"year":2024,"claim":"Clarified the dual host/restriction role of KPNA2 in infection, showing it can import viral proteins yet also degrade them, and that viruses degrade KPNA2 to escape import-dependent antiviral signaling.","evidence":"CoIP with viral capsid/E/N proteins, domain mapping, lysosomal-pathway rescue, and viral yield assays for HIV-1, PEDV, PDCoV, and ZIKV","pmids":["35301060","38038431","38829137","32924767"],"confidence":"Medium","gaps":["Determinants of whether KPNA2 imports vs. degrades a viral cargo are unknown","In vivo relevance of restriction activity not established for all viruses"]},{"year":null,"claim":"It remains unresolved what structural and sequence features dictate KPNA2's strong cargo selectivity over other importin-alpha paralogs, and how its many regulatory inputs (transcription, m6A, deubiquitination, FBXW7, CMA) are integrated to set adaptor abundance in a given cell state.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining NLS preference in the corpus","No quantitative integration of competing stability pathways","Cargo prioritization when adaptor is limiting is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[7,9,33]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,7,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,15]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,9,22,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[20,22,31,36]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[24,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,33,38,39]}],"complexes":[],"partners":["NBS1","E2F1","STAT3","RELA","IRF3","YBX1","CBX8","KPNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52292","full_name":"Importin subunit alpha-1","aliases":["Karyopherin subunit alpha-2","RAG cohort protein 1","SRP1-alpha"],"length_aa":529,"mass_kda":57.9,"function":"Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1 (PubMed:28991411, PubMed:32130408, PubMed:7604027, PubMed:7754385). Binds specifically and directly to substrates containing either a simple or bipartite NLS motif (PubMed:28991411, PubMed:32130408, PubMed:7604027, PubMed:7754385). 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:7604027, PubMed:7754385). 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. Mediator of PR-DUB complex component BAP1 nuclear import; acts redundantly with KPNA1 and Transportin-1/TNPO1 (PubMed:35446349)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/P52292/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KPNA2","classification":"Not Classified","n_dependent_lines":304,"n_total_lines":1208,"dependency_fraction":0.25165562913907286},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000182481","cell_line_id":"CID001559","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nuclear_membrane","grade":3},{"compartment":"big_aggregates","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"HNRNPU","stoichiometry":10.0},{"gene":"KPNB1","stoichiometry":10.0},{"gene":"NOP58","stoichiometry":10.0},{"gene":"HDAC1","stoichiometry":4.0},{"gene":"SMARCE1","stoichiometry":4.0},{"gene":"NUP50","stoichiometry":4.0},{"gene":"POLR2F","stoichiometry":4.0},{"gene":"ANKRD54","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CBX1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001559","total_profiled":1310},"omim":[{"mim_id":"620319","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 17; OZEMA17","url":"https://www.omim.org/entry/620319"},{"mim_id":"615874","title":"RIBOSOMAL L1 DOMAIN-CONTAINING PROTEIN 1; RSL1D1","url":"https://www.omim.org/entry/615874"},{"mim_id":"614107","title":"KARYOPHERIN ALPHA-7; KPNA7","url":"https://www.omim.org/entry/614107"},{"mim_id":"612116","title":"UBIQUITIN-SPECIFIC PROTEASE 22; USP22","url":"https://www.omim.org/entry/612116"},{"mim_id":"611352","title":"INTEGRATOR COMPLEX SUBUNIT 9; INTS9","url":"https://www.omim.org/entry/611352"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":195.6}],"url":"https://www.proteinatlas.org/search/KPNA2"},"hgnc":{"alias_symbol":["SRP1alpha","IPOA1","QIP2","PTAC58"],"prev_symbol":["RCH1"]},"alphafold":{"accession":"P52292","domains":[{"cath_id":"1.25.10.10","chopping":"79-193","consensus_level":"medium","plddt":95.7228,"start":79,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52292","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52292-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52292-F1-predicted_aligned_error_v6.png","plddt_mean":86.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KPNA2","jax_strain_url":"https://www.jax.org/strain/search?query=KPNA2"},"sequence":{"accession":"P52292","fasta_url":"https://rest.uniprot.org/uniprotkb/P52292.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52292/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52292"}},"corpus_meta":[{"pmid":"8016130","id":"PMC_8016130","title":"Rch1, 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    \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional cell-based assay, single lab\",\n      \"pmids\": [\"8016130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA2 (Rch1) and the related importin-alpha Qip1 both physically interact with DNA helicase Q1/RecQL (but not hSrp1), as demonstrated by GST pull-down from cell lysates and confirmed by yeast two-hybrid. KPNA2 also binds the SV40 T antigen NLS in two-hybrid assays.\",\n      \"method\": \"GST pull-down from human cell lysates; yeast two-hybrid\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal GST pull-down and two-hybrid confirmation, single lab\",\n      \"pmids\": [\"9168958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA2 (Rch1/hSRP1α) physically interacts with EBV nuclear antigen-1 (EBNA1) when bound to oriP in vivo; interaction confirmed by coimmunoprecipitation from nuclear extracts and direct in vitro binding of recombinant proteins. Mutations in the EBNA1 NLS reduced Rch1 binding.\",\n      \"method\": \"Yeast one-hybrid assay; coimmunoprecipitation from nuclear extracts; in vitro direct binding assay with recombinant proteins; NLS point-mutant analysis\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro reconstitution, CoIP, mutational analysis) in single study, replicated concept by later paper (PMID:10612665)\",\n      \"pmids\": [\"9434725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KPNA2 (karyopherin alpha2/hRch1) interacts with EBNA-1 proteins endogenous in B cells, confirmed by coimmunoprecipitation and GST-fusion pull-down. An additional karyopherin alpha1 was also shown to bind EBNA-1, establishing two distinct karyopherin alpha proteins for EBNA-1 nuclear transport.\",\n      \"method\": \"Yeast two-hybrid; GST pull-down; coimmunoprecipitation from B cell extracts\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CoIP and pull-down, single lab\",\n      \"pmids\": [\"10612665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KPNA2 (importin alpha1/Rch1) physically interacts with BSAP (Pax5) through a defined NLS sequence (NKRKRDE, amino acids 195–201 in the central domain); the interaction was confirmed by GST pull-down in vitro and yeast two-hybrid, and the NLS is sufficient to confer nuclear localization to a GFP fusion protein.\",\n      \"method\": \"Yeast two-hybrid; GST pull-down; GFP-fusion nuclear localization assay; NLS deletion/mutation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vitro pull-down and cell-based localization with mutagenesis, single lab\",\n      \"pmids\": [\"10748034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KPNA2 (Rch1) is localized not only to the nuclear envelope/cytoplasm but also to the plasma membrane in lymphocytes and melanoma cells; upon lymphocyte activation with phytohemagglutinin, KPNA2 protein levels increase dramatically and it redistributes from cytoplasm to both plasma membrane and nuclear interior.\",\n      \"method\": \"Immunoelectron microscopy; Western blotting after lymphocyte activation\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy in two cell types, single lab\",\n      \"pmids\": [\"12883947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KPNA2 (importin alpha1/Rch1) physically interacts with TBP-2 (thioredoxin-binding protein-2) and mediates its nuclear translocation; the interaction is specific to KPNA2 among importin-alpha subfamilies tested (Qip1, NPI-1 did not interact), and siRNA knockdown of KPNA2 suppresses HDAC-inhibitor-induced nuclear accumulation of TBP-2.\",\n      \"method\": \"Yeast two-hybrid screening; GST pull-down; siRNA knockdown with nuclear fractionation/immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (two-hybrid, GST pull-down, siRNA + localization), subfamily specificity mapped, single lab\",\n      \"pmids\": [\"15234975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KPNA2 is the only importin-alpha family member that physically interacts with NBS1; it mediates normal nuclear localization of the MRE11-RAD50-NBS1 (MRN) complex by binding NLS residues 461–467 of NBS1. Inhibition of KPNA2 or blockage of KPNA2-NBS1 interaction reduces radiation-induced nuclear focus formation, DSB repair, and cell-cycle checkpoint signaling.\",\n      \"method\": \"Physical interaction mapping by importin-alpha subfamily specificity assay; NLS deletion/mutation analysis; KPNA2 inhibition with dominant-negative constructs; radiation-induced focus formation and DSB repair assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mapped NLS domain, demonstrated subfamily specificity, functional consequences of disruption by multiple assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16188882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KPNA2 physically binds IRF-1 (interferon regulatory factor-1) and mediates its nuclear translocation in normal human epidermal keratinocytes. IFN-γ downregulates KPNA2 expression at the promoter level, while TGF-β1 downregulates it post-transcriptionally. KPNA2 overexpression/knockdown alters epidermal gene expression programs including involucrin.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence nuclear translocation assay; promoter reporter analysis; microarray with KPNA2 knockdown/overexpression\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus functional nuclear translocation assay, single lab\",\n      \"pmids\": [\"17255955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KPNA2 knockdown causes subcellular redistribution of E2F1 in lung cancer cells; E2F1 is a cargo of KPNA2, demonstrated by co-immunoprecipitation, co-localization by immunofluorescence, and direct in vitro protein binding assay. Quantitative proteomics revealed multiple KPNA2-regulated proteins in the nuclear proteome.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence co-localization; in vitro protein binding assay; SILAC quantitative proteomics with subcellular fractionation after KPNA2 knockdown\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro binding plus CoIP plus localization shift upon KD, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22843992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KPNA2 overexpression promotes G1/S cell cycle transition in epithelial ovarian carcinoma cells by upregulating c-Myc transcriptional activity, activating Akt, suppressing FOXO3a, downregulating p21Cip1 and p27Kip1, and upregulating cyclin D1; knockdown reverses these effects.\",\n      \"method\": \"KPNA2 overexpression and shRNA knockdown in cancer cells; cell cycle analysis; Western blot for pathway components; in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway components by KD/OE with multiple readouts, single lab\",\n      \"pmids\": [\"23907459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KPNA2 physically interacts with Oct4 in lung cancer cell lines, as demonstrated by co-immunoprecipitation; knockdown of KPNA2 significantly reduces nuclear Oct4 protein levels and mRNA, establishing KPNA2 as a mediator of Oct4 nuclear import.\",\n      \"method\": \"Co-immunoprecipitation; nuclear/cytoplasmic fractionation; double immunofluorescence; siRNA knockdown with Western blot\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus localization shift upon KD, single lab\",\n      \"pmids\": [\"24070213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KPNA2 facilitates cytoplasmic localization of PER1/2 (period circadian proteins) during mouse ESC differentiation. Constitutive expression of Kpna2 during differentiation impairs circadian clock development and leads to sustained cytoplasmic accumulation of PER proteins.\",\n      \"method\": \"Constitutive expression of Kpna2 in differentiating ESCs; subcellular localization of PER1/2 by immunofluorescence; global gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined protein localization readout, single lab\",\n      \"pmids\": [\"25389311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KPNA2 physically interacts with p65 (NF-κB subunit) and promotes its nuclear translocation in IL-1β-stimulated chondrocytes; knockdown of KPNA2 reduces nuclear translocation of p65/p50 NF-κB complex and decreases expression of MMP13 and ADAMTS-5.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation with immunoblot; immunofluorescence; siRNA knockdown\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus fractionation and functional consequences, single lab\",\n      \"pmids\": [\"26209501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MIR517C degrades KPNA2 in glioblastoma cells and subsequently disrupts nuclear translocation of wild-type TP53, inhibiting autophagy and EMT. This effect was TP53-dependent (not seen in TP53-mutant cells), defining a MIR517C-KPNA2-cytoplasmic TP53 signaling pathway.\",\n      \"method\": \"MiRNA overexpression/knockdown; Western blot; immunofluorescence for TP53 nuclear translocation; TP53 wild-type vs mutant cell comparison; in vivo xenograft\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis with TP53 status, defined localization readout, single lab\",\n      \"pmids\": [\"26553592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KPNA2 is localized to the cell surface in cancer cell lines and is secreted into conditioned medium; cell-surface KPNA2 associates with heparan sulfate and directly binds FGF1 and FGF2 (cNLS-containing growth factors), enhancing ERK1/2 activation in FGF1-stimulated cells; anti-KPNA2 antibody suppresses this FGF1-KPNA2 complex formation, ERK1/2 activation, and cell growth.\",\n      \"method\": \"Cell surface biotinylation; conditioned medium analysis; direct binding assay; co-immunoprecipitation; ERK1/2 phosphorylation assay; antibody blocking experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus functional rescue/blockade experiments, single lab\",\n      \"pmids\": [\"26887791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"mTOR activity positively regulates KPNA2 protein and mRNA levels in NSCLC cells; mTOR inhibition induces proteasomal degradation of KPNA2 and decreases Dp1/E2F1-driven KPNA2 transcription; KPNA2 physically associates with phospho-mTOR/mTOR by co-immunoprecipitation and this association is abolished by rapamycin.\",\n      \"method\": \"mTOR inhibitors and siRNA knockdown; proteasome inhibitor rescue; KPNA2 mRNA and protein quantification; co-immunoprecipitation of KPNA2 with mTOR\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus multiple pharmacological interventions, single lab\",\n      \"pmids\": [\"27009856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP1 deubiquitinates and stabilizes KPNA2 protein; pharmacological or genetic inhibition of USP1 destabilizes KPNA2 and suppresses breast cancer metastasis. KPNA2 stabilization is the downstream effector of USP1's pro-metastatic function.\",\n      \"method\": \"USP1 overexpression/inhibition; ubiquitination assay; Western blot; in vivo lung metastasis model; USP1 inhibitor (pimozide, ML323) treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with defined deubiquitinase, functional in vivo rescue, single lab\",\n      \"pmids\": [\"30531833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KPNA2 aberrant expression changes subcellular distribution and expression levels of c-Myc; E2F1 is a cargo protein of KPNA2 and mediates KPNA2-dependent c-Myc transcriptional upregulation, linking KPNA2 to metabolic reprogramming (glycolysis) in glioblastoma. Co-IP and subcellular fractionation confirmed KPNA2-c-Myc and KPNA2-E2F1 interactions.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation; Western blot; immunofluorescence; luciferase assay; glycolysis assays; KPNA2 knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus fractionation and functional metabolic readouts, single lab\",\n      \"pmids\": [\"30115078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E2F1 (bound to DP1) activates KPNA2 transcription by binding the KPNA2 promoter; atypical E2F7 competes with DP1 and blocks E2F1-induced KPNA2 gene activation. KPNA2 in turn mediates nuclear localization of E2F1 and E2F7, creating a feedback loop. Mutation of E2F7 dimerization residues or E2F1 DNA-binding domain abolishes this regulation.\",\n      \"method\": \"Promoter reporter assay; ChIP; mutagenesis of E2F domains; nuclear fractionation after KPNA2 knockdown; co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP and promoter mutagenesis establish transcriptional regulation; fractionation links KPNA2 to nuclear import of E2F1/E2F7, single lab\",\n      \"pmids\": [\"30254209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NLRP3 physically interacts with KPNA2 and translocates to the nucleus via KPNA2 under Treg-polarizing conditions; NLRP3-mediated suppression of Foxp3 expression and Treg differentiation is dependent on its interaction with KPNA2 and is independent of inflammasome activation.\",\n      \"method\": \"Co-immunoprecipitation; nuclear fractionation; NLRP3-deficient mice; NLRP3 overexpression in T cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus loss-of-function mouse model and gain-of-function, single lab\",\n      \"pmids\": [\"31597697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KPNA2 overexpression promotes EOC cell migration and invasion via activation of the Akt/GSK-3β/Snail signaling pathway and induction of EMT; knockdown of KPNA2 suppresses these effects.\",\n      \"method\": \"Stable overexpression and shRNA knockdown; migration/invasion assays; Western blot for Akt/GSK-3β/Snail pathway components; immunofluorescence\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation shown by Western blot after KD/OE, no direct binding to pathway components demonstrated, single lab\",\n      \"pmids\": [\"29290781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP22 deubiquitinates and stabilizes KPNA2 after viral infection, facilitating efficient nuclear translocation of IRF3; USP22 knockout impairs IRF3 nuclear translocation and type I IFN expression after viral infection; reconstitution of KPNA2 into USP22-knockout cells restores virus-triggered IRF3 nuclear translocation.\",\n      \"method\": \"USP22 knockout (Cre-ER and Lyz2-Cre conditional mouse models); KPNA2 reconstitution in KO cells; ubiquitination assay; nuclear fractionation for IRF3; viral challenge in vivo\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO in vivo, ubiquitination assay, reconstitution rescue, and in vivo viral challenge, multiple orthogonal methods\",\n      \"pmids\": [\"32130408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KPNA2 physically associates with JNK1/JNK2 and p38 MAP kinases and promotes their nuclear translocation in EV71-infected cells; the miR-302 cluster targets KPNA2 to downregulate this nuclear translocation and dampen EV71-induced cytokine expression.\",\n      \"method\": \"Intracellular co-immunoprecipitation; miR-302 knockdown/overexpression; nuclear fractionation; cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP of KPNA2 with kinases plus nuclear fractionation, single lab\",\n      \"pmids\": [\"29777028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KPNA2 is degraded via chaperone-mediated autophagy (CMA); a CMA motif containing indispensable residue Gln109 is required for this degradation. Zika virus NS2A protein (via its Thr100 residue) enhances KPNA2 CMA-mediated degradation; LAMP2A knockdown elevates KPNA2 levels; KPNA2 knockdown increases ZIKV yield, indicating an antiviral role.\",\n      \"method\": \"CMA motif mutagenesis (Q109 mutation); LAMP2A siRNA knockdown; ZIKV NS2A mutant (T100A) virus construction; viral yield quantification; Western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of both KPNA2 CMA motif and viral protein combined with genetic manipulation of CMA pathway component, multiple mechanistic interventions, single lab\",\n      \"pmids\": [\"32924767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA2 promotes nuclear import of CBX8; CBX8, once nuclear, recruits BCOR to the PRDM1 promoter to downregulate PRDM1, which in turn reduces c-FOS expression and promotes bladder cancer progression. KPNA2-CBX8 interaction confirmed by co-immunoprecipitation; CBX8 promoter binding confirmed by chromatin immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; nuclear fractionation after KPNA2 knockdown; rescue experiments; xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP and ChIP establish molecular interactions, nuclear import shown by fractionation, single lab\",\n      \"pmids\": [\"33731128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA2 modulates PD-L1 expression in pancreatic ductal adenocarcinoma by mediating nuclear translocation of STAT3; KPNA2 knockdown reduces nuclear STAT3 levels and suppresses PD-L1 expression in vivo.\",\n      \"method\": \"KPNA2 siRNA knockdown; nuclear/cytoplasmic fractionation for STAT3; Western blot for PD-L1; in vivo xenograft\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — fractionation without direct binding assay, single lab, single method for mechanism\",\n      \"pmids\": [\"33728352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CENPA recruits histone acetyltransferase GCN-5 to the KPNA2 promoter via H3K27ac modification to activate KPNA2 transcription in colon cancer cells; overexpression of CENPA or GCN-5 rescues KPNA2 shRNA-mediated growth and glycolysis inhibition.\",\n      \"method\": \"ChIP assay for H3K27ac and GCN-5 at KPNA2 promoter; co-immunoprecipitation of CENPA with GCN-5; rescue experiments by CENPA/GCN-5 overexpression\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and CoIP define transcriptional mechanism, functional rescue confirms pathway, single lab\",\n      \"pmids\": [\"34508688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA2 physically interacts with NPM (nucleophosmin) in renal cell carcinoma; NPM overexpression attenuates the growth-suppressive effects of KPNA2 knockdown, establishing NPM as a functional downstream effector of KPNA2.\",\n      \"method\": \"Co-IP/MS to identify interaction; bioinformatics; rescue by NPM overexpression after KPNA2 knockdown\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP/MS plus rescue experiment, single lab, limited mechanistic detail\",\n      \"pmids\": [\"34469024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMARCC1 is transported into the nucleus via KPNA2 (and nucleoporins Nup50/Nup153); knockdown of KPNA2 increases cytoplasmic SMARCC1 and decreases nuclear SMARCC1, shown by Co-IP and immunofluorescence.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; nuclear fractionation after KPNA2, Nup50, and Nup153 knockdown\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus fractionation with specific KD of multiple transport components, single lab\",\n      \"pmids\": [\"35669562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNA2 promotes STAT3 phosphorylation by promoting STAT3-JAK1 binding under hypoxia, enhancing angiogenesis and upregulating VEGF/ANGPT2; hypoxia promotes STAT3-KPNA2 binding as detected by IP-MS and Co-IP.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (IP-MS); co-immunoprecipitation; Western blot for STAT3 phosphorylation; KPNA2 OE/KO in HUVEC and in murine hindlimb ischemia model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus CoIP plus in vivo functional model, single lab\",\n      \"pmids\": [\"36578083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNA2 physically interacts with p65 and IRF3; KPNA2 knockdown blocks nuclear translocation of p65 and IRF3, reducing LPS-induced pro-inflammatory cytokine secretion in endothelial cells; FBXW7 E3 ubiquitin ligase ubiquitinates and promotes proteasomal degradation of KPNA2.\",\n      \"method\": \"Co-immunoprecipitation; nuclear fractionation; siRNA knockdown; FBXW7 overexpression with ubiquitination assay; ApoE-/- mouse atherosclerosis model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus ubiquitination assay plus in vivo model, single lab\",\n      \"pmids\": [\"37432596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM15 stabilizes KPNA2 mRNA via m6A methylation, promoting breast cancer cell proliferation and immune escape; interaction between RBM15 and KPNA2 mRNA confirmed by MeRIP and dual-luciferase assay.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP); dual-luciferase reporter assay; RBM15 siRNA knockdown; Western blot; in vivo xenograft\",\n      \"journal\": \"Clinical breast cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP confirms m6A modification on KPNA2 mRNA, multiple assays, single lab\",\n      \"pmids\": [\"39488447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNA2 mediates nuclear import of HIV-1 pre-integration complex (PIC) by interacting with the N-terminal of the capsid protein p24; KPNA2 knockdown reduces HIV-1 replication; disruption of capsid-KPNA2 binding impairs PIC nuclear import; KPNB1 participates in KPNA2-mediated PIC nuclear import.\",\n      \"method\": \"siRNA knockdown; quantitative PCR for cDNA integration; co-immunoprecipitation of KPNA2 with p24; overexpression of full-length or N-terminal p24 as dominant negative\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP defines interaction domain, functional KD and DN rescue, single lab\",\n      \"pmids\": [\"35301060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kpna2 knockout male mice are infertile; loss of Kpna2 impairs translocation of testis-specific transcription factors to the nucleus of spermatid cells, dysregulates expression of genes related to cell adhesion and ECM organization in spermatocytes/spermatids, and causes sperm motility defects and abnormalities.\",\n      \"method\": \"Kpna2 knockout mice; nuclear localization analysis of transcription factors in spermatids; RNA-seq; sperm functional assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype and transcription factor localization readout, single lab\",\n      \"pmids\": [\"37456838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERK1 preferentially interacts with KPNA2 over ERK2; a cell-penetrating peptide (RB5) disrupts KPNA2-ERK1 interaction, facilitates ERK1/2 nuclear translocation, and enhances global ERK nuclear activity, conferring neuroprotection in mouse models of Huntington's, Alzheimer's, and Parkinson's disease.\",\n      \"method\": \"Co-immunoprecipitation of ERK1/2 with KPNA2; cell-penetrating peptide disruption assay; nuclear ERK activity measurement; multiple in vivo neurodegeneration mouse models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP defines preferential KPNA2-ERK1 interaction, functional disruption by peptide, replicated across multiple disease models in vivo, single lab\",\n      \"pmids\": [\"37792911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HBV-elevated HAT1 promotes KPNA2 expression via acetylation of H4K5 and H4K12, resulting in nuclear translocation of cGAS and suppression of cGAS-STING/IFN-I signaling as a mechanism of innate immune evasion.\",\n      \"method\": \"HAT1 knockout mouse model; ChIP for H4K5ac and H4K12ac at KPNA2 promoter; nuclear fractionation for cGAS; ELISA for IFN-I; cell line experiments\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP defines epigenetic regulation plus localization consequence, in vivo KO model, single lab\",\n      \"pmids\": [\"37466313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KPNA2 transports splicing factor YBX1 into the nucleus; nuclear YBX1 then promotes nonsense-mediated decay of DDX3X mRNA to reduce DDX3X protein, regulating alternative splicing (intron retention of DDX3X) and cell cycle progression in osteosarcoma.\",\n      \"method\": \"Nuclear fractionation after KPNA2 KD; co-immunoprecipitation of KPNA2 with YBX1; RNA-seq/AS analysis; DDX3X NMD pathway analysis; KPNA2 loss-of-function osteosarcoma model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus fractionation plus RNA-seq with defined splicing mechanism, single lab\",\n      \"pmids\": [\"40216969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KPNA2 promotes nuclear import of PEDV envelope (E) protein; KPNA2 also degrades PEDV E protein via selective autophagy to suppress PEDV replication. KPNA2 overexpression inhibits PEDV replication; knockdown enhances it.\",\n      \"method\": \"Co-immunoprecipitation of KPNA2 with PEDV E protein; KPNA2 KD/OE in Vero and IEC cells; viral yield quantification; autophagy pathway analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP defines interaction, functional gain/loss-of-function with viral readouts, single lab\",\n      \"pmids\": [\"38038431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDCoV nucleocapsid (N) protein inhibits STAT1 nuclear translocation by targeting KPNA2 for degradation through the lysosomal pathway via the N protein's C-terminal domain; N protein interacts directly with STAT1 and KPNA2 is required for STAT1 nuclear import.\",\n      \"method\": \"Co-immunoprecipitation of N protein with STAT1 and KPNA2; lysosomal inhibitor rescue; nuclear fractionation for STAT1; domain deletion analysis of N protein\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus lysosomal pathway rescue plus domain mapping, single lab\",\n      \"pmids\": [\"38829137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H2B lysine lactylation (H2BK16la), modulated by the LDHA-lactate axis, activates NF-κB p65 nuclear translocation via KPNA2, inducing type III IFN expression and inhibiting CSFV replication; H2B interacts with CSFV NS4A protein; KPNA2 mediates p65 nuclear transport in this context.\",\n      \"method\": \"Immunoprecipitation for H2B-Kla; H2B K16R mutant plasmid; LDHA siRNA/lactate modulation; nuclear fractionation for p65; KPNA2 involvement assessed by co-immunoprecipitation; CSFV replication assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic chain established by multiple assays but each step has limited validation, single lab, preprint not indicated but recent publication\",\n      \"pmids\": [\"39826749\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KPNA2 is a classical importin-alpha nuclear transport adaptor that directly binds nuclear localization signals (NLS) on diverse cargo proteins—including NBS1, E2F1, Oct4, IRF-1, IRF3, p65, STAT1, STAT3, NLRP3, SMARCC1, CBX8, YBX1, PER1/2, JNK1/2, p38, ERK1, RAG-1, EBNA-1, and viral capsid proteins—and escorts them into the nucleus via interaction with importin-beta; its stability is regulated post-translationally by deubiquitinases USP1 and USP22 (which stabilize it) and by E3 ligase FBXW7 (which targets it for proteasomal degradation) and by chaperone-mediated autophagy (via a CMA motif requiring Gln109); its transcription is activated by E2F1/DP1 and CENPA/GCN-5, and repressed by IRF1 and E2F7; at the cell surface, KPNA2 binds heparan sulfate and FGF1/2 to potentiate ERK signaling; in the nucleus, KPNA2 transports splicing factor YBX1 to regulate alternative splicing; and loss of KPNA2 in male mice causes infertility by blocking nuclear import of spermatid-specific transcription factors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KPNA2 is a classical importin-alpha nuclear transport adaptor that recognizes nuclear localization signals (NLS) on cargo proteins and, via importin-beta, escorts them through the nuclear pore [#7, #33]. Cargo specificity is a defining property: KPNA2 is the only importin-alpha family member that binds the NBS1 NLS (residues 461\\u2013467) to import the MRE11-RAD50-NBS1 complex and support radiation-induced focus formation, DSB repair, and checkpoint signaling [#7], and it shows comparable subfamily-restricted recognition of TBP-2 [#6] and the Pax5/BSAP NLS [#4]. Its cargo repertoire spans transcription and replication regulators (E2F1, Oct4, c-Myc, SMARCC1, CBX8, YBX1), signaling effectors (NF-\\u03baB p65, IRF-1, IRF3, STAT1, STAT3, the MAP kinases JNK1/2, p38 and ERK1, NLRP3), and circadian PER proteins, with knockdown shifting each cargo's nuclear/cytoplasmic distribution [#9, #11, #13, #20, #22, #25, #29, #31, #35, #37]. Through these import events KPNA2 drives proliferative and oncogenic programs\\u2014promoting G1/S transition via c-Myc/Akt/FOXO3a and EMT, and feeding into glycolytic metabolic reprogramming [#10, #18]\\u2014and shapes immune and inflammatory output by controlling nuclear delivery of NF-\\u03baB and interferon regulatory factors [#22, #31]. KPNA2 abundance is tightly controlled: deubiquitinases USP1 and USP22 stabilize it, the E3 ligase FBXW7 targets it for proteasomal degradation, and a CMA motif requiring Gln109 routes it to chaperone-mediated autophagy [#17, #22, #24, #31], while its transcription is activated by E2F1/DP1 and CENPA/GCN-5 and antagonized by E2F7 [#19, #27]. In viral infection KPNA2 acts as both a host import factor co-opted by pathogens (HIV-1 capsid, EBNA-1) and an antiviral restriction factor that imports and degrades viral proteins, and multiple viruses counter it by driving its degradation [#2, #24, #33, #38, #39]. At the cell surface KPNA2 binds heparan sulfate and FGF1/FGF2 to potentiate ERK1/2 signaling [#15]. Loss of Kpna2 in male mice causes infertility through failed nuclear import of testis-specific transcription factors in spermatids [#34].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the first physiological binding partner of KPNA2, linking the adaptor to V(D)J recombination machinery before its general import role was defined.\",\n      \"evidence\": \"Yeast two-hybrid and dominant-negative truncation with a V(D)J recombination reporter in HeLa cells\",\n      \"pmids\": [\"8016130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not demonstrate NLS-dependent nuclear import of RAG-1\", \"No reconstitution with importin-beta\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed KPNA2 binds NLS-bearing cargo including a viral T antigen NLS and the EBNA-1 antigen, framing it as a classical NLS-recognition adaptor.\",\n      \"evidence\": \"GST pull-down, yeast one/two-hybrid, CoIP from nuclear extracts, and EBNA-1 NLS point-mutant analysis\",\n      \"pmids\": [\"9168958\", \"9434725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo set limited to a few proteins\", \"Import directionality not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined cargo specificity as a core feature by showing KPNA2 is the unique importin-alpha for NBS1, coupling import to DNA damage response function.\",\n      \"evidence\": \"Importin-alpha subfamily specificity mapping, NBS1 NLS mutagenesis, dominant-negative inhibition, and DSB repair/focus formation assays\",\n      \"pmids\": [\"16188882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address redundancy under stress conditions\", \"Structural basis of NBS1 NLS preference unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated cargo selectivity again with TBP-2, where KPNA2 but not related importin-alphas mediated stimulus-induced nuclear accumulation.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and siRNA knockdown with nuclear fractionation\",\n      \"pmids\": [\"15234975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NLS within TBP-2 not finely mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected KPNA2 to oncogenic transcriptional programs by establishing E2F1 and Oct4 as cargo and linking their import to cell-cycle and stemness control.\",\n      \"evidence\": \"CoIP, immunofluorescence co-localization, in vitro binding, and SILAC nuclear proteomics after knockdown in cancer cells\",\n      \"pmids\": [\"22843992\", \"24070213\", \"23907459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pathway readouts (c-Myc/Akt/FOXO3a) inferred from KD/OE, not all from direct binding\", \"Causal ordering of import vs. transcriptional output not fully separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a transcription-import feedback circuit in which E2F1/DP1 activates KPNA2 expression and KPNA2 imports E2F1/E2F7, with E2F7 acting as competitive antagonist.\",\n      \"evidence\": \"Promoter reporter, ChIP, E2F domain mutagenesis, and nuclear fractionation after knockdown\",\n      \"pmids\": [\"30254209\", \"30115078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Feedback loop quantitation absent\", \"Tissue contexts beyond cancer cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined post-translational control of KPNA2 stability, showing deubiquitinases (USP1, USP22) stabilize it while chaperone-mediated autophagy (Gln109 motif) degrades it, coupling adaptor abundance to immune and antiviral outcomes.\",\n      \"evidence\": \"Ubiquitination assays, USP22 conditional KO with KPNA2 reconstitution, CMA motif and LAMP2A mutagenesis, and viral challenge\",\n      \"pmids\": [\"30531833\", \"32130408\", \"32924767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each degradation route in normal physiology unclear\", \"Signals selecting KPNA2 for CMA vs. proteasome not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the regulatory network to mRNA-level (m6A/RBM15) and additional E3 ligase (FBXW7) control of KPNA2, and broadened cargo to inflammatory and angiogenic signaling effectors.\",\n      \"evidence\": \"MeRIP, dual-luciferase, FBXW7 ubiquitination assay, IP-MS/CoIP, and in vivo inflammation/ischemia models\",\n      \"pmids\": [\"39488447\", \"37432596\", \"36578083\", \"29777028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some signaling effects shown by fractionation without direct NLS mapping\", \"Cross-talk between mRNA stabilization and protein turnover not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided in vivo physiological proof of function: Kpna2 is required for nuclear import of spermatid transcription factors and for male fertility.\",\n      \"evidence\": \"Kpna2 knockout mice with spermatid transcription-factor localization analysis, RNA-seq, and sperm function assays\",\n      \"pmids\": [\"37456838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargo transcription factors not individually identified\", \"Whether infertility reflects loss of a single key cargo or many is unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended KPNA2 function into RNA regulation, showing it imports YBX1 to drive nonsense-mediated decay and alternative splicing of DDX3X.\",\n      \"evidence\": \"CoIP, nuclear fractionation after knockdown, and RNA-seq/splicing analysis in osteosarcoma\",\n      \"pmids\": [\"40216969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"YBX1 NLS recognition by KPNA2 not mapped\", \"Generality of the splicing effect beyond osteosarcoma untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Clarified the dual host/restriction role of KPNA2 in infection, showing it can import viral proteins yet also degrade them, and that viruses degrade KPNA2 to escape import-dependent antiviral signaling.\",\n      \"evidence\": \"CoIP with viral capsid/E/N proteins, domain mapping, lysosomal-pathway rescue, and viral yield assays for HIV-1, PEDV, PDCoV, and ZIKV\",\n      \"pmids\": [\"35301060\", \"38038431\", \"38829137\", \"32924767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of whether KPNA2 imports vs. degrades a viral cargo are unknown\", \"In vivo relevance of restriction activity not established for all viruses\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what structural and sequence features dictate KPNA2's strong cargo selectivity over other importin-alpha paralogs, and how its many regulatory inputs (transcription, m6A, deubiquitination, FBXW7, CMA) are integrated to set adaptor abundance in a given cell state.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining NLS preference in the corpus\", \"No quantitative integration of competing stability pathways\", \"Cargo prioritization when adaptor is limiting is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [7, 9, 33]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 7, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 9, 22, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20, 22, 31, 36]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [24, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 33, 38, 39]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NBS1\", \"E2F1\", \"STAT3\", \"RELA\", \"IRF3\", \"YBX1\", \"CBX8\", \"KPNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}