{"gene":"KPNB1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2013,"finding":"KPNB1 is the major importin β receptor mediating NF-κB/p65 nuclear import in a NLS-dependent manner following TNF-α stimulation, acting via the canonical KPNA2/KPNB1 pathway; siRNA knockdown of KPNB1 reduced nuclear p65 and decreased NF-κB transcriptional activity.","method":"High-content siRNA screening of 17 importin β family members, followed by nuclear fractionation and reporter assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic siRNA screen across importin family plus mechanistic NLS-dependence validation, independently replicated in follow-up studies","pmids":["23906023"],"is_preprint":false},{"year":2015,"finding":"KPNB1 mediates nuclear translocation of PER proteins (and the PER/CRY repressor complex) in a circadian fashion and independently of importin α, thereby enabling negative feedback regulation of the mammalian circadian clock; RNAi depletion of KPNB1 traps PER/CRY in the cytoplasm and disrupts clock function.","method":"RNAi knockdown in human cells with cytoplasmic/nuclear fractionation and co-immunoprecipitation; inducible inhibition of Drosophila importin β in lateral neurons abolished behavioral rhythms","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi in human cells with defined molecular phenotype, cross-species validation in Drosophila","pmids":["26319354"],"is_preprint":false},{"year":2014,"finding":"EZH2 epigenetically suppresses miR-30d transcription, which relieves repression of KPNB1 (miR-30d targets KPNB1 3′ UTR), resulting in elevated KPNB1 that promotes MPNST cell survival; forced KPNB1 overexpression rescues apoptosis induced by EZH2 knockdown, placing KPNB1 downstream of the EZH2-miR-30d axis.","method":"Genetic epistasis: EZH2 knockdown, miR-30d overexpression, KPNB1 overexpression rescue; 3′ UTR luciferase reporter assay; xenograft tumor model","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by rescue experiment, 3′ UTR reporter, in vitro and in vivo validation","pmids":["24132643"],"is_preprint":false},{"year":2015,"finding":"miR-30a also targets the KPNB1 3′ UTR in MPNST cells, contributing to EZH2/miR-30a,d/KPNB1 signaling axis; pharmacological EZH2 inhibition (DZNep) downregulates KPNB1 protein and suppresses tumor growth.","method":"3′ UTR luciferase reporter assay; Western blot; xenograft mouse model with IHC","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3′ UTR reporter plus in vivo validation, single lab","pmids":["25890085"],"is_preprint":false},{"year":2017,"finding":"KPNB1 acts as a master regulator of cell cycle-related proteins (including p21, p27, and APC/C); genetic and pharmacological inhibition of KPNB1 causes multiphase cell cycle arrest and apoptosis induction in epithelial ovarian cancer cells in vitro and in vivo.","method":"shRNA dropout screen in xenografts, CRISPR/Cas9 genome-wide screen, pharmacological inhibition, proteomics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal genome-scale screens (shRNA and CRISPR/Cas9) with proteomics validation","pmids":["28811376"],"is_preprint":false},{"year":2017,"finding":"KPNB1 is required for translocation of NF-κB and AP-1 transcription factors into the nucleus in cervical cancer cells; siRNA or small-molecule inhibition of KPNB1 (INI-43) causes cytoplasmic retention of NF-κB and decreases AP-1 transcriptional activity, reducing expression of IL-6, IL-1β, TNF-α, and GM-CSF, and impairing cancer cell migration and invasion.","method":"siRNA knockdown; small-molecule inhibition with INI-43; nuclear fractionation; transcriptional reporter assays; Transwell migration/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal inhibition methods (siRNA + small molecule), multiple functional readouts, single lab","pmids":["28427184"],"is_preprint":false},{"year":2018,"finding":"KPNB1 inhibition in glioblastoma cells causes cytosolic retention of cargo proteins, elevated polyubiquitination, aggresome-like-induced structure (ALIS) formation, and unfolded protein response (UPR) activation; chronic UPR (eIF2α/ATF4 cascade) upregulates pro-apoptotic Bcl-2 family members Puma and Noxa, frees Bax/Bak from Mcl-1, and induces MOMP and apoptosis.","method":"siRNA knockdown; pharmacological inhibition; Western blot for ubiquitination and UPR markers; rescue by KPNB1 overexpression or protein synthesis inhibitors; combination with proteasome/autophagy inhibitors","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic + pharmacological) with mechanistic rescue experiments in single rigorous study","pmids":["29520102"],"is_preprint":false},{"year":2019,"finding":"KPNB1 inhibition in glioblastoma potentiates TRAIL-induced apoptosis via UPR-mediated ATF4 upregulation of DR5 and 4E-BP1 (suppressing cap-dependent translation of FLIPL/FLIPS), freeing Bax/Bak from Mcl-1, and promoting DISC assembly; KPNB1 inhibition-induced autophagy counteracts by degrading cleaved caspase-8.","method":"Genetic (siRNA) and pharmacological KPNB1 inhibition; caspase activity assays; Western blot for DISC components; autophagy flux inhibitors","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal inhibition methods with detailed mechanistic pathway dissection, single lab","pmids":["30742128"],"is_preprint":false},{"year":2019,"finding":"KPNB1 mediates nuclear import of E2F1 in CML cells; KPNB1 inhibition (siRNA or importazole) blocks E2F1 nuclear translocation, reduces c-Myc and KPNA2 expression downstream of E2F1, and induces G2/M arrest and apoptosis.","method":"siRNA knockdown; pharmacological inhibition (importazole); immunofluorescence for E2F1 localization; Western blot for E2F1 targets; flow cytometry","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal inhibition methods, direct localization evidence for E2F1 trafficking, single lab","pmids":["31819526"],"is_preprint":false},{"year":2020,"finding":"KPNB1 facilitates nuclear translocation of PD-L1 in NSCLC cells; nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, drives Gas6 mRNA synthesis and secretion, activating MerTK signaling to promote cancer cell proliferation.","method":"Co-immunoprecipitation (KPNB1-PD-L1 binding); nuclear fractionation; PD-L1 knockdown; ChIP for Sp1/nPD-L1 on Gas6 promoter; in vitro and in vivo proliferation assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus nuclear fractionation plus ChIP with in vivo validation, single lab","pmids":["33139930"],"is_preprint":false},{"year":2021,"finding":"KPNB1 mediates nuclear import of IRF1 following ionizing radiation; KPNB1 inhibitor importazole reduces both IRF1 protein upregulation and its nuclear localization, thereby attenuating radiation-increased PD-L1 surface expression on tumor cells.","method":"siRNA knockdown of IRF1; pharmacological KPNB1 inhibition (importazole); immunofluorescence and Western blot for IRF1 nuclear localization; flow cytometry for surface PD-L1","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal approaches (siRNA + pharmacological), direct localization imaging, single lab","pmids":["34069326"],"is_preprint":false},{"year":2022,"finding":"KPNB1 mediates nuclear import of NFAT5 via direct interaction with a unique NFAT5 nuclear localization signal (NFAT5-NLS), independently of karyopherin α; siRNA screening showed only KPNB1 (not karyopherin α) is required for tonicity-responsive NFAT5 nuclear import.","method":"siRNA screening of importin family; Co-IP; nuclear fractionation; NLS mutagenesis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic siRNA screen plus Co-IP with NLS validation, multiple orthogonal methods in one study","pmids":["35635291"],"is_preprint":false},{"year":2022,"finding":"KPNB1 directly interacts with both wild-type and polyQ-expanded ataxin-3 but modulating KPNB1 does not alter ataxin-3 intracellular localization; instead, KPNB1 overexpression reduces ataxin-3 protein levels and aggregate load via protein fragmentation dependent on mitochondrial protease CLPP, improving cell viability in MJD models.","method":"Co-immunoprecipitation; label-free quantitative proteomics; KPNB1 knockdown/overexpression; CLPP knockdown; MJD mouse model and iPSC analysis","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, proteomics, and genetic rescue with multiple model systems, single lab","pmids":["35794401"],"is_preprint":false},{"year":2022,"finding":"PCDH1 interacts with KPNB1 and enhances p65 nuclear localization, thereby activating NF-κB signaling to promote pancreatic ductal adenocarcinoma progression.","method":"Co-immunoprecipitation (PCDH1-KPNB1); nuclear fractionation of p65; NF-κB reporter assay; cell proliferation/invasion assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional readouts, single lab, mechanism partially indirect","pmids":["35864095"],"is_preprint":false},{"year":2024,"finding":"USP7 stabilizes KPNB1 through deubiquitination (K48-linked ubiquitination removal); KPNB1 mediates nuclear import of transcription factor YBX1, which then binds the NLGN3 promoter to drive NLGN3 expression and promote glioblastoma progression.","method":"Ubiquitination assays; Co-IP/mass spectrometry (KPNB1-YBX1 interaction); nuclear-cytoplasmic fractionation; immunofluorescence; ChIP for YBX1 on NLGN3 promoter; intracranial tumor model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ubiquitination assay, IP-MS, ChIP, fractionation) with in vivo validation in single rigorous study","pmids":["38254206"],"is_preprint":false},{"year":2024,"finding":"TMEM209 binds to KPNB1 and competitively blocks the interaction between KPNB1 and E3 ubiquitin ligase RCHY1, preventing K48-linked ubiquitination-dependent degradation of KPNB1; stabilized KPNB1 then activates the Wnt/β-catenin signaling pathway to promote hepatocellular carcinoma progression.","method":"Co-immunoprecipitation (TMEM209-KPNB1 and KPNB1-RCHY1); ubiquitination assays; Western blot; xenograft tumor model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay with competitive binding analysis, single lab","pmids":["39414762"],"is_preprint":false},{"year":2024,"finding":"KPNB1 specifically recognizes amino acids 280-299 within the NLS of transcription factor ATF4, mediating ATF4 nuclear import; nuclear ATF4 then binds the BNIP3 promoter (at approximately -1292 to -1279 bp and -1185 to -1172 bp) to drive BNIP3-dependent mitophagy and promote odontoblastic differentiation of dental pulp stem cells.","method":"IP-mass spectrometry (KPNB1-ATF4); NLS wild-type/mutant plasmid constructs; dual-luciferase reporter and ChIP for ATF4-BNIP3 promoter; nuclear fractionation; mitochondrial function assays; in vivo implantation model","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — IP-MS, NLS mutagenesis, ChIP with promoter mapping, and in vivo validation in one study","pmids":["39604846"],"is_preprint":false},{"year":2025,"finding":"KPNB1 directly transports VCP (valosin-containing protein) into the nucleus to support DNA damage repair; withaferin A (WA) covalently binds CYS 158 of KPNB1 to retard VCP nuclear localization and impair DDR.","method":"Chemical pulldown combined with immunoprecipitation-mass spectrometry; biochemical Co-IP; covalent binding site mapping (CYS 158 mutagenesis); in vivo xenograft DDR assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — chemical + IP-MS identification, active-site covalent binding with mutagenesis, in vivo validation in single rigorous study","pmids":["40339118"],"is_preprint":false},{"year":2025,"finding":"KPNB1 mediates nuclear import of HMGB2 in AML cells; KPNB1 inhibition impairs HMGB2 nuclear entry, leading to compromised DNA damage repair and sensitization of AML cells to venetoclax.","method":"Co-immunoprecipitation; nuclear fractionation; siRNA/importazole inhibition; xenograft AML mouse model; patient-derived cell viability assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus nuclear fractionation with functional rescue and in vivo validation, single lab","pmids":["40082556"],"is_preprint":false},{"year":2023,"finding":"RTEL1 interacts with KPNB1 through a distinct C-terminal domain (separate from its NUP153-binding domain), and this interaction connects protein nuclear import to nuclear envelope stability during S-phase; overexpression of the RTEL1 C-terminal domain protects against nuclear envelope anomalies caused by protein import inhibition.","method":"Co-immunoprecipitation; domain deletion/truncation mapping; high-resolution microscopy (KPNB1 localization at nuclear pore); nuclear envelope stability assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus functional nuclear envelope protection assay, single lab","pmids":["38132118"],"is_preprint":false},{"year":2020,"finding":"NLS-RARα is transported into the nucleus by binding to both KPNA2 (importin α1) and KPNB1 (importin β1); knockdown of KPNA2/KPNB1 inhibits nuclear accumulation of NLS-RARα, and nuclear NLS-RARα inhibits myeloid cell differentiation.","method":"Mass spectrometry of co-immunoprecipitated proteins; Co-IP validation; siRNA knockdown; nuclear/cytoplasmic fractionation; immunofluorescence","journal":"Xi bao yu fen zi mian yi xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus Co-IP validation with siRNA functional test, single lab","pmids":["32696739"],"is_preprint":false},{"year":2025,"finding":"KPNB1 is identified as a reader protein for O-GlcNAcylated RNA Polymerase II CTD (at Ser-5); OGT-mediated O-GlcNAcylation of RNA Pol II promotes its nuclear entry in a KPNB1-dependent manner, connecting metabolic state to global transcription regulation.","method":"WGA lectin pulldown combined with mass spectrometry (O-GlcNAcylated CTD interactome); structural modeling; ChIP (wChIP technique); siRNA/inhibitor functional assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based identification plus functional validation with two orthogonal methods, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"KPNA2/KPNB1 complex sequesters C9orf72 poly(proline-arginine) (polyPR) in the cytoplasm, protecting cells from polyPR nuclear toxicity; genetic silencing of KPNB1 converts PR20-resistant cells to sensitive cells, and KPNB1 overexpression rescues JQ1-induced PR20 nuclear entry and cell death.","method":"FITC-labeled PR20 tracking; siRNA knockdown of KPNB1/KPNA2; overexpression rescue; JQ1-mediated KPNB1 downregulation","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fluorescent cargo tracking with genetic gain- and loss-of-function, single lab","pmids":["39891383"],"is_preprint":false},{"year":2024,"finding":"NAT10 upregulates KPNB1 expression through ac4C RNA modification of KPNB1 mRNA; elevated KPNB1 in turn facilitates PD-L1 nuclear translocation to promote immune escape and radiotherapy resistance in NSCLC.","method":"NAT10 knockdown; ac4C RNA modification assays; KPNB1 overexpression; nuclear fractionation for PD-L1; immune cell co-culture assays","journal":"Open life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic link between ac4C modification and KPNB1 upregulation shown indirectly by knockdown, single lab, limited biochemical validation of direct ac4C on KPNB1 mRNA","pmids":["40109769"],"is_preprint":false}],"current_model":"KPNB1 (karyopherin β1/importin β1) is the primary nuclear import receptor that directly transports a broad range of cargo proteins—including NF-κB/p65, PER/CRY circadian repressors, PD-L1, E2F1, YBX1, ATF4, VCP, HMGB2, NFAT5, and IRF1—from the cytoplasm into the nucleus via the nuclear pore complex, acting either through the canonical KPNA2/KPNB1 pathway (cargo recognition via importin α adaptor) or through direct NLS-binding independent of importin α; its protein stability is regulated by USP7-mediated deubiquitination (counteracting RCHY1-dependent K48-ubiquitination), and its expression is post-transcriptionally repressed by miR-30a/d targeting its 3′ UTR downstream of EZH2; loss of KPNB1 function disrupts proteostasis by causing cytosolic accumulation of nuclear cargo, triggering UPR and Bcl-2 family-mediated apoptosis, making it an essential regulator of cell cycle progression, circadian rhythm, immune signaling, and DNA damage repair."},"narrative":{"mechanistic_narrative":"KPNB1 (karyopherin β1/importin β1) is the principal nuclear import receptor that ferries a structurally and functionally diverse set of cargo proteins through the nuclear pore complex, operating both through the classical importin α (KPNA2) adaptor pathway and through direct, importin-α-independent recognition of cargo nuclear localization signals [PMID:23906023, PMID:35635291, PMID:39604846]. It drives nuclear translocation of inducible transcription factors—NF-κB/p65 following TNF-α stimulation [PMID:23906023], the PER/CRY repressor complex to close the negative feedback loop of the mammalian circadian clock [PMID:26319354], E2F1 [PMID:31819526], the tonicity-responsive factor NFAT5 via direct binding to a unique NFAT5-NLS [PMID:35635291], and ATF4 via recognition of residues 280-299 of its NLS to license downstream BNIP3-dependent mitophagy [PMID:39604846]. The same receptor imports nuclear-localized PD-L1, IRF1, YBX1, VCP, and HMGB2, coupling KPNB1 to immune-evasion programs and DNA damage repair [PMID:33139930, PMID:34069326, PMID:38254206, PMID:40339118, PMID:40082556]. As an apical hub for nucleocytoplasmic transport, KPNB1 functions as a master regulator of cell-cycle proteins, and its genetic or pharmacological inhibition triggers cytosolic retention of nuclear cargo, polyubiquitination, aggresome-like structure formation, and chronic unfolded protein response signaling through the eIF2α/ATF4 axis, culminating in Bcl-2-family-mediated apoptosis [PMID:28811376, PMID:29520102]. KPNB1 protein abundance is set by competing ubiquitination events—USP7-mediated deubiquitination and TMEM209-mediated shielding from RCHY1-dependent K48-linked degradation stabilize the receptor, while an EZH2-controlled miR-30a/miR-30d axis represses it post-transcriptionally [PMID:24132643, PMID:25890085, PMID:38254206, PMID:39414762]. Withaferin A covalently engages Cys158 of KPNB1 to block VCP import and impair DNA damage repair, defining a druggable site on the receptor [PMID:40339118].","teleology":[{"year":2013,"claim":"Established which importin β family member carries activated NF-κB into the nucleus, defining KPNB1 as the dominant receptor for inflammatory transcription factor import.","evidence":"High-content siRNA screen across 17 importin β members with nuclear fractionation and NF-κB reporter assays in TNF-α-stimulated cells","pmids":["23906023"],"confidence":"High","gaps":["Did not resolve whether p65 import is fully importin-α dependent or partly direct","No structural detail of cargo recognition"]},{"year":2014,"claim":"Connected KPNB1 abundance to an upstream epigenetic/miRNA circuit, showing KPNB1 is a survival effector downstream of EZH2 via miR-30d derepression.","evidence":"Genetic epistasis with EZH2 knockdown, miR-30d overexpression, KPNB1 rescue, 3'UTR luciferase reporter, and xenografts in MPNST","pmids":["24132643"],"confidence":"High","gaps":["Generalizability beyond MPNST not tested","Direct miRNA-mRNA binding inferred from reporter only"]},{"year":2015,"claim":"Demonstrated KPNB1 can act independently of importin α, importing the PER/CRY repressor to complete circadian negative feedback.","evidence":"RNAi with fractionation and reciprocal Co-IP in human cells plus inducible importin β inhibition in Drosophila lateral neurons","pmids":["26319354"],"confidence":"High","gaps":["NLS/binding interface on PER not mapped","Stoichiometry of PER/CRY complex import unresolved"]},{"year":2017,"claim":"Defined KPNB1 as a master regulator of cell-cycle protein localization whose loss causes multiphase arrest and death, validating it as a cancer dependency.","evidence":"Orthogonal shRNA dropout and genome-wide CRISPR/Cas9 screens with proteomics and pharmacological inhibition in ovarian cancer","pmids":["28811376"],"confidence":"High","gaps":["Direct vs indirect effects on p21/p27/APC/C not fully separated","Which cargo losses are rate-limiting for arrest unclear"]},{"year":2017,"claim":"Showed KPNB1 inhibition simultaneously blocks NF-κB and AP-1 import, linking the receptor to cytokine output and invasion via a small-molecule inhibitor.","evidence":"siRNA and INI-43 inhibition with fractionation, reporter assays, and Transwell migration/invasion in cervical cancer","pmids":["28427184"],"confidence":"Medium","gaps":["Inhibitor selectivity not exhaustively profiled","Single lab, single tumor type"]},{"year":2018,"claim":"Mechanistically explained how KPNB1 loss kills cells: cytosolic cargo accumulation triggers proteotoxic UPR and Bcl-2-family-driven apoptosis.","evidence":"Genetic and pharmacological inhibition with ubiquitination/UPR Western blots and rescue by KPNB1 overexpression or translation inhibitors in glioblastoma","pmids":["29520102"],"confidence":"High","gaps":["Identity of cargo whose mislocalization initiates UPR not pinpointed","Tumor-type specificity of UPR threshold unknown"]},{"year":2019,"claim":"Extended the death mechanism to TRAIL sensitization and identified an autophagy-mediated resistance counterforce upon KPNB1 inhibition.","evidence":"siRNA and pharmacological inhibition with caspase assays, DISC component blots, and autophagy flux inhibitors in glioblastoma","pmids":["30742128"],"confidence":"Medium","gaps":["Whether autophagy counteraction generalizes beyond glioblastoma untested","Single lab"]},{"year":2019,"claim":"Identified E2F1 as a KPNB1 cargo, linking import to c-Myc/KPNA2 expression and G2/M control in CML.","evidence":"siRNA and importazole inhibition with E2F1 immunofluorescence, target Western blots, and flow cytometry","pmids":["31819526"],"confidence":"Medium","gaps":["Direct KPNB1-E2F1 binding not shown","Importazole off-target effects not excluded"]},{"year":2020,"claim":"Revealed a non-canonical nuclear role for PD-L1 trafficked by KPNB1, coupling it to Sp1-driven Gas6/MerTK proliferative signaling.","evidence":"Co-IP, fractionation, PD-L1 knockdown, ChIP on Gas6 promoter, and in vivo proliferation assays in NSCLC","pmids":["33139930"],"confidence":"Medium","gaps":["NLS on PD-L1 recognized by KPNB1 not mapped","Single lab"]},{"year":2020,"claim":"Confirmed canonical KPNA2/KPNB1 cooperation for an oncogenic cargo (NLS-RARα) controlling myeloid differentiation.","evidence":"IP-MS, Co-IP validation, siRNA, fractionation, and immunofluorescence","pmids":["32696739"],"confidence":"Medium","gaps":["Relative contribution of α vs β not quantified","Single lab"]},{"year":2021,"claim":"Placed KPNB1 in the radiation-induced immune-evasion axis by importing IRF1 to upregulate surface PD-L1.","evidence":"IRF1 siRNA, importazole inhibition, IRF1 localization imaging, and surface PD-L1 flow cytometry","pmids":["34069326"],"confidence":"Medium","gaps":["Direct KPNB1-IRF1 binding not demonstrated","Importazole specificity caveat"]},{"year":2022,"claim":"Provided clean evidence for importin-α-independent cargo recognition via a unique NFAT5-NLS, sharpening KPNB1's direct-binding mode.","evidence":"Importin-family siRNA screen, Co-IP, fractionation, and NLS mutagenesis for tonicity-responsive NFAT5 import","pmids":["35635291"],"confidence":"High","gaps":["Structural basis of the KPNB1-NFAT5-NLS interface not solved"]},{"year":2022,"claim":"Uncovered an import-independent function: KPNB1 binding to ataxin-3 lowers polyQ aggregate load via CLPP-dependent fragmentation.","evidence":"Co-IP, label-free proteomics, KPNB1 and CLPP perturbation across MJD mouse and iPSC models","pmids":["35794401"],"confidence":"Medium","gaps":["How KPNB1 routes ataxin-3 to mitochondrial CLPP mechanistically unclear","Single lab"]},{"year":2022,"claim":"Showed adaptor proteins can tune KPNB1 cargo flux, with PCDH1 enhancing p65 import to drive PDAC.","evidence":"PCDH1-KPNB1 Co-IP, p65 fractionation, NF-κB reporter, and proliferation/invasion assays","pmids":["35864095"],"confidence":"Medium","gaps":["Whether PCDH1 acts as cargo, adaptor, or stabilizer not resolved","Mechanism partially indirect"]},{"year":2023,"claim":"Linked KPNB1-mediated import machinery to nuclear envelope integrity during S-phase through an RTEL1 C-terminal interaction.","evidence":"Co-IP, domain truncation mapping, high-resolution microscopy, and nuclear envelope stability assays","pmids":["38132118"],"confidence":"Medium","gaps":["Functional consequence of RTEL1-KPNB1 binding for import cargo unknown","Single lab"]},{"year":2024,"claim":"Established USP7 as a positive regulator of KPNB1 stability and identified YBX1 as a cargo driving NLGN3-dependent glioblastoma progression.","evidence":"Ubiquitination assays, IP-MS, fractionation, immunofluorescence, ChIP on NLGN3 promoter, and intracranial tumor model","pmids":["38254206"],"confidence":"High","gaps":["Site of USP7 deubiquitination on KPNB1 not mapped","Direct YBX1-NLS recognition not shown"]},{"year":2024,"claim":"Defined the degradative arm of KPNB1 stability control: RCHY1 K48-ubiquitination opposed by TMEM209 shielding, feeding Wnt/β-catenin oncogenesis.","evidence":"TMEM209-KPNB1 and KPNB1-RCHY1 Co-IP, ubiquitination assays, Western blot, and xenografts in HCC","pmids":["39414762"],"confidence":"Medium","gaps":["Direct ubiquitination site on KPNB1 not identified","Single lab"]},{"year":2024,"claim":"Mapped a precise ATF4 NLS (residues 280-299) recognized by KPNB1, connecting receptor function to BNIP3 mitophagy and odontoblastic differentiation.","evidence":"IP-MS, NLS wild-type/mutant constructs, dual-luciferase and ChIP promoter mapping, and in vivo implantation","pmids":["39604846"],"confidence":"High","gaps":["Structural interface of KPNB1-ATF4-NLS not solved","Whether other stress contexts use the same NLS untested"]},{"year":2024,"claim":"Proposed an RNA-modification route (NAT10/ac4C) for upregulating KPNB1 to drive PD-L1 import and radiotherapy resistance.","evidence":"NAT10 knockdown, ac4C assays, KPNB1 overexpression, PD-L1 fractionation, and immune co-culture in NSCLC","pmids":["40109769"],"confidence":"Low","gaps":["Direct ac4C deposition on KPNB1 mRNA not biochemically confirmed","Effect inferred indirectly from knockdown","Single lab"]},{"year":2025,"claim":"Identified VCP as a KPNB1 cargo essential for DNA damage repair and defined Cys158 as a covalent druggable site exploited by withaferin A.","evidence":"Chemical pulldown with IP-MS, Co-IP, Cys158 mutagenesis, and in vivo xenograft DDR assays","pmids":["40339118"],"confidence":"High","gaps":["VCP NLS recognized by KPNB1 not mapped","Selectivity of Cys158 engagement across karyopherins untested"]},{"year":2025,"claim":"Extended KPNB1's DDR role to HMGB2 import in AML, providing a venetoclax-sensitization strategy via import blockade.","evidence":"Co-IP, fractionation, siRNA/importazole inhibition, patient-derived viability assays, and xenografts","pmids":["40082556"],"confidence":"Medium","gaps":["Direct KPNB1-HMGB2 binding interface not defined","Single lab"]},{"year":2025,"claim":"Showed the KPNA2/KPNB1 complex can act protectively by cytoplasmic sequestration of toxic C9orf72 polyPR dipeptides.","evidence":"FITC-PR20 tracking with KPNB1/KPNA2 siRNA, overexpression rescue, and JQ1-mediated downregulation","pmids":["39891383"],"confidence":"Medium","gaps":["Whether sequestration vs import dominates in neurons untested","Single lab"]},{"year":2025,"claim":"Identified KPNB1 as a reader of O-GlcNAcylated RNA Pol II CTD, linking metabolic modification to polymerase nuclear entry and global transcription.","evidence":"WGA lectin pulldown with MS, structural modeling, wChIP, and siRNA/inhibitor functional assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct CTD-Ser5-O-GlcNAc binding by KPNB1 needs structural confirmation"]},{"year":null,"claim":"The structural rules governing how a single receptor distinguishes importin-α-dependent versus direct-NLS cargo, and how its many described stability inputs are integrated in vivo, remain unresolved.","evidence":"No discovery in the timeline provides a high-resolution structure of KPNB1 bound to a direct-binding cargo NLS or an integrated model of competing ubiquitination/deubiquitination control","pmids":[],"confidence":"Low","gaps":["No experimental structure of KPNB1-cargo NLS complexes in the corpus","Hierarchy among USP7, RCHY1, TMEM209, and miR-30 control not reconciled","Cargo selection determinants for direct vs adaptor-mediated import undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,11,16,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,11,16]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,11,16,17]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[17,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[1]}],"complexes":["KPNA2/KPNB1 importin complex"],"partners":["KPNA2","USP7","RCHY1","TMEM209","PCDH1","RTEL1","VCP","ATF4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14974","full_name":"Importin subunit beta-1","aliases":["Importin-90","Karyopherin subunit beta-1","Nuclear factor p97","Pore targeting complex 97 kDa subunit","PTAC97"],"length_aa":876,"mass_kda":97.2,"function":"Functions in nuclear protein import, either in association with an adapter protein, like an importin-alpha subunit, which binds to nuclear localization signals (NLS) in cargo substrates, or by acting as autonomous nuclear transport receptor (PubMed:10228156, PubMed:11682607, PubMed:11891849, PubMed:19386897, PubMed:20818336, PubMed:24699649, PubMed:7615630, PubMed:9687515). Acting autonomously, serves itself as NLS receptor (PubMed:10228156, PubMed:11682607, PubMed:11891849, PubMed:19386897, PubMed:20818336, PubMed:24699649, PubMed:7615630, PubMed:9687515). 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:10228156, PubMed:11682607, PubMed:11891849, PubMed:19386897, PubMed:20818336, PubMed:24699649, PubMed:7615630, PubMed:9687515). 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:10228156, PubMed:11682607, PubMed:11891849, PubMed:19386897, PubMed:20818336, PubMed:24699649, PubMed:7615630, PubMed:9687515). 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:10228156, PubMed:11682607, PubMed:11891849, PubMed:19386897, PubMed:24699649, PubMed:7615630, PubMed:9687515). Mediates autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5 (PubMed:11682607, PubMed:9687515). In association with IPO7, mediates the nuclear import of H1 histone (PubMed:10228156). In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones (By similarity). Imports MRTFA, SNAI1 and PRKCI into the nucleus (PubMed:11891849, PubMed:19386897, PubMed:20818336, PubMed:24699649) (Microbial infection) In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev","subcellular_location":"Cytoplasm; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/Q14974/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KPNB1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108424","cell_line_id":"CID001564","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"nuclear_membrane","grade":2},{"compartment":"cytoplasmic","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"HNRNPU","stoichiometry":10.0},{"gene":"IPO7","stoichiometry":10.0},{"gene":"KPNA2","stoichiometry":10.0},{"gene":"RANBP1","stoichiometry":10.0},{"gene":"NUP50","stoichiometry":10.0},{"gene":"NOLC1","stoichiometry":10.0},{"gene":"RSL1D1","stoichiometry":10.0},{"gene":"KPNA1","stoichiometry":4.0},{"gene":"KPNA3","stoichiometry":4.0},{"gene":"KPNA4","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001564","total_profiled":1310},"omim":[{"mim_id":"620391","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 16; PARP16","url":"https://www.omim.org/entry/620391"},{"mim_id":"617167","title":"SOLUTE CARRIER FAMILY 35, MEMBER G1; SLC35G1","url":"https://www.omim.org/entry/617167"},{"mim_id":"615820","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 8; DCAF8","url":"https://www.omim.org/entry/615820"},{"mim_id":"614107","title":"KARYOPHERIN ALPHA-7; KPNA7","url":"https://www.omim.org/entry/614107"},{"mim_id":"610889","title":"IMPORTIN 11; IPO11","url":"https://www.omim.org/entry/610889"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear membrane","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KPNB1"},"hgnc":{"alias_symbol":["NTF97","IPOB","MGC2155","MGC2156","MGC2157","IMB1","Impnb","IPO1"],"prev_symbol":[]},"alphafold":{"accession":"Q14974","domains":[{"cath_id":"1.25.10.10","chopping":"211-333_341-397","consensus_level":"medium","plddt":97.296,"start":211,"end":397},{"cath_id":"1.25.40","chopping":"707-876","consensus_level":"medium","plddt":94.0126,"start":707,"end":876}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14974","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14974-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14974-F1-predicted_aligned_error_v6.png","plddt_mean":94.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KPNB1","jax_strain_url":"https://www.jax.org/strain/search?query=KPNB1"},"sequence":{"accession":"Q14974","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14974.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14974/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14974"}},"corpus_meta":[{"pmid":"33139930","id":"PMC_33139930","title":"KPNB1-mediated 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mediating NF-κB/p65 nuclear import in a NLS-dependent manner following TNF-α stimulation, acting via the canonical KPNA2/KPNB1 pathway; siRNA knockdown of KPNB1 reduced nuclear p65 and decreased NF-κB transcriptional activity.\",\n      \"method\": \"High-content siRNA screening of 17 importin β family members, followed by nuclear fractionation and reporter assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic siRNA screen across importin family plus mechanistic NLS-dependence validation, independently replicated in follow-up studies\",\n      \"pmids\": [\"23906023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KPNB1 mediates nuclear translocation of PER proteins (and the PER/CRY repressor complex) in a circadian fashion and independently of importin α, thereby enabling negative feedback regulation of the mammalian circadian clock; RNAi depletion of KPNB1 traps PER/CRY in the cytoplasm and disrupts clock function.\",\n      \"method\": \"RNAi knockdown in human cells with cytoplasmic/nuclear fractionation and co-immunoprecipitation; inducible inhibition of Drosophila importin β in lateral neurons abolished behavioral rhythms\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi in human cells with defined molecular phenotype, cross-species validation in Drosophila\",\n      \"pmids\": [\"26319354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EZH2 epigenetically suppresses miR-30d transcription, which relieves repression of KPNB1 (miR-30d targets KPNB1 3′ UTR), resulting in elevated KPNB1 that promotes MPNST cell survival; forced KPNB1 overexpression rescues apoptosis induced by EZH2 knockdown, placing KPNB1 downstream of the EZH2-miR-30d axis.\",\n      \"method\": \"Genetic epistasis: EZH2 knockdown, miR-30d overexpression, KPNB1 overexpression rescue; 3′ UTR luciferase reporter assay; xenograft tumor model\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by rescue experiment, 3′ UTR reporter, in vitro and in vivo validation\",\n      \"pmids\": [\"24132643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-30a also targets the KPNB1 3′ UTR in MPNST cells, contributing to EZH2/miR-30a,d/KPNB1 signaling axis; pharmacological EZH2 inhibition (DZNep) downregulates KPNB1 protein and suppresses tumor growth.\",\n      \"method\": \"3′ UTR luciferase reporter assay; Western blot; xenograft mouse model with IHC\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3′ UTR reporter plus in vivo validation, single lab\",\n      \"pmids\": [\"25890085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KPNB1 acts as a master regulator of cell cycle-related proteins (including p21, p27, and APC/C); genetic and pharmacological inhibition of KPNB1 causes multiphase cell cycle arrest and apoptosis induction in epithelial ovarian cancer cells in vitro and in vivo.\",\n      \"method\": \"shRNA dropout screen in xenografts, CRISPR/Cas9 genome-wide screen, pharmacological inhibition, proteomics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal genome-scale screens (shRNA and CRISPR/Cas9) with proteomics validation\",\n      \"pmids\": [\"28811376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KPNB1 is required for translocation of NF-κB and AP-1 transcription factors into the nucleus in cervical cancer cells; siRNA or small-molecule inhibition of KPNB1 (INI-43) causes cytoplasmic retention of NF-κB and decreases AP-1 transcriptional activity, reducing expression of IL-6, IL-1β, TNF-α, and GM-CSF, and impairing cancer cell migration and invasion.\",\n      \"method\": \"siRNA knockdown; small-molecule inhibition with INI-43; nuclear fractionation; transcriptional reporter assays; Transwell migration/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal inhibition methods (siRNA + small molecule), multiple functional readouts, single lab\",\n      \"pmids\": [\"28427184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KPNB1 inhibition in glioblastoma cells causes cytosolic retention of cargo proteins, elevated polyubiquitination, aggresome-like-induced structure (ALIS) formation, and unfolded protein response (UPR) activation; chronic UPR (eIF2α/ATF4 cascade) upregulates pro-apoptotic Bcl-2 family members Puma and Noxa, frees Bax/Bak from Mcl-1, and induces MOMP and apoptosis.\",\n      \"method\": \"siRNA knockdown; pharmacological inhibition; Western blot for ubiquitination and UPR markers; rescue by KPNB1 overexpression or protein synthesis inhibitors; combination with proteasome/autophagy inhibitors\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic + pharmacological) with mechanistic rescue experiments in single rigorous study\",\n      \"pmids\": [\"29520102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KPNB1 inhibition in glioblastoma potentiates TRAIL-induced apoptosis via UPR-mediated ATF4 upregulation of DR5 and 4E-BP1 (suppressing cap-dependent translation of FLIPL/FLIPS), freeing Bax/Bak from Mcl-1, and promoting DISC assembly; KPNB1 inhibition-induced autophagy counteracts by degrading cleaved caspase-8.\",\n      \"method\": \"Genetic (siRNA) and pharmacological KPNB1 inhibition; caspase activity assays; Western blot for DISC components; autophagy flux inhibitors\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal inhibition methods with detailed mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"30742128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KPNB1 mediates nuclear import of E2F1 in CML cells; KPNB1 inhibition (siRNA or importazole) blocks E2F1 nuclear translocation, reduces c-Myc and KPNA2 expression downstream of E2F1, and induces G2/M arrest and apoptosis.\",\n      \"method\": \"siRNA knockdown; pharmacological inhibition (importazole); immunofluorescence for E2F1 localization; Western blot for E2F1 targets; flow cytometry\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal inhibition methods, direct localization evidence for E2F1 trafficking, single lab\",\n      \"pmids\": [\"31819526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KPNB1 facilitates nuclear translocation of PD-L1 in NSCLC cells; nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, drives Gas6 mRNA synthesis and secretion, activating MerTK signaling to promote cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (KPNB1-PD-L1 binding); nuclear fractionation; PD-L1 knockdown; ChIP for Sp1/nPD-L1 on Gas6 promoter; in vitro and in vivo proliferation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus nuclear fractionation plus ChIP with in vivo validation, single lab\",\n      \"pmids\": [\"33139930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNB1 mediates nuclear import of IRF1 following ionizing radiation; KPNB1 inhibitor importazole reduces both IRF1 protein upregulation and its nuclear localization, thereby attenuating radiation-increased PD-L1 surface expression on tumor cells.\",\n      \"method\": \"siRNA knockdown of IRF1; pharmacological KPNB1 inhibition (importazole); immunofluorescence and Western blot for IRF1 nuclear localization; flow cytometry for surface PD-L1\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal approaches (siRNA + pharmacological), direct localization imaging, single lab\",\n      \"pmids\": [\"34069326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNB1 mediates nuclear import of NFAT5 via direct interaction with a unique NFAT5 nuclear localization signal (NFAT5-NLS), independently of karyopherin α; siRNA screening showed only KPNB1 (not karyopherin α) is required for tonicity-responsive NFAT5 nuclear import.\",\n      \"method\": \"siRNA screening of importin family; Co-IP; nuclear fractionation; NLS mutagenesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic siRNA screen plus Co-IP with NLS validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35635291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNB1 directly interacts with both wild-type and polyQ-expanded ataxin-3 but modulating KPNB1 does not alter ataxin-3 intracellular localization; instead, KPNB1 overexpression reduces ataxin-3 protein levels and aggregate load via protein fragmentation dependent on mitochondrial protease CLPP, improving cell viability in MJD models.\",\n      \"method\": \"Co-immunoprecipitation; label-free quantitative proteomics; KPNB1 knockdown/overexpression; CLPP knockdown; MJD mouse model and iPSC analysis\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, proteomics, and genetic rescue with multiple model systems, single lab\",\n      \"pmids\": [\"35794401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCDH1 interacts with KPNB1 and enhances p65 nuclear localization, thereby activating NF-κB signaling to promote pancreatic ductal adenocarcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation (PCDH1-KPNB1); nuclear fractionation of p65; NF-κB reporter assay; cell proliferation/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional readouts, single lab, mechanism partially indirect\",\n      \"pmids\": [\"35864095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP7 stabilizes KPNB1 through deubiquitination (K48-linked ubiquitination removal); KPNB1 mediates nuclear import of transcription factor YBX1, which then binds the NLGN3 promoter to drive NLGN3 expression and promote glioblastoma progression.\",\n      \"method\": \"Ubiquitination assays; Co-IP/mass spectrometry (KPNB1-YBX1 interaction); nuclear-cytoplasmic fractionation; immunofluorescence; ChIP for YBX1 on NLGN3 promoter; intracranial tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ubiquitination assay, IP-MS, ChIP, fractionation) with in vivo validation in single rigorous study\",\n      \"pmids\": [\"38254206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM209 binds to KPNB1 and competitively blocks the interaction between KPNB1 and E3 ubiquitin ligase RCHY1, preventing K48-linked ubiquitination-dependent degradation of KPNB1; stabilized KPNB1 then activates the Wnt/β-catenin signaling pathway to promote hepatocellular carcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation (TMEM209-KPNB1 and KPNB1-RCHY1); ubiquitination assays; Western blot; xenograft tumor model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay with competitive binding analysis, single lab\",\n      \"pmids\": [\"39414762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KPNB1 specifically recognizes amino acids 280-299 within the NLS of transcription factor ATF4, mediating ATF4 nuclear import; nuclear ATF4 then binds the BNIP3 promoter (at approximately -1292 to -1279 bp and -1185 to -1172 bp) to drive BNIP3-dependent mitophagy and promote odontoblastic differentiation of dental pulp stem cells.\",\n      \"method\": \"IP-mass spectrometry (KPNB1-ATF4); NLS wild-type/mutant plasmid constructs; dual-luciferase reporter and ChIP for ATF4-BNIP3 promoter; nuclear fractionation; mitochondrial function assays; in vivo implantation model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — IP-MS, NLS mutagenesis, ChIP with promoter mapping, and in vivo validation in one study\",\n      \"pmids\": [\"39604846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KPNB1 directly transports VCP (valosin-containing protein) into the nucleus to support DNA damage repair; withaferin A (WA) covalently binds CYS 158 of KPNB1 to retard VCP nuclear localization and impair DDR.\",\n      \"method\": \"Chemical pulldown combined with immunoprecipitation-mass spectrometry; biochemical Co-IP; covalent binding site mapping (CYS 158 mutagenesis); in vivo xenograft DDR assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chemical + IP-MS identification, active-site covalent binding with mutagenesis, in vivo validation in single rigorous study\",\n      \"pmids\": [\"40339118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KPNB1 mediates nuclear import of HMGB2 in AML cells; KPNB1 inhibition impairs HMGB2 nuclear entry, leading to compromised DNA damage repair and sensitization of AML cells to venetoclax.\",\n      \"method\": \"Co-immunoprecipitation; nuclear fractionation; siRNA/importazole inhibition; xenograft AML mouse model; patient-derived cell viability assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus nuclear fractionation with functional rescue and in vivo validation, single lab\",\n      \"pmids\": [\"40082556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RTEL1 interacts with KPNB1 through a distinct C-terminal domain (separate from its NUP153-binding domain), and this interaction connects protein nuclear import to nuclear envelope stability during S-phase; overexpression of the RTEL1 C-terminal domain protects against nuclear envelope anomalies caused by protein import inhibition.\",\n      \"method\": \"Co-immunoprecipitation; domain deletion/truncation mapping; high-resolution microscopy (KPNB1 localization at nuclear pore); nuclear envelope stability assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus functional nuclear envelope protection assay, single lab\",\n      \"pmids\": [\"38132118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NLS-RARα is transported into the nucleus by binding to both KPNA2 (importin α1) and KPNB1 (importin β1); knockdown of KPNA2/KPNB1 inhibits nuclear accumulation of NLS-RARα, and nuclear NLS-RARα inhibits myeloid cell differentiation.\",\n      \"method\": \"Mass spectrometry of co-immunoprecipitated proteins; Co-IP validation; siRNA knockdown; nuclear/cytoplasmic fractionation; immunofluorescence\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus Co-IP validation with siRNA functional test, single lab\",\n      \"pmids\": [\"32696739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KPNB1 is identified as a reader protein for O-GlcNAcylated RNA Polymerase II CTD (at Ser-5); OGT-mediated O-GlcNAcylation of RNA Pol II promotes its nuclear entry in a KPNB1-dependent manner, connecting metabolic state to global transcription regulation.\",\n      \"method\": \"WGA lectin pulldown combined with mass spectrometry (O-GlcNAcylated CTD interactome); structural modeling; ChIP (wChIP technique); siRNA/inhibitor functional assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based identification plus functional validation with two orthogonal methods, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KPNA2/KPNB1 complex sequesters C9orf72 poly(proline-arginine) (polyPR) in the cytoplasm, protecting cells from polyPR nuclear toxicity; genetic silencing of KPNB1 converts PR20-resistant cells to sensitive cells, and KPNB1 overexpression rescues JQ1-induced PR20 nuclear entry and cell death.\",\n      \"method\": \"FITC-labeled PR20 tracking; siRNA knockdown of KPNB1/KPNA2; overexpression rescue; JQ1-mediated KPNB1 downregulation\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fluorescent cargo tracking with genetic gain- and loss-of-function, single lab\",\n      \"pmids\": [\"39891383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 upregulates KPNB1 expression through ac4C RNA modification of KPNB1 mRNA; elevated KPNB1 in turn facilitates PD-L1 nuclear translocation to promote immune escape and radiotherapy resistance in NSCLC.\",\n      \"method\": \"NAT10 knockdown; ac4C RNA modification assays; KPNB1 overexpression; nuclear fractionation for PD-L1; immune cell co-culture assays\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic link between ac4C modification and KPNB1 upregulation shown indirectly by knockdown, single lab, limited biochemical validation of direct ac4C on KPNB1 mRNA\",\n      \"pmids\": [\"40109769\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KPNB1 (karyopherin β1/importin β1) is the primary nuclear import receptor that directly transports a broad range of cargo proteins—including NF-κB/p65, PER/CRY circadian repressors, PD-L1, E2F1, YBX1, ATF4, VCP, HMGB2, NFAT5, and IRF1—from the cytoplasm into the nucleus via the nuclear pore complex, acting either through the canonical KPNA2/KPNB1 pathway (cargo recognition via importin α adaptor) or through direct NLS-binding independent of importin α; its protein stability is regulated by USP7-mediated deubiquitination (counteracting RCHY1-dependent K48-ubiquitination), and its expression is post-transcriptionally repressed by miR-30a/d targeting its 3′ UTR downstream of EZH2; loss of KPNB1 function disrupts proteostasis by causing cytosolic accumulation of nuclear cargo, triggering UPR and Bcl-2 family-mediated apoptosis, making it an essential regulator of cell cycle progression, circadian rhythm, immune signaling, and DNA damage repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KPNB1 (karyopherin β1/importin β1) is the principal nuclear import receptor that ferries a structurally and functionally diverse set of cargo proteins through the nuclear pore complex, operating both through the classical importin α (KPNA2) adaptor pathway and through direct, importin-α-independent recognition of cargo nuclear localization signals [#0, #11, #16]. It drives nuclear translocation of inducible transcription factors—NF-κB/p65 following TNF-α stimulation [#0], the PER/CRY repressor complex to close the negative feedback loop of the mammalian circadian clock [#1], E2F1 [#8], the tonicity-responsive factor NFAT5 via direct binding to a unique NFAT5-NLS [#11], and ATF4 via recognition of residues 280-299 of its NLS to license downstream BNIP3-dependent mitophagy [#16]. The same receptor imports nuclear-localized PD-L1, IRF1, YBX1, VCP, and HMGB2, coupling KPNB1 to immune-evasion programs and DNA damage repair [#9, #10, #14, #17, #18]. As an apical hub for nucleocytoplasmic transport, KPNB1 functions as a master regulator of cell-cycle proteins, and its genetic or pharmacological inhibition triggers cytosolic retention of nuclear cargo, polyubiquitination, aggresome-like structure formation, and chronic unfolded protein response signaling through the eIF2α/ATF4 axis, culminating in Bcl-2-family-mediated apoptosis [#4, #6]. KPNB1 protein abundance is set by competing ubiquitination events—USP7-mediated deubiquitination and TMEM209-mediated shielding from RCHY1-dependent K48-linked degradation stabilize the receptor, while an EZH2-controlled miR-30a/miR-30d axis represses it post-transcriptionally [#2, #3, #14, #15]. Withaferin A covalently engages Cys158 of KPNB1 to block VCP import and impair DNA damage repair, defining a druggable site on the receptor [#17].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established which importin β family member carries activated NF-κB into the nucleus, defining KPNB1 as the dominant receptor for inflammatory transcription factor import.\",\n      \"evidence\": \"High-content siRNA screen across 17 importin β members with nuclear fractionation and NF-κB reporter assays in TNF-α-stimulated cells\",\n      \"pmids\": [\"23906023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether p65 import is fully importin-α dependent or partly direct\", \"No structural detail of cargo recognition\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected KPNB1 abundance to an upstream epigenetic/miRNA circuit, showing KPNB1 is a survival effector downstream of EZH2 via miR-30d derepression.\",\n      \"evidence\": \"Genetic epistasis with EZH2 knockdown, miR-30d overexpression, KPNB1 rescue, 3'UTR luciferase reporter, and xenografts in MPNST\",\n      \"pmids\": [\"24132643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability beyond MPNST not tested\", \"Direct miRNA-mRNA binding inferred from reporter only\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated KPNB1 can act independently of importin α, importing the PER/CRY repressor to complete circadian negative feedback.\",\n      \"evidence\": \"RNAi with fractionation and reciprocal Co-IP in human cells plus inducible importin β inhibition in Drosophila lateral neurons\",\n      \"pmids\": [\"26319354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NLS/binding interface on PER not mapped\", \"Stoichiometry of PER/CRY complex import unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined KPNB1 as a master regulator of cell-cycle protein localization whose loss causes multiphase arrest and death, validating it as a cancer dependency.\",\n      \"evidence\": \"Orthogonal shRNA dropout and genome-wide CRISPR/Cas9 screens with proteomics and pharmacological inhibition in ovarian cancer\",\n      \"pmids\": [\"28811376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect effects on p21/p27/APC/C not fully separated\", \"Which cargo losses are rate-limiting for arrest unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed KPNB1 inhibition simultaneously blocks NF-κB and AP-1 import, linking the receptor to cytokine output and invasion via a small-molecule inhibitor.\",\n      \"evidence\": \"siRNA and INI-43 inhibition with fractionation, reporter assays, and Transwell migration/invasion in cervical cancer\",\n      \"pmids\": [\"28427184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitor selectivity not exhaustively profiled\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mechanistically explained how KPNB1 loss kills cells: cytosolic cargo accumulation triggers proteotoxic UPR and Bcl-2-family-driven apoptosis.\",\n      \"evidence\": \"Genetic and pharmacological inhibition with ubiquitination/UPR Western blots and rescue by KPNB1 overexpression or translation inhibitors in glioblastoma\",\n      \"pmids\": [\"29520102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of cargo whose mislocalization initiates UPR not pinpointed\", \"Tumor-type specificity of UPR threshold unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the death mechanism to TRAIL sensitization and identified an autophagy-mediated resistance counterforce upon KPNB1 inhibition.\",\n      \"evidence\": \"siRNA and pharmacological inhibition with caspase assays, DISC component blots, and autophagy flux inhibitors in glioblastoma\",\n      \"pmids\": [\"30742128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autophagy counteraction generalizes beyond glioblastoma untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified E2F1 as a KPNB1 cargo, linking import to c-Myc/KPNA2 expression and G2/M control in CML.\",\n      \"evidence\": \"siRNA and importazole inhibition with E2F1 immunofluorescence, target Western blots, and flow cytometry\",\n      \"pmids\": [\"31819526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KPNB1-E2F1 binding not shown\", \"Importazole off-target effects not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-canonical nuclear role for PD-L1 trafficked by KPNB1, coupling it to Sp1-driven Gas6/MerTK proliferative signaling.\",\n      \"evidence\": \"Co-IP, fractionation, PD-L1 knockdown, ChIP on Gas6 promoter, and in vivo proliferation assays in NSCLC\",\n      \"pmids\": [\"33139930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NLS on PD-L1 recognized by KPNB1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed canonical KPNA2/KPNB1 cooperation for an oncogenic cargo (NLS-RARα) controlling myeloid differentiation.\",\n      \"evidence\": \"IP-MS, Co-IP validation, siRNA, fractionation, and immunofluorescence\",\n      \"pmids\": [\"32696739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of α vs β not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed KPNB1 in the radiation-induced immune-evasion axis by importing IRF1 to upregulate surface PD-L1.\",\n      \"evidence\": \"IRF1 siRNA, importazole inhibition, IRF1 localization imaging, and surface PD-L1 flow cytometry\",\n      \"pmids\": [\"34069326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KPNB1-IRF1 binding not demonstrated\", \"Importazole specificity caveat\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided clean evidence for importin-α-independent cargo recognition via a unique NFAT5-NLS, sharpening KPNB1's direct-binding mode.\",\n      \"evidence\": \"Importin-family siRNA screen, Co-IP, fractionation, and NLS mutagenesis for tonicity-responsive NFAT5 import\",\n      \"pmids\": [\"35635291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the KPNB1-NFAT5-NLS interface not solved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered an import-independent function: KPNB1 binding to ataxin-3 lowers polyQ aggregate load via CLPP-dependent fragmentation.\",\n      \"evidence\": \"Co-IP, label-free proteomics, KPNB1 and CLPP perturbation across MJD mouse and iPSC models\",\n      \"pmids\": [\"35794401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How KPNB1 routes ataxin-3 to mitochondrial CLPP mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed adaptor proteins can tune KPNB1 cargo flux, with PCDH1 enhancing p65 import to drive PDAC.\",\n      \"evidence\": \"PCDH1-KPNB1 Co-IP, p65 fractionation, NF-κB reporter, and proliferation/invasion assays\",\n      \"pmids\": [\"35864095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PCDH1 acts as cargo, adaptor, or stabilizer not resolved\", \"Mechanism partially indirect\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked KPNB1-mediated import machinery to nuclear envelope integrity during S-phase through an RTEL1 C-terminal interaction.\",\n      \"evidence\": \"Co-IP, domain truncation mapping, high-resolution microscopy, and nuclear envelope stability assays\",\n      \"pmids\": [\"38132118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of RTEL1-KPNB1 binding for import cargo unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established USP7 as a positive regulator of KPNB1 stability and identified YBX1 as a cargo driving NLGN3-dependent glioblastoma progression.\",\n      \"evidence\": \"Ubiquitination assays, IP-MS, fractionation, immunofluorescence, ChIP on NLGN3 promoter, and intracranial tumor model\",\n      \"pmids\": [\"38254206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site of USP7 deubiquitination on KPNB1 not mapped\", \"Direct YBX1-NLS recognition not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the degradative arm of KPNB1 stability control: RCHY1 K48-ubiquitination opposed by TMEM209 shielding, feeding Wnt/β-catenin oncogenesis.\",\n      \"evidence\": \"TMEM209-KPNB1 and KPNB1-RCHY1 Co-IP, ubiquitination assays, Western blot, and xenografts in HCC\",\n      \"pmids\": [\"39414762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination site on KPNB1 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a precise ATF4 NLS (residues 280-299) recognized by KPNB1, connecting receptor function to BNIP3 mitophagy and odontoblastic differentiation.\",\n      \"evidence\": \"IP-MS, NLS wild-type/mutant constructs, dual-luciferase and ChIP promoter mapping, and in vivo implantation\",\n      \"pmids\": [\"39604846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface of KPNB1-ATF4-NLS not solved\", \"Whether other stress contexts use the same NLS untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed an RNA-modification route (NAT10/ac4C) for upregulating KPNB1 to drive PD-L1 import and radiotherapy resistance.\",\n      \"evidence\": \"NAT10 knockdown, ac4C assays, KPNB1 overexpression, PD-L1 fractionation, and immune co-culture in NSCLC\",\n      \"pmids\": [\"40109769\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct ac4C deposition on KPNB1 mRNA not biochemically confirmed\", \"Effect inferred indirectly from knockdown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified VCP as a KPNB1 cargo essential for DNA damage repair and defined Cys158 as a covalent druggable site exploited by withaferin A.\",\n      \"evidence\": \"Chemical pulldown with IP-MS, Co-IP, Cys158 mutagenesis, and in vivo xenograft DDR assays\",\n      \"pmids\": [\"40339118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"VCP NLS recognized by KPNB1 not mapped\", \"Selectivity of Cys158 engagement across karyopherins untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended KPNB1's DDR role to HMGB2 import in AML, providing a venetoclax-sensitization strategy via import blockade.\",\n      \"evidence\": \"Co-IP, fractionation, siRNA/importazole inhibition, patient-derived viability assays, and xenografts\",\n      \"pmids\": [\"40082556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KPNB1-HMGB2 binding interface not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed the KPNA2/KPNB1 complex can act protectively by cytoplasmic sequestration of toxic C9orf72 polyPR dipeptides.\",\n      \"evidence\": \"FITC-PR20 tracking with KPNB1/KPNA2 siRNA, overexpression rescue, and JQ1-mediated downregulation\",\n      \"pmids\": [\"39891383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether sequestration vs import dominates in neurons untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified KPNB1 as a reader of O-GlcNAcylated RNA Pol II CTD, linking metabolic modification to polymerase nuclear entry and global transcription.\",\n      \"evidence\": \"WGA lectin pulldown with MS, structural modeling, wChIP, and siRNA/inhibitor functional assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct CTD-Ser5-O-GlcNAc binding by KPNB1 needs structural confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural rules governing how a single receptor distinguishes importin-α-dependent versus direct-NLS cargo, and how its many described stability inputs are integrated in vivo, remain unresolved.\",\n      \"evidence\": \"No discovery in the timeline provides a high-resolution structure of KPNB1 bound to a direct-binding cargo NLS or an integrated model of competing ubiquitination/deubiquitination control\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of KPNB1-cargo NLS complexes in the corpus\", \"Hierarchy among USP7, RCHY1, TMEM209, and miR-30 control not reconciled\", \"Cargo selection determinants for direct vs adaptor-mediated import undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 11, 16, 17]},\n      {\"term_id\": \"GO:0008565\", \"supporting_discovery_ids\": [0, 11, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 11, 16]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 11, 16, 17]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [17, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"KPNA2/KPNB1 importin complex\"],\n    \"partners\": [\"KPNA2\", \"USP7\", \"RCHY1\", \"TMEM209\", \"PCDH1\", \"RTEL1\", \"VCP\", \"ATF4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}