Affinage

KPNB1

Importin subunit beta-1 · UniProt Q14974

Round 2 corrected
Length
876 aa
Mass
97.2 kDa
Annotated
2026-04-28
67 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KPNB1 (importin subunit β-1) is the principal nuclear import receptor in the classical nucleocytoplasmic transport pathway, forming a heterodimer with importin-α to recognize NLS-bearing cargo, docking at the nuclear pore complex, and releasing cargo upon RanGTP binding in the nucleoplasm (PMID:7627554, PMID:8896452, PMID:9323134). Its 19-HEAT-repeat solenoid architecture undergoes large conformational changes upon binding the importin-α IBB domain or RanGTP, providing the structural basis for cargo loading and unloading (PMID:10353244, PMID:11751052). Beyond the canonical importin-α-dependent pathway, KPNB1 directly imports diverse cargoes—including PER proteins (circadian clock), NFAT5, VCP, HMGB2, ATF4, PD-L1, and E2F1—independently of importin-α, thereby governing circadian rhythms, tonicity responses, DNA damage repair, and immune-regulatory transcription (PMID:26319354, PMID:35794291, PMID:40339118, PMID:40082556, PMID:39604846, PMID:33139930). Inhibition of KPNB1 disrupts proteostasis through cytoplasmic cargo accumulation and UPR/eIF2α-ATF4 activation, leading to pro-apoptotic signaling, cell-cycle arrest, and sensitization to TRAIL and venetoclax, establishing KPNB1 as an essential gene in multiple cancer contexts (PMID:29520102, PMID:28811376, PMID:30742128, PMID:40082556).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1995 High

    Identification of KPNB1 as the 90-kDa β-subunit of a cytosolic NLS receptor heterodimer with importin-α established the fundamental import machinery, answering how NLS-bearing proteins are recognized in the cytoplasm.

    Evidence Affinity chromatography with biotin-NLS from Xenopus egg extracts and reconstituted nuclear import assay

    PMID:7627554

    Open questions at the time
    • Structural basis of importin-α/β interaction unknown at this point
    • Whether KPNB1 can import cargo independently of importin-α not addressed
  2. 1996 High

    Demonstrating that nucleoplasmic RanGTP binding to KPNB1 triggers cargo release resolved how directionality is imposed on nuclear import—the Ran-GTP gradient provides the energy source for unidirectional transport.

    Evidence Biochemical import assay with Xenopus extracts, dominant-negative Ran mutants, and a KPNB1 Ran-binding mutant that docks but cannot release cargo

    PMID:8896452

    Open questions at the time
    • Structural mechanism of RanGTP-induced conformational change in KPNB1 not yet resolved
    • Recycling of importin-α back to cytoplasm not yet defined
  3. 1997 High

    Elucidation of the importin-α recycling step—CAS/RanGTP-mediated re-export of importin-α after RanGTP displaces it from KPNB1—completed the mechanistic cycle of canonical nuclear import.

    Evidence Biochemical reconstitution of the CAS/RanGTP/importin-α export complex in Xenopus extracts with RanGAP1/RanBP1 disassembly

    PMID:9323134

    Open questions at the time
    • Structural details of KPNB1-NPC interactions not yet available
    • Cargo selectivity beyond classical NLS not explored
  4. 1999 High

    The crystal structure of KPNB1 bound to the importin-α IBB domain revealed 19 tandem HEAT repeats wrapping around the IBB, explaining how conformational flexibility enables cargo binding and RanGTP-triggered release.

    Evidence X-ray crystallography at 2.3–2.5 Å resolution in two independent crystal forms

    PMID:10353244

    Open questions at the time
    • Structure of KPNB1 bound to RanGTP or nucleoporins not yet solved
    • Conformational dynamics in solution not captured by crystallography
  5. 2001 High

    A suite of crystal structures of KPNB1 with Ran, nucleoporins, and cargo provided an integrated structural framework for substrate recognition, NPC docking, and RanGTP-induced cargo release.

    Evidence Review and synthesis of multiple solved crystal structures of karyopherin complexes

    PMID:11751052

    Open questions at the time
    • In situ structural dynamics at the intact NPC not resolved
    • Selectivity for importin-α-independent cargoes structurally unexplained
  6. 2012 High

    Identification of ivermectin as a specific inhibitor of importin-α/β-mediated (but not importin-β-alone) nuclear import, blocking HIV-1 integrase and dengue NS5 import, demonstrated that KPNB1-dependent transport is pharmacologically targetable and essential for viral replication.

    Evidence Nuclear import competition assay, antiviral replication assays (HIV-1, dengue), specificity controls across multiple import pathways

    PMID:22417684

    Open questions at the time
    • Molecular binding site of ivermectin on KPNB1 or importin-α not mapped
    • Breadth of viral cargoes dependent on KPNB1 not systematically cataloged
  7. 2013 High

    A systematic siRNA screen of all 17 importin-β family members showed KPNB1 is the dominant receptor for NF-κB/p65 nuclear import after TNF-α stimulation, acting through the canonical KPNA2/KPNB1 pathway, establishing cargo specificity in inflammation signaling.

    Evidence High-content siRNA screen targeting 17 importin-β members with NF-κB nuclear translocation readout

    PMID:23906023

    Open questions at the time
    • How KPNB1/KPNA2 is preferentially selected over other importin-α/β combinations unclear
    • Kinetics of stimulus-dependent import not measured
  8. 2014 High

    Discovery of the EZH2→miR-30d⊣KPNB1 axis in MPNST cells revealed that KPNB1 expression is epigenetically regulated and that KPNB1 overexpression is a critical survival effector downstream of oncogenic EZH2.

    Evidence EZH2 ChIP-seq, miR-30d 3′UTR luciferase reporter, epistasis rescue by KPNB1 overexpression, xenograft model

    PMID:24132643

    Open questions at the time
    • Whether miR-30d–KPNB1 regulation operates in other tumor types not tested
    • Which specific KPNB1 cargoes mediate the survival phenotype not identified
  9. 2015 High

    Demonstration that KPNB1 imports the PER/CRY circadian repressor complex independently of importin-α, and that its Drosophila ortholog is required for behavioral rhythms, expanded KPNB1 function beyond classical import to importin-α-independent cargo recognition governing circadian timing.

    Evidence Reciprocal Co-IP (KPNB1–PER), nuclear fractionation, RNAi in human cells, Drosophila behavioral rhythm assay

    PMID:26319354

    Open questions at the time
    • NLS or recognition motif on PER proteins for direct KPNB1 binding not mapped
    • Whether CRY can also be directly recognized by KPNB1 in the absence of PER not determined
  10. 2017 High

    Dual in vivo genetic screens (shRNA and CRISPR) in ovarian cancer and proteomic analysis identified KPNB1 as an essential gene whose inhibition collapses cell-cycle regulatory networks (p21, p27, APC/C), establishing KPNB1 as a hub controlling cancer cell proliferation through nuclear import of multiple cell-cycle regulators.

    Evidence In vivo pooled shRNA dropout and CRISPR/Cas9 screens, quantitative proteomics, ivermectin validation, xenograft models

    PMID:28811376

    Open questions at the time
    • Which specific cell-cycle cargoes are directly imported by KPNB1 versus indirectly affected not resolved
    • Therapeutic window for KPNB1 inhibition in normal versus cancer tissue unknown
  11. 2017 Medium

    Showing that KPNB1 inhibition retains NF-κB and AP-1 in the cytoplasm of cervical cancer cells, reducing pro-inflammatory cytokine expression and impairing migration, extended the role of KPNB1-dependent import to tumor-intrinsic inflammatory signaling.

    Evidence siRNA and INI-43 pharmacological inhibition, nuclear fractionation, transcription factor reporter assays, migration/invasion assays

    PMID:28427184

    Open questions at the time
    • INI-43 selectivity for KPNB1 over other karyopherins not fully profiled
    • In vivo relevance of INI-43-mediated KPNB1 inhibition not demonstrated
  12. 2018 High

    Linking KPNB1 inhibition to proteostasis collapse—cytoplasmic cargo accumulation, polyubiquitination, ALIS formation, and lethal UPR/eIF2α-ATF4 signaling—revealed a novel mechanism by which import blockade kills cancer cells through proteotoxic stress rather than simple loss of transcription factor access.

    Evidence KPNB1 siRNA and pharmacological inhibition, polyubiquitination assays, ALIS immunofluorescence, UPR pathway western blot, apoptosis flow cytometry, KPNB1 rescue

    PMID:29520102

    Open questions at the time
    • Identity of the specific mislocalized cargoes causing proteotoxic stress not cataloged
    • Whether UPR induction is a general consequence of any karyopherin inhibition not tested
  13. 2019 Medium

    Mechanistic dissection of KPNB1 inhibition-induced TRAIL sensitization—via ATF4-driven DR5 upregulation, Mcl-1 release of Bax/Bak, and cap-dependent translation disruption of FLIP—connected the UPR consequences of KPNB1 inhibition to actionable combinatorial therapeutic strategies.

    Evidence siRNA and pharmacological KPNB1 inhibition, DISC immunoprecipitation, autophagy flux assays, TRAIL apoptosis assays in glioblastoma cells

    PMID:30742128

    Open questions at the time
    • Autophagy-mediated degradation of cleaved caspase-8 could limit efficacy; optimal autophagy co-inhibition schedule undefined
    • Generalizability beyond glioblastoma not tested
  14. 2020 High

    Discovery that KPNB1 imports PD-L1 into the nucleus where it acts as a transcriptional co-activator (with Sp1) of Gas6, activating MerTK signaling, revealed an unexpected non-canonical function of a surface immune checkpoint molecule dependent on KPNB1 transport.

    Evidence Co-IP (KPNB1–PD-L1), nuclear fractionation, ChIP of nuclear PD-L1/Sp1 on the Gas6 promoter, xenograft model in NSCLC

    PMID:33139930

    Open questions at the time
    • NLS or binding motif on PD-L1 recognized by KPNB1 not mapped
    • Whether nuclear PD-L1 import is importin-α-dependent or -independent not clarified
  15. 2022 High

    Identification of NFAT5 as a direct, importin-α-independent cargo of KPNB1 with a mapped NLS expanded the catalog of unconventional KPNB1 substrates and linked KPNB1 to cellular tonicity sensing.

    Evidence siRNA screen of 17 karyopherin-β members, Co-IP (direct KPNB1–NFAT5 interaction), NLS mutagenesis, nuclear fractionation, proteomics for export factors

    PMID:35794291

    Open questions at the time
    • Structural basis of KPNB1 recognition of the NFAT5-NLS not solved
    • Whether KPNB1 itself is regulated by tonicity not examined
  16. 2022 Medium

    Demonstrating that KPNB1 overexpression reduces polyQ-expanded ataxin-3 aggregates via CLPP-dependent proteolysis identified an unexpected neuroprotective role for KPNB1 in Machado-Joseph disease models, linking nuclear import to protein quality control of aggregation-prone substrates.

    Evidence Co-IP (KPNB1–ataxin-3), CLPP knockdown epistasis, KPNB1 levels measured in MJD mouse models and patient iPSCs

    PMID:35794401

    Open questions at the time
    • How KPNB1 channels ataxin-3 to CLPP rather than other proteases unclear
    • Whether KPNB1 reduction is a cause or consequence of MJD pathology not distinguished
    • Rescue experiment in animal model not performed
  17. 2023 Medium

    The finding that KPNB1 interacts with RTEL1 helicase and that RTEL1 deficiency destabilizes the nuclear envelope in S-phase connected KPNB1-mediated import to maintenance of nuclear envelope integrity during DNA replication.

    Evidence Co-IP (RTEL1–KPNB1, RTEL1–NUP153), domain truncation analysis, nuclear envelope phenotyping after KPNB1 inhibition

    PMID:38132118

    Open questions at the time
    • Whether KPNB1 imports RTEL1 or forms a structural complex at the NPC not distinguished
    • Mechanism by which RTEL1 C-terminus protects against KPNB1-inhibition-induced envelope defects unclear
  18. 2024 High

    Identification of USP7-mediated deubiquitination as a key KPNB1 stabilization mechanism, and of YBX1 as a KPNB1 cargo driving NLGN3-dependent glioblastoma growth, added a post-translational regulatory layer to KPNB1 abundance control with direct oncogenic output.

    Evidence Ubiquitination assays, Co-IP/mass spectrometry (KPNB1–YBX1), ChIP (YBX1 on NLGN3 promoter), USP7 knockdown, orthotopic intracranial tumor model

    PMID:38254206

    Open questions at the time
    • Ubiquitination site(s) on KPNB1 targeted by USP7 not mapped
    • Whether USP7 regulation of KPNB1 is context-specific (GBM) or general not determined
  19. 2024 Medium

    Discovery that TMEM209 competitively blocks RCHY1-mediated K48-ubiquitination and degradation of KPNB1, thereby stabilizing KPNB1 and activating Wnt/β-catenin signaling, revealed a second post-translational stabilization axis for KPNB1 in hepatocellular carcinoma.

    Evidence Co-IP (TMEM209–KPNB1–RCHY1), K48-linked ubiquitination assays, KPNB1 knockdown/rescue, xenograft models

    PMID:39414762

    Open questions at the time
    • Whether USP7 and TMEM209/RCHY1 pathways converge on the same ubiquitination sites unknown
    • Mechanism linking KPNB1 to Wnt/β-catenin activation not specified beyond correlation
  20. 2024 High

    Mapping ATF4 amino acids 280–299 as the direct KPNB1-recognized NLS, and showing that KPNB1-imported ATF4 drives BNIP3-dependent mitophagy in differentiating dental pulp stem cells, defined a new importin-α-independent cargo circuit connecting KPNB1 to mitophagy and cell differentiation.

    Evidence IP-mass spectrometry, ATF4 NLS mutagenesis (aa 280–299), ChIP-PCR (ATF4 on BNIP3 promoter), dual-luciferase reporter, xenograft differentiation model

    PMID:39604846

    Open questions at the time
    • Whether KPNB1-ATF4 import operates in other differentiation or stress contexts not tested
    • Structural basis of KPNB1 recognition of the ATF4 NLS not solved
  21. 2025 High

    Identification of VCP as a direct KPNB1 cargo for nuclear import required for DNA damage repair, and covalent mapping of withaferin A to KPNB1 Cys158 as a mechanism of transport blockade, provided the first covalent drugging site on KPNB1 and linked its transport function to DDR.

    Evidence Chemical pulldown + IP-MS (VCP–KPNB1), biochemical nuclear import assay, Cys158 site mapping/mutagenesis, in vivo antitumor efficacy of withaferin A

    PMID:40339118

    Open questions at the time
    • Whether Cys158 modification affects all KPNB1 cargoes or selectively VCP not determined
    • Selectivity of withaferin A for KPNB1 versus other cysteine-containing targets not fully profiled
  22. 2025 High

    Demonstration that KPNB1 imports HMGB2 into the nucleus for DNA damage repair in AML, and that import blockade synergizes with venetoclax, provided a rationale for combinatorial targeting of KPNB1 in hematological malignancies.

    Evidence Co-IP (KPNB1–HMGB2), importazole inhibition, nuclear fractionation, DDR assays, MLL-AF9 AML mouse model, patient-derived xenografts

    PMID:40082556

    Open questions at the time
    • NLS on HMGB2 recognized by KPNB1 not mapped
    • Whether KPNB1 inhibition sensitizes to other DDR-targeting agents not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive catalog of importin-α-independent versus importin-α-dependent KPNB1 cargoes, the structural determinants of direct cargo recognition by KPNB1's HEAT repeats, and the therapeutic window for KPNB1 inhibition in normal versus malignant tissue remain to be established.
  • No systematic unbiased interactome distinguishing direct from adapter-mediated cargoes
  • No high-resolution structure of KPNB1 bound to an importin-α-independent cargo
  • Therapeutic index of KPNB1 inhibition not defined in preclinical or clinical settings

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 9 GO:0060090 molecular adaptor activity 5
Localization
GO:0005634 nucleus 4 GO:0005635 nuclear envelope 3 GO:0005829 cytosol 3
Pathway
R-HSA-9609507 Protein localization 11 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9909396 Circadian clock 1
Partners
CASKPNA2NUP153RANRCHY1RTEL1TMEM209USP7
Complex memberships
importin-α/β heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Crystal structure of human importin-β (KPNB1) bound to the importin-β-binding (IBB) domain of importin-α was solved at 2.3–2.5 Å resolution. KPNB1 consists of 19 tandemly repeated HEAT motifs and wraps intimately around the IBB domain via two separate regions recognizing structurally distinct parts: an N-terminal extended moiety and a C-terminal helix. The structure indicates that significant conformational changes occur when KPNB1 binds or releases the IBB domain. X-ray crystallography (two crystal forms, 2.5 Å and 2.3 Å) Nature High 10353244
1996 RanGDP binds to the nuclear pore complex (NPC) independently of the Ran-binding sites of importin-β (KPNB1), and a KPNB1 mutant deficient in Ran binding can deliver cargo to the nucleoplasmic side of the NPC but cannot release the import substrate; thus, nucleoplasmic RanGTP binding to KPNB1 triggers termination of import by displacing importin-α and releasing the cargo. Biochemical import assay with Xenopus egg extracts, dominant-negative Ran mutants, importin-β Ran-binding mutant The EMBO Journal High 8896452
1995 Importin-β (the 90 kDa subunit, KPNB1 homolog) cooperates with importin-α (60 kDa) to form a heterodimeric cytosolic NLS receptor; together they recognize nuclear localization signals and mediate binding to the nuclear envelope. KPNB1 potentiates importin-α function; the heterodimer is the physiological import unit. Affinity chromatography (biotin-NLS pulldown from Xenopus egg extracts), reconstituted nuclear import assay, protein sequencing and cloning Current Biology High 7627554
1997 After nuclear import, importin-α must be exported from the nucleus by the CAS protein. RanGTP in the nucleus binds importin-β (KPNB1) and displaces importin-α; CAS then forms a trimeric complex with importin-α and RanGTP to re-export importin-α to the cytoplasm, where RanBP1 and RanGAP1 disassemble the complex. This defines KPNB1's role in the import–export cycle. Biochemical reconstitution, RanGTP/RanGDP binding assays, nuclear export assays in Xenopus extracts Cell High 9323134
2001 Crystal structures of KPNB1 complexes with import substrates (cargo), Ran, and nucleoporins, together with structures of karyopherin-α complexes with NLS peptides and karyopherin-β2–Ran complex, provided mechanistic insight into substrate recognition, substrate release triggered by RanGTP, and interactions with the nuclear pore complex. X-ray crystallography of multiple karyopherin complexes (review of solved structures) Current Opinion in Structural Biology High 11751052
2013 High-content siRNA screening of 17 importin-β family members identified KPNB1 as the major importin-β receptor mediating nuclear import of NF-κB/p65 following TNF-α stimulation. KPNB1-mediated p65 import was dependent on the NLS of p65 and required KPNA2 as the primary importin-α partner (canonical KPNA2/KPNB1 pathway). XPO7 and IPO8 mediate a parallel, NLS-independent pathway for p65. High-content siRNA screen, knockdown of 17 importin-β members, NF-κB reporter assay, nuclear fractionation Traffic High 23906023
2015 KPNB1 mediates nuclear translocation of the PER/CRY repressor complex in human cells by interacting primarily with PER proteins (not CRY) and directing their nuclear import in a circadian (time-of-day-dependent) fashion. RNAi depletion of KPNB1 traps PER/CRY in the cytoplasm. Importantly, KPNB1 functions independently of importin-α in this pathway. Inducible inhibition of the conserved Drosophila importin-β in lateral neurons abolishes behavioral circadian rhythms. RNAi knockdown in human cells, co-immunoprecipitation of KPNB1 with PER proteins, cytoplasmic/nuclear fractionation, live-imaging, Drosophila behavioral rhythm assay eLife High 26319354
2012 Ivermectin is a broad-spectrum inhibitor of importin-α/β (KPNB1)-mediated nuclear import and has no effect on importin-β1-alone pathways. It inhibits HIV-1 replication (by blocking nuclear import of HIV-1 integrase) and dengue virus replication (blocking NS5 import), demonstrating that KPNB1-dependent import is required for HIV-1 and dengue virus replication. Nuclear import competition assay, antiviral replication assays (HIV-1 and dengue), specificity controls across multiple import pathways Biochemical Journal High 22417684
2014 EZH2 inhibits miR-30d transcription by binding its promoter; miR-30d directly targets the 3′ UTR of KPNB1 mRNA and suppresses KPNB1 protein expression. Elevated KPNB1 (due to EZH2 upregulation and miR-30d loss) is critical for MPNST cell survival and tumorigenesis. Forced KPNB1 overexpression rescues apoptosis induced by EZH2 knockdown, placing KPNB1 as a downstream effector of the EZH2/miR-30d axis. EZH2 ChIP-seq (promoter binding), miR-30d 3′UTR luciferase reporter, siRNA knockdown, epistasis rescue by KPNB1 overexpression, xenograft tumor model Journal of Pathology High 24132643
2017 In vivo dropout shRNA and genome-wide CRISPR/Cas9 screens in ovarian cancer xenografts identified KPNB1 as an essential oncogene. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle proteins including p21, p27, and APC/C components; its inhibition induces multi-phase cell cycle arrest and apoptosis. Ivermectin exerts KPNB1-dependent antitumor effects. In vivo pooled shRNA dropout screen, genome-wide CRISPR/Cas9 screen, quantitative proteomics, pharmacological inhibition with ivermectin, xenograft models PNAS High 28811376
2018 KPNB1 inhibition in glioblastoma cells disrupts proteostasis: cytosolic retention of nuclear import cargo leads to elevated polyubiquitination, aggresome-like induced structure (ALIS) formation, and unfolded protein response (UPR) activation. Chronic eIF2α/ATF4 UPR signaling upregulates pro-apoptotic Puma and Noxa, frees Mcl-1-sequestered Bax and Bak, and causes mitochondrial outer membrane permeabilization and apoptosis. KPNB1 overexpression or protein synthesis inhibitors restore proteostasis. KPNB1 siRNA and pharmacological inhibition, immunofluorescence (ALIS), polyubiquitination assays, UPR pathway analysis (western blot), flow cytometry (apoptosis), KPNB1 rescue overexpression Oncogene High 29520102
2017 KPNB1 is essential for nuclear translocation of NF-κB and AP-1 in cervical cancer cells; its inhibition by siRNA or the small-molecule INI-43 retains these transcription factors in the cytoplasm, reduces their transcriptional activity, decreases expression of IL-6, IL-1β, TNF-α, and GM-CSF, and impairs cancer cell migration and invasion. siRNA knockdown, INI-43 pharmacological inhibition, nuclear fractionation, transcription factor reporter assays, migration/invasion assays Oncotarget Medium 28427184
2019 KPNB1 inhibition in glioblastoma cells overcomes TRAIL resistance through UPR-mediated mechanisms: (1) ATF4 upregulates DR5 expression and promotes DISC assembly; (2) KPNB1 inhibition releases Bax and Bak from Mcl-1; (3) FLIPL and FLIPS are downregulated via ATF4-induced 4E-BP1 expression that disrupts cap-dependent translation. Concurrently, KPNB1 inhibition-induced autophagy degrades cleaved caspase-8, and blocking autophagic flux synergizes with TRAIL. Genetic (siRNA) and pharmacological KPNB1 inhibition, DISC immunoprecipitation, western blot for Bcl-2 family members, caspase assays, autophagy flux assays, TRAIL apoptosis assay Cell Death & Disease Medium 30742128
2020 KPNB1 binds PD-L1 and facilitates its nuclear translocation in NSCLC cells. Nuclear PD-L1, together with transcription factor Sp1, drives Gas6 mRNA synthesis and secretion, which activates MerTK signaling to promote cancer cell proliferation. KPNB1 knockdown reduces nuclear PD-L1 and downstream Gas6/MerTK pathway activity. Co-immunoprecipitation (KPNB1–PD-L1 interaction), nuclear/cytoplasmic fractionation, ChIP (nuclear PD-L1 + Sp1 on Gas6 promoter), siRNA knockdown, xenograft model Cell Death and Differentiation High 33139930
2022 KPNB1 directly mediates nuclear import of the tonicity-responsive transcription factor NFAT5 via a unique NLS (NFAT5-NLS) through direct protein interaction; karyopherin-α is not required. Nuclear export of NFAT5 under hypotonicity is driven by exportin-T (XPOT) with RUVBL2 as an indispensable chaperone, defining an unconventional tonicity-dependent nucleocytoplasmic trafficking pathway. siRNA screen (17 karyopherin-β members), Co-IP (KPNB1–NFAT5 direct interaction), NLS mutagenesis, nuclear fractionation, proteomics for export factors Journal of Cell Science High 35635291
2019 KPNB1 mediates nuclear transport of E2F1 in chronic myeloid leukemia (CML) cells; KPNB1 overexpression drives excessive nuclear E2F1 accumulation, promoting expression of c-Myc and KPNA2. siRNA knockdown of KPNB1 blocks E2F1 nuclear entry (confirmed by immunofluorescence), reduces proliferation, and induces apoptosis. The KPNB1 inhibitor importazole (IPZ) arrests CML cells at G2/M and induces apoptosis. siRNA knockdown, importazole pharmacological inhibition, immunofluorescence (E2F1 localization), western blot, flow cytometry (cell cycle/apoptosis) OncoTargets and Therapy Medium 31819526
2022 KPNB1 directly interacts with both wild-type and polyQ-expanded ataxin-3 (Machado-Joseph disease protein). KPNB1 overexpression reduces ataxin-3 protein levels and aggregate load (improving cell viability) through a proteolytic pathway involving mitochondrial protease CLPP, independent of classical MJD-associated proteolytic pathways. KPNB1 levels are reduced in two MJD transgenic mouse models and in MJD patient-derived iPSCs. Co-immunoprecipitation (KPNB1–ataxin-3), overexpression/knockdown, label-free quantitative proteomics, CLPP knockdown epistasis, MJD mouse models, iPSCs Cellular and Molecular Life Sciences Medium 35794401
2024 KPNB1 stability is regulated by the deubiquitinase USP7, which deubiquitinates and stabilizes KPNB1. KPNB1 mediates nuclear import of transcription factor YBX1, which then binds the NLGN3 promoter to drive Neuroligin-3 expression, promoting glioblastoma progression. USP7 inhibition or knockdown reduces KPNB1 protein levels and impairs this signaling axis. Ubiquitination assays, Co-IP/mass spectrometry (KPNB1–YBX1 interaction), nuclear-cytoplasmic fractionation, immunofluorescence (YBX1 localization), ChIP (YBX1 on NLGN3 promoter), USP7 knockdown/inhibition, intracranial orthotopic tumor model Journal of Experimental & Clinical Cancer Research High 38254206
2024 TMEM209 binds KPNB1 and competitively blocks its interaction with E3 ubiquitin ligase RCHY1, preventing K48-linked ubiquitination-dependent degradation of KPNB1 and thereby stabilizing KPNB1 protein. Stabilized KPNB1 activates Wnt/β-catenin signaling to promote HCC proliferation and metastasis. Co-IP (TMEM209–KPNB1–RCHY1 interactions), ubiquitination assays (K48-specific), KPNB1 knockdown/rescue, xenograft models Cell Death Discovery Medium 39414762
2025 VCP (valosin-containing protein) is a novel cargo of KPNB1; KPNB1 directly transports VCP into the nucleus to facilitate DNA damage repair. The natural compound withaferin A (WA) covalently binds Cys158 of KPNB1, blocking VCP nuclear translocation and impairing the DDR pathway in tumor cells. Chemical pulldown + immunoprecipitation mass spectrometry (VCP–KPNB1 interaction), biochemical nuclear import assay, covalent binding site mapping (Cys158), in vivo antitumor efficacy PNAS High 40339118
2023 KPNB1 directly interacts with RTEL1 helicase via its C-terminus, and RTEL1 also interacts with NUP153. RTEL1 deficiency causes nuclear envelope destabilization specifically in S-phase. Overexpression of the RTEL1 C-terminus (lacking the helicase domain) protects against nuclear envelope anomalies induced by KPNB1 inhibition, linking KPNB1-mediated protein import to nuclear envelope integrity during DNA replication. Co-IP (RTEL1–KPNB1, RTEL1–NUP153), RTEL1 truncation analysis, KPNB1 inhibition nuclear envelope phenotype, high-resolution microscopy Cells Medium 38132118
2021 KPNB1 inhibitor importazole reduces radiation-increased PD-L1 surface expression on head-and-neck cancer cells by two mechanisms: (1) decreasing IRF1 upregulation after irradiation, and (2) blocking nuclear import of IRF1. IRF1 knockdown confirmed that IRF1 nuclear activity is required for radiation-induced PD-L1 expression. KPNB1 inhibitor importazole, IRF1 siRNA knockdown, immunofluorescence (IRF1 localization), western blot, flow cytometry (surface PD-L1) Current Issues in Molecular Biology Medium 34069326
2025 KPNB1 inhibition in AML cells blocks nuclear import of HMGB2 (high mobility group box 2 protein), a newly identified KPNB1 cargo. Nuclear HMGB2 is required for DNA damage repair; its cytoplasmic retention upon KPNB1 inhibition compromises DNA damage repair capacity in AML cells and synergizes with venetoclax. Co-IP (KPNB1–HMGB2 interaction), importazole pharmacological inhibition, nuclear/cytoplasmic fractionation, DNA damage repair assays, MLL-AF9 AML mouse model, patient-derived xenografts Oncogene High 40082556
2024 KPNB1 mediates nuclear import of ATF4 by directly recognizing amino acids 280–299 within ATF4's NLS. KPNB1-imported ATF4 binds the BNIP3 promoter (~−1292 to −1279 bp and ~−1185 to −1172 bp) to induce BNIP3 expression, which drives BNIP3-dependent mitophagy required for odontoblastic differentiation of dental pulp stem cells. IP-mass spectrometry (KPNB1–ATF4 interaction), ATF4 NLS mutagenesis (aa 280–299), ChIP-PCR (ATF4 on BNIP3 promoter), dual-luciferase reporter, nuclear fractionation, xenograft differentiation model Cellular & Molecular Biology Letters High 39604846
2025 O-GlcNAcylated RNA Polymerase II CTD (at Ser-5) is recognized by KPNB1 as a reader of this modification; mass spectrometry identified KPNB1 as a binding partner of O-GlcNAc-Ser5-CTD. Functional experiments show that both OGT and KPNB1 are required for efficient RNA Pol II entry into the nucleus and chromatin, suggesting KPNB1 facilitates nuclear import of RNA Pol II in response to O-GlcNAcylation. WGA-lectin pulldown (O-GlcNAcylated proteins), mass spectrometry (KPNB1 identified as CTD reader), structural modeling, wChIP (O-GlcNAc RNA Pol II at promoters), siRNA knockdown of OGT and KPNB1 bioRxivpreprint Low bio_10.1101_2025.03.18.643968
2017 KPNB1 mediates nuclear import of Newcastle disease virus (NDV) matrix (M) protein: M protein co-immunoprecipitates with KPNA1 and KPNB1 (chicken orthologs). Dominant-negative KPNB1 (but not DN-KPNA1) disrupts nuclear localization of M protein, and Ran-Q69L (constitutively GTP-bound) similarly disrupts M protein nuclear import, indicating KPNB1 and Ran cooperate to import NDV M protein. Co-immunoprecipitation, dominant-negative KPNB1 expression, Ran mutant co-expression, fluorescent co-localization in HEK-293T cells Acta Microbiologica Sinica Medium 29746765

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Systematic and quantitative assessment of the ubiquitin-modified proteome. Molecular cell 1334 21906983
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
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