Affinage

KPNA3

Importin subunit alpha-4 · UniProt O00505

Length
521 aa
Mass
57.8 kDa
Annotated
2026-06-10
26 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KPNA3 (importin α4/hSRP1γ) is a cytosolic adaptor of the classical nuclear import pathway that directly and specifically recognizes simple and bipartite nuclear localization signals (NLS) on cargo proteins and escorts them to the nuclear pore (PMID:7754385). It functions as an adaptor by tethering NLS substrates to importin β (p97) through a short, conserved N-terminal domain that is necessary and sufficient for importin β binding, while a separate C-terminal region engages cargo NLS motifs (PMID:8617227, PMID:9211983). Within the importin α family KPNA3 displays isoform-selective cargo discrimination, recognizing substrates such as the DNA helicase RecQL/Q1 that other family members do not (PMID:9168958). Through this activity KPNA3 drives the nuclear import of a range of transcriptional and regulatory factors, including heat shock factor (HSF) in the late heat shock response (PMID:26367326), NF-κB p65 (PMID:37392568), TFEB and CREB to sustain autophagy and neurotrophin expression (PMID:40294738), and the osteoblast master regulator Runx2 (PMID:41903133). Beyond passive shuttling, KPNA3 actively regulates the biophysical state of its cargo: by binding NPAT and Runx2 it sterically blocks self-association motifs, suppressing aberrant cytoplasmic phase separation and condensate formation while enabling proper nuclear assembly such as histone locus body formation (PMID:39621428, PMID:41903133). KPNA3 is also exploited by viral proteins to support nuclear import-dependent replication (PMID:33616472). Patient-derived KPNA3 variants causing hereditary spastic paraplegia alter its expression, localization, and interactions, establishing dysfunctional nucleocytoplasmic shuttling as a disease pathomechanism (PMID:34564892).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Established that KPNA3 is a bona fide cytosolic NLS receptor, answering how NLS-bearing proteins are first recognized for nuclear delivery.

    Evidence In vitro NLS-binding, nuclear envelope docking, and reconstitution of complete import with recombinant Ran

    PMID:7754385

    Open questions at the time
    • Did not define the importin β-binding interface
    • Cargo repertoire beyond model NLS substrates unaddressed
  2. 1996 High

    Defined KPNA3 as an adaptor by localizing importin β binding to a short N-terminal domain, explaining how NLS cargo is physically coupled to the import machinery.

    Evidence Deletion mutagenesis with in vitro import inhibition, reporter fusion import, and in vivo nuclear exit assays

    PMID:8617227

    Open questions at the time
    • Did not map the cargo-binding region structurally
    • Regulation of adaptor cycling not addressed
  3. 1997 Medium

    Confirmed KPNA3/importin β complex formation drives generic NLS-substrate import and revealed isoform-specific cargo discrimination and a defined C-terminal cargo-binding region.

    Evidence In vitro import with BSA-NLS, complex-formation assays, yeast two-hybrid, GST pulldown, and deletion mapping for RecQL and p120

    PMID:9168958 PMID:9211983 PMID:9435235

    Open questions at the time
    • Physiological relevance of RecQL and p120 import not tested in cells
    • Basis of isoform selectivity not structurally resolved
  4. 2015 Medium

    Linked KPNA3 to a specific physiological output by showing its import of HSF is required for the late heat shock response.

    Evidence Pull-down and GST-pulldown with recombinant proteins plus RNAi knockdown with HSP mRNA quantification (Bombyx mori ortholog)

    PMID:26367326

    Open questions at the time
    • Demonstrated in insect ortholog, not human
    • Mechanism of timing-specific (late peak) regulation unclear
  5. 2021 Medium

    Connected KPNA3 dysfunction to human disease, establishing impaired nucleocytoplasmic shuttling as a cause of hereditary spastic paraplegia.

    Evidence Trio whole-exome sequencing with cellular/biochemical assays of variant expression, localization, and interaction

    PMID:34564892

    Open questions at the time
    • Specific cargo whose mislocalization drives neurodegeneration not identified
    • Variant effects not modeled in neurons
  6. 2021 Medium

    Showed viral proteins hijack KPNA3 for replication, mapping a viral NLS interaction and demonstrating functional dependence on KPNA3.

    Evidence Co-interaction assay, CRISPR knockout and overexpression, and rescue with Fiber-2 deletion mutant in replication assays (FAdV-4)

    PMID:33616472

    Open questions at the time
    • Redundancy with KPNA4 not fully separated
    • Structural basis of Fiber-2 NLS recognition unresolved
  7. 2024 High

    Revealed a moonlighting function beyond transport: KPNA3 sterically suppresses cytoplasmic cargo phase separation, answering how it ensures proper nuclear condensate assembly.

    Evidence Co-IP, in vitro import and phase-separation assays, domain mapping, live-cell imaging, and structural modeling of NPAT

    PMID:39621428

    Open questions at the time
    • Generality across other condensate-forming cargoes initially untested
    • Quantitative thresholds for steric suppression undefined
  8. 2025 Medium

    Extended KPNA3 cargo physiology to TFEB and CREB, linking its import activity to autophagy and neurotrophin programs downstream of SDF2L1.

    Evidence Proteomics, knockdown/overexpression, nuclear/cytoplasmic fractionation, and SDF2L1 KO mouse rescue in Schwann cells

    PMID:40294738

    Open questions at the time
    • Direct NLS binding to TFEB/CREB not biochemically dissected
    • Mechanism linking SDF2L1 to KPNA3 expression unclear
  9. 2026 High

    Generalized the dual transport/anti-aggregation role to Runx2, showing KPNA3 import and condensate control are required for osteoblast differentiation and depend on a polyQ-regulated NLS.

    Evidence KPNA3 depletion, Co-IP, import and phase-separation assays, structural modeling, and osteoblast differentiation readout

    PMID:41903133

    Open questions at the time
    • In vivo skeletal consequences not tested
    • Interplay between polyQ length and NLS accessibility not fully quantified
  10. 2026 Medium

    Implicated KPNA3 in cancer signaling and identified it as a druggable target, with ivermectin binding KPNA3 to promote myeloma apoptosis.

    Evidence KPNA3 knockdown in vitro/in vivo, direct ivermectin-binding assay, hedgehog pathway and apoptosis readouts in multiple myeloma

    PMID:41813919

    Open questions at the time
    • Mechanism linking KPNA3 to ALDH2 transcription unclear
    • Selectivity of ivermectin for KPNA3 over other importins not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KPNA3 cargo selectivity and its anti-phase-separation activity are coordinated and regulated across tissues, and which cargo defects underlie its disease associations, remains unresolved.
  • No unifying structural model of isoform-specific NLS recognition
  • Regulation of the steric anti-condensation function unknown
  • Disease-causal cargo for HSP not pinpointed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140104 molecular carrier activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-74160 Gene expression (Transcription) 3
Partners
CREBHSFKPNB1NPATRECQLRUNX2TFEB
Complex memberships
importin α/β heterodimer

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 hSRP1α (KPNA3 alias) binds in vitro directly and specifically to substrates containing either a simple or bipartite NLS motif, promotes docking of import substrates to the nuclear envelope, and together with recombinant human Ran reconstitutes complete nuclear protein import in vitro, establishing it as a cytosolic receptor for NLS motifs. In vitro NLS-binding assay, nuclear envelope docking assay, in vitro nuclear import reconstitution with recombinant proteins Science High 7754385
1996 A short conserved amino-terminal domain of hSRP1α is necessary and sufficient for interaction with the p97 (importin β) subunit; fusion of this domain to a cytoplasmic reporter is sufficient to promote complete nuclear import, and addition of the domain alone inhibits import of NLS-containing proteins in vitro. Full-length hSRP1α can exit the nucleus, but the amino-terminal domain alone cannot, establishing hSRP1α as an adaptor tethering NLS substrates to the import machinery via its N-terminal p97-binding domain. Deletion mutagenesis, in vitro nuclear import inhibition assay, reporter fusion import assay, in vivo nuclear exit assay The EMBO journal High 8617227
1997 hSRP1γ (KPNA3) can form a complex with importin β and mediates import of a BSA-NLS substrate in an in vitro nuclear import system, demonstrating its functional activity as an importin α adaptor. Complex formation assay, in vitro nuclear import assay with BSA-NLS substrate Proceedings of the National Academy of Sciences of the United States of America Medium 9435235
1997 KPNA3 (Qip1/hSrp1) interacts with DNA helicase Q1/RecQL via a putative NLS in Q1; unlike hSrp1, Qip1 and Rch1 but not hSrp1 interact with the Q1 NLS in two-hybrid assays, indicating isoform-specific substrate discrimination among importin α family members. Yeast two-hybrid screening, GST pulldown from human cell lysates Biochemical and biophysical research communications Medium 9168958
1997 KPNA3 (hSRP1) binds proliferation-related nucleolar protein p120 through p120's NLS (amino acids 96–119) and requires the C-terminus of hSRP1 (amino acids 453–491); interaction confirmed by yeast two-hybrid and co-expression in Sf9 cells. Yeast two-hybrid screen, deletion mutagenesis, co-expression/co-immunoprecipitation in Sf9 insect cells Chromosoma Medium 9211983
2015 KPNA3 in Bombyx mori interacts directly with heat shock transcription factor (HSF) and transports it into the nucleus; KPNA3 knockdown eliminates the second HSP mRNA expression peak at 24 h after heat shock without reducing HSF protein levels, demonstrating that KPNA3-mediated nuclear import of HSF is required for the late heat shock response. Pull-down assay from tissue lysates, GST-pulldown with recombinant proteins, RNAi knockdown with mRNA quantification Gene Medium 26367326
2021 KPNA3 variants associated with hereditary spastic paraplegia show altered expression levels, subcellular distribution, and protein interaction, implicating dysfunctional nucleocytoplasmic shuttling as a pathomechanism for HSP. Trio whole-exome sequencing, bioinformatics, cellular and biochemical assays measuring protein expression, subcellular localization, and protein interaction Annals of neurology Medium 34564892
2021 The N-terminal domain (1–40 aa) of FAdV-4 Fiber-2 protein interacts with KPNA3/4; overexpression of KPNA3/4 enhances FAdV-4 replication, while knockout reduces it; deletion of residues 7–40 in Fiber-2 attenuates the virus, demonstrating KPNA3 assists nuclear import-dependent viral replication. Co-interaction assay, KPNA3/4 overexpression and CRISPR-Cas9 knockout, rescue of virus with Fiber-2 deletion mutant, in vitro and in vivo replication assays Virulence Medium 33616472
2023 miR-26a inhibits nuclear translocation of NF-κB p65 by targeting KPNA3; KPNA3 mediates p65 nuclear import in OA chondrocytes, and p65 transcriptionally activates LOC727924, forming a p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop. miRNA inhibitor/mimic experiments, KPNA3 knockdown/overexpression, nuclear/cytoplasmic fractionation, luciferase reporter, in vivo DMM mouse model with immunostaining International immunopharmacology Medium 37392568
2024 KPNA3 specifically drives nuclear import of NPAT by binding its NLS, and simultaneously sterically blocks a C-terminal self-interaction facilitator (C-SIF) motif-dependent NPAT self-association, thereby suppressing aberrant cytoplasmic NPAT phase separation/condensation and enabling proper histone locus body (HLB) formation in the nucleus. Co-immunoprecipitation, in vitro nuclear import assay, phase separation/condensation assays, deletion and domain-mapping mutagenesis, live-cell imaging, structural modeling The Journal of cell biology High 39621428
2025 KPNA3 mediates nuclear import of transcription factors TFEB and CREB in Schwann cells; SDF2L1 knockdown reduces KPNA3 expression, impairing TFEB and CREB nuclear accumulation and consequently suppressing autophagy and neurotrophin expression; KPNA3 overexpression rescues these deficits. Proteomics, KPNA3 knockdown/overexpression, nuclear/cytoplasmic fractionation, in vivo SDF2L1 KO mouse model Experimental neurology Medium 40294738
2026 KPNA3/importin α4 specifically governs Runx2 nuclear import; depletion of KPNA3 inhibits osteoblast differentiation. The polyQ repeat of Runx2 keeps the NLS accessible for KPNA3 binding; polyQ deletion causes folding of the N-terminus (blocking KPNA3 access) and leads to aberrant cytoplasmic Runx2 aggregation. KPNA3 also modulates Runx2 liquid-like condensate state. KPNA3 depletion (KO/KD), co-immunoprecipitation, nuclear import assays, structural modeling, condensation/phase-separation assays, osteoblast differentiation assay Cell reports High 41903133
2026 KPNA3 knockdown in multiple myeloma cells inhibits ALDH2 transcription and downregulates hedgehog pathway activity; ivermectin binds directly to KPNA3, reduces KPNA3 protein levels, and promotes MM cell apoptosis. KPNA3 knockdown (in vitro and in vivo), drug-binding assay (ivermectin-KPNA3 direct binding), pathway activity measurements, apoptosis assays Apoptosis Medium 41813919

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Identification of hSRP1 alpha as a functional receptor for nuclear localization sequences. Science (New York, N.Y.) 320 7754385
1996 The conserved amino-terminal domain of hSRP1 alpha is essential for nuclear protein import. The EMBO journal 227 8617227
2018 LncRNA DLEU1 contributes to colorectal cancer progression via activation of KPNA3. Molecular cancer 115 30098595
1998 Cloning and characterization of hSRP1 gamma, a tissue-specific nuclear transport factor. Proceedings of the National Academy of Sciences of the United States of America 97 9435235
1997 Cloning of a cDNA encoding a novel importin-alpha homologue, Qip1: discrimination of Qip1 and Rch1 from hSrp1 by their ability to interact with DNA helicase Q1/RecQL. Biochemical and biophysical research communications 82 9168958
2021 Exosomal Long Non-coding RNA HOTTIP Increases Resistance of Colorectal Cancer Cells to Mitomycin via Impairing MiR-214-Mediated Degradation of KPNA3. Frontiers in cell and developmental biology 39 33585440
2021 Domain in Fiber-2 interacted with KPNA3/4 significantly affects the replication and pathogenicity of the highly pathogenic FAdV-4. Virulence 30 33616472
2019 KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition. Journal of Cancer 27 31417635
2023 SIRT1 promotes the progression and chemoresistance of colorectal cancer through the p53/miR-101/KPNA3 axis. Cancer biology & therapy 25 37575080
1997 Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RCH1. Cytogenetics and cell genetics 23 9154134
2012 KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence. Disease markers 17 22960338
2016 A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma. Cold Spring Harbor molecular case studies 14 27626065
2006 A combined effect of the KPNA3 and KPNB3 genes on susceptibility to schizophrenia. Neuroscience letters 12 16644122
2021 Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia. Annals of neurology 11 34564892
2022 Importin α3 (KPNA3) Deficiency Augments Effortful Reward-Seeking Behavior in Mice. Frontiers in neuroscience 10 35844217
2005 The KPNA3 gene may be a susceptibility candidate for schizophrenia. Neuroscience research 10 15882913
2023 The p65-LOC727924-miR-26a/KPNA3-p65 regulatory loop mediates vasoactive intestinal peptide effects on osteoarthritis chondrocytes. International immunopharmacology 9 37392568
2024 KPNA3 regulates histone locus body formation by modulating condensation and nuclear import of NPAT. The Journal of cell biology 6 39621428
2020 C/EBPα-mediated transcriptional activation of miR-134-5p entails KPNA3 inhibition and modulates focal hypoxic-ischemic brain damage in neonatal rats. Brain research bulletin 6 32814091
2025 SDF2L1 downregulation mediates high glucose-caused Schwann cell dysfunction by inhibiting nuclear import of TFEB and CREB via KPNA3. Experimental neurology 3 40294738
2023 KPNA3 promotes epithelial-mesenchymal transition by regulating TGF-β and AKT signaling pathways in MDA-MB-231, a triple-negative breast cancer cell line. BMB reports 3 36593106
2025 Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice. Genes 1 40565582
2015 KPNA3-knockdown eliminates the second heat shock protein peak associated with the heat shock response of male silkworm pupae (Bombyx mori) by reducing heat shock factor transport into the nucleus. Gene 1 26367326
2026 The role of KPNA3 in multiple myeloma: implications for targeting nuclear import. Apoptosis : an international journal on programmed cell death 0 41813919
2026 Polyglutamine homorepeat regulates Runx2 condensation and cellular localization in a KPNA3-dependent manner. Cell reports 0 41903133
1997 Human proliferation-related protein p120 interacts with HSRP1. Chromosoma 0 9211983

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