Affinage

KPNA4

Importin subunit alpha-3 · UniProt O00629

Round 2 corrected
Length
521 aa
Mass
57.9 kDa
Annotated
2026-04-28
55 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KPNA4 (importin subunit α-3/Qip1) is a classical nuclear import adaptor of the importin-α/β pathway that recognizes nuclear localization signals on cargo proteins—including NF-κB p65, p53, SV40 T antigen, and influenza A nucleoprotein—and mediates their translocation through the nuclear pore complex (PMID:9168958, PMID:33798680, PMID:27941876). By controlling nuclear access of NF-κB p65, KPNA4 activates NF-κB target gene programs that drive epithelial-mesenchymal transition, cancer cell invasion, and macrophage polarization in prostate cancer and glioblastoma models (PMID:27941876, PMID:26283154, PMID:33188837). KPNA4 is required for lens homeostasis through p53 nuclear import, as kpna4-knockout zebrafish develop cataract-like lens defects with cytoplasmic p53 accumulation (PMID:33798680), and Kpna4-knockout mice display a hypermotor, ADHD-like behavioral phenotype (PMID:40565582). Beyond its canonical transport role, KPNA4 contributes to influenza A vRNA replication through a nuclear-transport-independent mechanism (PMID:23383277).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1997 Medium

    Identification of KPNA4 as a distinct importin-α family member answered whether additional NLS-recognition adaptors exist beyond hSrp1, establishing that KPNA4 binds SV40 T-antigen NLS and preferentially recognizes DNA helicase Q1.

    Evidence Yeast two-hybrid and GST pulldown from human cell lysates

    PMID:9168958

    Open questions at the time
    • No in vivo nuclear import assay performed
    • Specificity over other importin-α paralogs not systematically compared
    • Structural basis of NLS discrimination unknown
  2. 2013 Medium

    Discovery that KPNA4 silencing reduces influenza vRNA replication independently of NP nuclear localization established a non-canonical, transport-independent function for an importin-α adaptor in viral RNA metabolism.

    Evidence siRNA knockdown with NP alanine-substitution mutant viruses, vRNA transcription/replication assays

    PMID:23383277

    Open questions at the time
    • Molecular mechanism of transport-independent vRNA replication support undefined
    • Whether other importin-α paralogs share this activity not tested
    • No reconstitution of the KPNA4–NP complex activity in vitro
  3. 2015 Medium

    Demonstration that KPNA4 is the functional effector downstream of miR-181b in glioblastoma EMT placed KPNA4 as a rate-limiting node connecting NF-κB nuclear import to mesenchymal gene programs in brain tumors.

    Evidence miR-181b overexpression with KPNA4 rescue, in vitro invasion assays and in vivo xenograft

    PMID:26283154

    Open questions at the time
    • Direct KPNA4–p65 binding in glioblastoma cells not demonstrated
    • Contribution of other importin-α isoforms not excluded
    • Single-lab finding
  4. 2016 High

    In vivo evidence that KPNA4 knockdown suppresses prostate cancer metastasis and remodels the tumor microenvironment via TNF signaling established KPNA4-mediated NF-κB nuclear import as a driver of metastatic progression and immune modulation.

    Evidence Stable shRNA in PCa cell lines, mouse metastasis models, TNF cytokine measurements, miR-708 target validation

    PMID:27941876

    Open questions at the time
    • Whether KPNA4 imports other pro-metastatic transcription factors besides NF-κB not examined
    • Macrophage polarization mechanism downstream of TNF not fully dissected
  5. 2020 Medium

    Reporter and fractionation experiments in thyroid cancer cells confirmed that KPNA4 directly controls NF-κB p65 nuclear accumulation and downstream transcriptional output, generalizing the KPNA4–NF-κB axis beyond prostate cancer.

    Evidence KPNA4 overexpression/siRNA, nuclear fractionation for p65, NF-κB luciferase reporter, xenograft model

    PMID:33188837

    Open questions at the time
    • Whether KPNA4 is the sole importin-α transporting p65 in thyroid cells unclear
    • Single-lab validation
  6. 2021 High

    KPNA4 knockout in zebrafish causing cataract-like lens defects with cytoplasmic p53 accumulation demonstrated a non-redundant physiological role for KPNA4 in p53 nuclear import and lens homeostasis.

    Evidence CRISPR/Cas9 kpna4-KO zebrafish, TEM, immunofluorescence of p53, H₂O₂ apoptosis model in human lens epithelial cells

    PMID:33798680

    Open questions at the time
    • Whether the lens phenotype is solely p53-dependent or involves additional cargo not resolved
    • Mammalian lens phenotype of Kpna4 loss not reported
  7. 2025 Medium

    Kpna4-knockout mice exhibiting hypermotor/ADHD-like behavior without motor neuron dysfunction revealed a requirement for KPNA4 in behavioral regulation, raising it as a candidate ADHD-associated factor.

    Evidence Kpna4-KO mouse model with longitudinal locomotion and behavioral testing

    PMID:40565582

    Open questions at the time
    • Nuclear import cargo responsible for the behavioral phenotype not identified
    • No human genetic association data linking KPNA4 variants to ADHD reported in this study
    • Single study, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full cargo repertoire of KPNA4 versus other importin-α paralogs, the structural basis for its selective NLS recognition, and the molecular mechanism of its transport-independent role in viral RNA replication remain unresolved.
  • No systematic comparison of KPNA4 versus KPNA1/KPNA2 cargo selectivity
  • No crystal structure of KPNA4 in complex with unconventional NLS cargoes
  • Transport-independent mechanism in influenza replication molecularly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005215 transporter activity 3
Localization
GO:0005634 nucleus 3 GO:0005635 nuclear envelope 1 GO:0005829 cytosol 1
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 1
Partners
NPRECQLRELATP53

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 KPNA4 (Qip1) was identified as a novel importin-alpha homologue that binds the NLS of SV40 T antigen and interacts with DNA helicase Q1/RecQL via its putative NLS, distinguishing it from hSrp1 which does not interact with DNA helicase Q1. Yeast two-hybrid screening, GST pulldown with bacterially expressed Qip1 fused to GST followed by coprecipitation from human cell lysates Biochemical and biophysical research communications Medium 9168958
2013 KPNA4 (Qip1/importin alpha3) preferentially binds the N-terminal 110-amino acid region of influenza A NP containing an unconventional NLS with the S9A mutation, and silencing of Qip1 decreases vRNA transcription and replication of the S9A NP mutant virus independently of nuclear localization, indicating a nuclear-transport-independent role for KPNA4 in viral RNA replication. siRNA knockdown of Qip1 in cells infected with NP alanine-substitution mutant viruses, measurement of nuclear localization by immunofluorescence, vRNA transcription/replication assays, binding assays with NP mutants PloS one Medium 23383277
2016 KPNA4 mediates nuclear import of NF-κB and promotes prostate cancer metastasis; stable knockdown of KPNA4 significantly reduces PCa invasion and distant metastasis in mouse models, and alters the tumor microenvironment by modulating macrophage polarization and osteoclastogenesis through TNF-α and TNF-β. KPNA4 is a direct target of miR-708. Stable shRNA knockdown in multiple PCa cell lines, in vivo mouse metastasis models, TNF cytokine measurements, miR-708 target validation Oncogene High 27941876
2015 miR-181b suppresses epithelial-mesenchymal transition (EMT) in glioblastoma by directly targeting KPNA4; restoration of KPNA4 expression abolishes the EMT-inhibitory effect of miR-181b, placing KPNA4 downstream of miR-181b in the NF-κB/EMT pathway. miRNA overexpression and rescue experiments with KPNA4 re-expression, invasion/proliferation assays in vitro, in vivo xenograft, TCGA/CGGA dataset correlation Scientific reports Medium 26283154
2020 KPNA4 promotes NF-κB pathway activation in papillary thyroid cancer cells; overexpression of KPNA4 increases nuclear NF-κB p65 levels and NF-κB luciferase reporter activity, while KPNA4 silencing reduces nuclear p65 and inhibits proliferation and invasion. KPNA4 is negatively regulated by miR-548b-3p. KPNA4 overexpression and siRNA knockdown, nuclear fractionation for p65, NF-κB luciferase reporter assay, xenograft mouse model, miRNA target validation Life sciences Medium 33188837
2021 KPNA4 is required for normal lens development and is involved in cataract formation by mediating nuclear import of p53; kpna4 knockout zebrafish develop lens defects recapitulating cataract features, and in hydrogen-peroxide-induced apoptosis in human lens epithelial cells, KPNA4 is upregulated concordantly with p53. Loss of Kpna4 results in accumulation of p53 in the center of the lens rather than in the nucleus. CRISPR/Cas9 kpna4 knockout zebrafish, bright-field microscopy and transmission electron microscopy of lens, immunofluorescence/localization of p53 in lens cells, H2O2-induced apoptosis model in human lens epithelial cells Gene High 33798680
2025 KPNA4 deficiency in mice produces a hypermotor/ADHD-like phenotype; Kpna4-KO mice show hypermotoric behavior without deficits in motor neuron function, providing functional evidence for KPNA4 as a candidate pathogenic factor in ADHD. Kpna4-KO mouse model, locomotion and motoric behavioral testing at multiple time points during aging Genes Medium 40565582
2026 SV40 exploits KPNA4 as the NPC-associated importin receptor for nuclear entry; after SV40 is targeted to the nuclear membrane via Nesprin-2 and SUN1, it binds KPNA4 which translocates the virus into the nucleus through the nuclear pore complex. siRNA knockdown and functional rescue, subcellular fractionation, co-immunoprecipitation, nuclear entry assays with SV40 bioRxivpreprint Medium 41959248

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2005 Nucleolar proteome dynamics. Nature 934 15635413
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1994 The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proceedings of the National Academy of Sciences of the United States of America 736 8041786
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
1993 A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 708 8105392
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2010 The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes & development 541 20504901
1992 Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proceedings of the National Academy of Sciences of the United States of America 513 1631159
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
1997 HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proceedings of the National Academy of Sciences of the United States of America 415 9275210
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2004 CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Molecular cell 397 14759373
2019 Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 359 30867594
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2014 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 325 25036637
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1997 HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. The EMBO journal 313 9303297
1995 HIV nuclear import is governed by the phosphotyrosine-mediated binding of matrix to the core domain of integrase. Cell 312 7585960
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
2019 YY1-mediated overexpression of long noncoding RNA MCM3AP-AS1 accelerates angiogenesis and progression in lung cancer by targeting miR-340-5p/KPNA4 axis. Journal of cellular biochemistry 62 31693222
2015 Upregulation of miR-181s reverses mesenchymal transition by targeting KPNA4 in glioblastoma. Scientific reports 60 26283154
2021 Circ_ZFR contributes to the paclitaxel resistance and progression of non-small cell lung cancer by upregulating KPNA4 through sponging miR-195-5p. Cancer cell international 44 33407505
2016 Inhibition of KPNA4 attenuates prostate cancer metastasis. Oncogene 42 27941876
2019 MiR-3619-5p hampers proliferation and cisplatin resistance in cutaneous squamous-cell carcinoma via KPNA4. Biochemical and biophysical research communications 40 30967266
2020 STAT3-induced upregulation of circCCDC66 facilitates the progression of non-small cell lung cancer by targeting miR-33a-5p/KPNA4 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 37 32151944
2021 Berberine Attenuates MPP+-Induced Neuronal Injury by Regulating LINC00943/miR-142-5p/KPNA4/NF-κB Pathway in SK-N-SH Cells. Neurochemical research 36 34427876
2020 LncRNA ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of lung adenocarcinoma. Cancer cell international 18 33327962
2021 Ginsenoside Rg3 inhibits osteosarcoma progression by reducing circ_0003074 expression in a miR-516b-5p/KPNA4-dependent manner. Journal of orthopaedic surgery and research 16 34930332
2022 Long noncoding RNA SNHG14 knockdown exerts a neuroprotective role in MPP+-induced Parkinson's disease cell model through mediating miR-135b-5p/KPNA4 axis. Metabolic brain disease 15 35781593
2013 Importin α3/Qip1 is involved in multiplication of mutant influenza virus with alanine mutation at amino acid 9 independently of nuclear transport function. PloS one 13 23383277
2021 LINC00467 facilitates osteosarcoma progression by sponging miR‑217 to regulate KPNA4 expression. International journal of molecular medicine 11 33537823
2020 KPNA4 regulated by miR-548b-3p promotes the malignant phenotypes of papillary thyroid cancer. Life sciences 11 33188837
2003 Generation of a rat monoclonal antibody specific for importin alpha3/Qip1. Hybridoma and hybridomics 11 14683601
2023 Circular RNA circ_0000376 promotes paclitaxel resistance and tumorigenesis of non-small cell lung cancer via positively modulating KPNA4 by sponging miR-1298-5p. Thoracic cancer 10 37455373
2006 The Caenorhabditis elegans muscle specific serpin, SRP-3, neutralizes chymotrypsin-like serine peptidases. Biochemistry 8 16584183
2021 KPNA4 is involved in cataract formation via the nuclear import of p53. Gene 7 33798680
2022 Long non-coding RNA UCA1 regulates MPP+-induced neuronal damage through the miR-671-5p/KPNA4 pathway in SK-N-SH cells. Metabolic brain disease 6 36515797
2022 Circular RNA hsa_circ_0008003 promotes the progression of non-small-cell lung cancer by sponging miR-548I and regulating KPNA4 expression. Thoracic cancer 5 36573325
2024 Hemoglobin nanoclusters-mediated regulation of KPNA4 in hypoxic tumor microenvironment enhances photodynamic therapy in hepatocellular carcinoma. Journal of nanobiotechnology 4 39135024
2020 MiR-596 activated by EP300 controls the tumorigenesis in epithelial ovarian cancer by declining BRD4 and KPNA4. Cancer cell international 4 32943995
2025 Deficiency in KPNA4, but Not in KPNA3, Causes Attention Deficit/Hyperactivity Disorder like Symptoms in Mice. Genes 1 40565582
2026 SV40 exploits the Nesprin-2-SUN1-KPNA4 axis for stepwise targeting and entry into the host nucleus to promote infection. bioRxiv : the preprint server for biology 0 41959248
2022 Systematic Characterization of the Clinical Relevance of KPNA4 in Pancreatic Ductal Adenocarcinoma. Frontiers in oncology 0 35425701