KPNA6

KPNA6 (importin α7/karyopherin α6) is a nuclear import adaptor that recognizes nuclear localization signal (NLS)-bearing cargo through its importin-α major groove and delivers them to the nucleus (PMID:21383067, PMID:42159396). Its cellular cargo repertoire spans transcriptional and regulatory proteins including Keap1 (PMID:21383067), the HNF1A transcription factor (PMID:33459938), the BCL-6 corepressor BCOR (PMID:30396568), and PHB2 (PMID:26052702), the latter two imported in NLS-dependent and stimulus-dependent fashion. Through Keap1 import, KPNA6 tunes the Nrf2 antioxidant response, both by importing Keap1 to attenuate Nrf2 signaling and by accelerating clearance of Nrf2 from the nucleus during the post-induction phase (PMID:21383067). KPNA6 import activity is physiologically essential in the male germline: loss of Kpna6 in mice causes infertility through impaired androgen receptor nuclear localization in Sertoli cells, disrupted histone-protamine exchange, and dysregulation of RFX2 target genes during spermiogenesis (PMID:34473250). A recurrent theme is exploitation of KPNA6 by RNA viruses: it is a required host factor for PRRSV and Zika virus replication, mediating nuclear import of PRRSV nsp1β and being stabilized against proteasomal degradation during infection (PMID:29444946, PMID:42159396), and viral proteins from Ebola (VP24), SARS-CoV-2 (M), and Newcastle disease virus (W) bind KPNA6 to suppress type I interferon responses by blocking IRF3 or sequestering import capacity (PMID:34950606, PMID:27974555, PMID:33441338). KPNA6 additionally regulates influenza polymerase activity through association with ANP32A/B and the vRNP complex (PMID:35044222). A timeline finding links HNF1A MODY-associated mutations to reduced KPNA6 binding and impaired HNF1A nuclear localization (PMID:33459938).

1. 2011 High

   Established KPNA6 as a functional import adaptor with a defined regulatory output by showing it imports Keap1 and thereby controls the magnitude and resolution of the Nrf2 antioxidant response.

   Evidence Co-IP, gain- and loss-of-function with Nrf2 target gene and Keap1 localization readouts in cells

   PMID:21383067

   Open questions at the time

   • Does not resolve karyopherin β dependence quantitatively
   • NLS within Keap1 not mapped
   • physiological tissue context of Keap1 import not addressed
2. 2011 Medium

   Showed KPNA6 mediates NLS-dependent nuclear import of an individual cargo (Orc6) independently of its complex partners, demonstrating cargo-selective transport.

   Evidence Protein purification, co-IP, and NLS-mutant nuclear localization assays

   PMID:21555516

   Open questions at the time

   • Single lab, not reciprocally validated in vivo
   • shared with KPNA1, specificity not dissected
3. 2012 Medium

   Placed KPNA6 in acrosome biogenesis by localizing it to the subacrosomal perinuclear theca and identifying SubH2Bv as a binding partner, extending its role beyond classical import.

   Evidence Immunocytochemistry, sperm head fractionation, recombinant protein pull-down

   PMID:22156475

   Open questions at the time

   • Functional requirement not tested by loss-of-function here
   • mechanism linking import adaptor to vesicle targeting unclear
4. 2015 Medium

   Defined estrogen-regulated PHB2 import as a KPNA6 function and identified BIG3 as an inhibitor of cargo binding, linking KPNA6 to ERα signaling control.

   Evidence Co-IP, siRNA knockdown, nuclear translocation assays in breast cancer cells

   PMID:26052702

   Open questions at the time

   • Redundancy with KPNA1/KPNA5 not resolved
   • single lab
5. 2017 High

   Provided rigorous in vitro evidence that KPNA-binding affinity of Ebola VP24 quantitatively governs interferon suppression and viral protein stability, establishing KPNA6 as a target hijacked for immune evasion.

   Evidence Purified-protein affinity measurements, mutagenesis, IFN reporter and half-life assays

   PMID:27974555

   Open questions at the time

   • Shared binding with KPNA1/KPNA5, KPNA6-specific contribution in vivo not isolated
6. 2018 High

   Demonstrated KPNA6 is a required proviral host factor whose stability is actively protected during infection, mediating nuclear import of viral proteins for PRRSV and Zika replication.

   Evidence siRNA, CRISPR KO, proteasome inhibition, nuclear translocation, viral replication and rescue assays

   PMID:29444946

   Open questions at the time

   • Mechanism of nsp12-induced degradation block not fully mapped
   • ZIKV cargo identity not defined in this study
7. 2018 Medium

   Extended the cargo repertoire to the transcriptional corepressor BCOR via NLS-dependent import, reinforcing a general role in nuclear delivery of gene-regulatory proteins.

   Evidence Co-IP, site-directed mutagenesis, nuclear translocation assays in periodontal ligament cells

   PMID:30396568

   Open questions at the time

   • Single cell type
   • in vivo relevance untested
8. 2021 High

   Provided the in vivo demonstration that KPNA6 is essential for male fertility, mechanistically tying its import function to androgen receptor localization and the spermiogenic transcriptional/chromatin program.

   Evidence Kpna6 knockout mouse, immunofluorescence, Western blot, nuclear localization analysis

   PMID:34473250

   Open questions at the time

   • Direct AR-KPNA6 binding not biochemically isolated here
   • relative contributions of Sertoli vs germ cell defects not separated
9. 2021 Medium

   Identified KPNA6 as the principal import receptor for HNF1A and linked MODY-causing HNF1A mutations to reduced KPNA6 binding and mislocalization, suggesting a disease-relevant import defect.

   Evidence Co-IP, molecular docking, immunolocalization in Min6 cells with mutant HNF1A

   PMID:33459938

   Open questions at the time

   • Causality in patient tissue not established
   • docking model not experimentally validated
10. 2021 Medium

    Broadened the immune-evasion paradigm by showing SARS-CoV-2 M and NDV W proteins bind KPNA6 to block IRF3/interferon responses.

    Evidence Co-IP, IFN reporter and nuclear translocation assays; NDV studied with NLS mutagenesis and reverse genetics

    PMID:33441338 PMID:34950606

    Open questions at the time

    • KPNA6-specific necessity vs other karyopherins not isolated
    • single lab per virus
11. 2022 Medium

    Revealed a non-canonical role in influenza replication where KPNA6 modulates polymerase activity through association with ANP32A/B and the vRNP, with both loss and excess being inhibitory.

    Evidence Co-IP, KO and overexpression with polymerase activity assays, domain mutagenesis

    PMID:35044222

    Open questions at the time

    • Mechanism of biphasic effect unclear
    • whether effect is import-dependent not fully resolved
12. 2026 Medium

    Mapped the ZIKV NS2B-KPNA6 interaction to the importin-α major groove and identified NS2B residues critical for both binding and viral replication.

    Evidence Co-IP, fluorescence microscopy, site-directed mutagenesis, viral replication assays

    PMID:42159396

    Open questions at the time

    • Functional consequence of perinuclear relocation for the import cycle unclear
    • single lab

• How KPNA6 cargo selectivity is established relative to redundant karyopherin-α paralogs, and how its import activity is rerouted or repurposed for non-import functions (acrosome targeting, influenza polymerase regulation), remain open.
• No structure of KPNA6-cargo complexes in the corpus
• paralog redundancy unresolved across most cargoes
• regulation of KPNA6 abundance/stability outside viral infection not characterized