IPO5

IPO5 (RanBP5/KPNB3) is an importin-beta family nuclear transport receptor that mediates the nuclear import of diverse cargoes by recognizing basic NLS sequences, coupling cargo binding and release to the RanGTP gradient (PMID:9271386, PMID:9687515). It was founded as a 124-kDa Ran-binding protein that binds RanGTP, stabilizes it against hydrolysis and exchange, associates with nuclear pore complexes, and assembles into a RanBP1-Ran-RanBP5 complex (PMID:9271386). As an import receptor it carries ribosomal proteins (L23a, S7, L5), binding the very basic region of rpL23a as an archetypal import signal (PMID:9687515), and it imports RNA-binding and signaling cargoes including CPEB3 (via its RRM1 domain) (PMID:22730302), Musashi-1 (PMID:25782991), and RASAL2, whose nuclear translocation activates RAS signaling in colorectal cancer cells (PMID:31288861). Crystal and cryo-EM structures of human RanBP5 define the IMB3 karyopherin-beta architecture and show that cargo NLS elements, such as the unstructured influenza PB1 NLS, are engaged in a wrapped conformation (PMID:32222384, PMID:39536408). IPO5 is essential in vivo: global knockout causes early embryonic lethality and germline-specific deletion ablates germ cells and causes meiotic failure (PMID:40652294). Viruses exploit IPO5 for nuclear trafficking, with the influenza A PA-PB1 heterodimer forming a stable complex in which polymerase RNA binding and import are mutually exclusive (PMID:27095520), and PCV2 capsid both imported and stabilized against proteasomal degradation by IPO5 (PMID:36409110).

1. 1997 High

   Established IPO5 as a Ran-binding member of the importin-beta family, answering whether this novel protein operates within the Ran-dependent transport system.

   Evidence Overlay assay with RanGTP, yeast two-hybrid, in vitro binding and subcellular fractionation

   PMID:9271386

   Open questions at the time

   • No cargo identified at this stage
   • Directionality of transport (import vs export) not defined
2. 1998 High

   Showed IPO5 acts as a bona fide import receptor for ribosomal proteins, identifying a basic NLS as the recognition signal and defining its physiological cargo class.

   Evidence In vitro reconstituted nuclear import assays and direct receptor-cargo binding in mammalian cells

   PMID:9687515

   Open questions at the time

   • Redundancy with importin-beta, transportin and RanBP7 leaves cargo specificity unresolved
   • No structural basis for NLS recognition
3. 2012 Medium

   Linked IPO5 cargo handling to physiological signaling by showing NMDAR-driven RanBP1 changes modulate the CPEB3-IPO5 interaction, establishing regulated, signal-responsive import.

   Evidence Co-IP, domain mapping (RRM1) and NMDAR stimulation in neurons

   PMID:22730302

   Open questions at the time

   • Single lab
   • In vivo neuronal relevance not tested genetically
4. 2015 Medium

   Extended the cargo repertoire to Musashi-1 and connected IPO5 to germline chromatin biology, showing its import activity has tissue-specific functional consequences.

   Evidence Co-IP, immunofluorescence and transgenic overexpression in mouse testis

   PMID:25782991

   Open questions at the time

   • Overexpression-based, not loss-of-function
   • NLS within MSI1 not mapped
5. 2016 High

   Defined a viral hijacking mechanism by showing IPO5 binds the influenza PA-PB1 heterodimer and that import and polymerase RNA binding are mutually exclusive.

   Evidence Reconstituted complexes, SAXS modelling and in vitro RNA-binding assays

   PMID:27095520

   Open questions at the time

   • No atomic-resolution interface
   • Cellular import dynamics inferred from in vitro data
6. 2019 Medium

   Connected IPO5-mediated import to oncogenic signaling by demonstrating it carries the RASAL2 NLS to activate RAS signaling in colorectal cancer.

   Evidence Mass spectrometry, Co-IP, fractionation, immunofluorescence and NLS mapping

   PMID:31288861

   Open questions at the time

   • Single lab
   • Causality between import and tumor progression not genetically dissected
7. 2020 High

   Provided the first structural framework for human RanBP5, confirming IMB3 subfamily architecture and validating NLS docking through mutations that disrupt influenza PA-PB1 binding.

   Evidence X-ray crystallography of two ligand-free isoforms with point mutagenesis and protein complementation

   PMID:32222384

   Open questions at the time

   • Structures are ligand-free
   • Cargo-bound conformations not captured here
8. 2022 High

   Revealed a dual function beyond transport by showing IPO5 imports PCV2 virions and stabilizes its capsid against proteasomal degradation, defining specific contact residues.

   Evidence GST pulldown, site-directed mutagenesis, knockdown, cycloheximide chase and proteasome inhibitor rescue

   PMID:36409110

   Open questions at the time

   • Mechanism of capsid stabilization not resolved
   • Whether stabilization extends to host cargoes unknown
9. 2024 High

   Resolved how IPO5 engages an unstructured cargo NLS by cryo-EM, showing the influenza PB1 NLS is wrapped by RanBP5 and identifying critical interface residues.

   Evidence Cryo-EM at 3.2 Å of the RanBP5-PB1 NLS complex with interface mutagenesis

   PMID:39536408

   Open questions at the time

   • Structure limited to a viral NLS fragment
   • Host cargo recognition modes not directly compared
10. 2025 High

    Defined the in vivo requirement for IPO5, showing it is essential for early embryogenesis and male germline/meiotic progression, and identified new binding partners.

    Evidence Conditional knockout mice (CMVCre, VasaCre, Stra8Cre) and IP-MS identifying SFPQ and XPO2

    PMID:40652294

    Open questions at the time

    • Cargoes responsible for the meiotic/embryonic phenotypes not established
    • Functional role of SFPQ and XPO2 interactions not characterized

• How IPO5 achieves cargo selectivity among overlapping importin-beta family receptors and which specific cargoes drive its essential developmental and germline functions remain unresolved.
• No unified determinant of cargo specificity defined
• Cargoes mediating embryonic lethality and meiotic failure unidentified
• Physiological role of capsid-stabilization activity for endogenous substrates unknown