NUP58

NUP58 is a central-channel nucleoporin that, together with Nup54 and Nup62, forms a conserved 1:1:1 coiled-coil complex constituting the FG-rich transport conduit of the nuclear pore complex (NPC) (PMID:24574455, PMID:26025361). Within this complex Nup54 occupies a central position binding both Nup62 and Nup58 directly, and the cognate coiled-coil segments of Nup58 and Nup54 interconvert between homo- and hetero-oligomeric rings, underlying a 'ring cycle' that constricts and dilates the central transport channel (PMID:26025361, PMID:24574455). This conformational switching is allosterically coupled to transport activity: multivalent binding of the transport factor Kapβ1 to the disordered FG domains of Nup58 stabilizes the structured Nup58–Nup54 hetero-oligomer, so that channel geometry tracks transport-factor occupancy (PMID:26046439), and these inner-ring nucleoporins indeed undergo transport-state-dependent conformational changes in living cells (PMID:33346731). Beyond interphase transport, the Nup62–Nup58–Nup54 complex has dedicated mitotic functions: it physically engages the Polo-box domain of PLK1 through Cdk1-primed docking sites, recruiting the kinase to the nuclear envelope to drive efficient nuclear envelope breakdown (PMID:29065307), while TIP60-mediated acetylation of Nup62 dissolves the complex at mitotic entry to enable correct spindle orientation and chromosome segregation (PMID:36190325). NUP58 itself redistributes from the nuclear rim to spindles, centrosomes, and midbodies in mitosis, and its loss causes centrosomal abnormalities, monopolar spindles, and delayed abscission (PMID:31388347, PMID:25621300). NUP58 is an essential gene whose hypomorphic loss is buffered by transcriptome rewiring and focal locus amplification (PMID:34528284), and it is also implicated in homologous-recombination DNA repair as a partner of Nup54 (PMID:29986057) and, in Drosophila, in flamenco-locus piRNA biogenesis (PMID:33856346).

1. 1995 High

   Established that Nup58 is a soluble, disassembly-competent nucleoporin that is actively incorporated into membrane-bound pore complexes, framing NPC assembly as a regulated, GTP-dependent process rather than a static structure.

   Evidence Cell-free reconstitution of annulate lamellae from Xenopus egg extracts with immunoblotting, EM, and membrane flotation, controlled with GTPγS

   PMID:7790348

   Open questions at the time

   • Did not define the GTPase or assembly machinery responsible
   • No information on Nup58's partners or position within the assembled pore
2. 2014 High

   Resolved the architecture of the central-channel module, showing Nup58 assembles with Nup54 and Nup62 in a fixed 1:1:1 stoichiometry with Nup54 bridging the two partners, conserved from yeast.

   Evidence Gel filtration and analytical ultracentrifugation of reconstituted complexes, compared to yeast Nsp1 complex

   PMID:24574455

   Open questions at the time

   • Did not address how the complex changes during transport
   • Higher-order assembly geometry within the intact NPC not resolved
3. 2015 High

   Defined the mechanistic basis for channel gating, showing interconvertible Nup58/Nup54 homo- and hetero-oligomeric rings provide a structural 'ring cycle' for constriction and dilation, and that Kapβ1 occupancy of disordered FG domains allosterically biases this equilibrium.

   Evidence X-ray crystallography of coiled-coil segments, solution biophysics, and quantitative multi-equilibrium binding analysis with in vitro Kapβ1 reconstitution

   PMID:26025361 PMID:26046439

   Open questions at the time

   • Demonstrated in vitro and from structures; in-cell validation of the ring cycle came later
   • Quantitative contribution of channel diameter change to transport selectivity not measured
4. 2017 High

   Extended Nup58 function beyond transport, showing the channel complex recruits PLK1 to the nuclear envelope via Polo-box interactions to drive nuclear envelope breakdown, linking the NPC directly to mitotic entry.

   Evidence C. elegans epistasis/RNAi, co-immunoprecipitation and direct interaction assays, live-cell NEBD imaging, and human cell validation

   PMID:29065307

   Open questions at the time

   • Relative contribution of Nup58 versus Nup54/Nup62 to PLK1 docking not isolated
   • Structural basis of the PBD–channel-Nup interaction not solved
5. 2018 Medium

   Implicated the channel complex in genome maintenance, linking Nup58 (as a Nup54 partner) to homologous-recombination repair and radiosensitivity.

   Evidence siRNA screen, HR reporter assays, Rad51 epistasis, and IR-induced SCE/foci measurements (primary functional data on Nup54)

   PMID:29986057

   Open questions at the time

   • Direct functional data are for Nup54; Nup58's own contribution to HR inferred from partnership
   • Mechanism by which a channel nucleoporin influences HR is unresolved
6. 2014 Medium

   Showed NUP58 is required for bipolar spindle formation, with its loss producing monopolar or poorly separated spindle poles during cell division.

   Evidence shRNA knockdown in a 3D MDCK cystogenesis model with confocal spindle morphology analysis

   PMID:25621300

   Open questions at the time

   • Molecular mechanism linking NUP58 to centrosome/pole separation not defined
   • Single knockdown approach in one model system
7. 2019 Medium

   Mapped the mitotic relocalization of NUP58 to spindles, centrosomes, and midbodies and tied its depletion to centrosomal defects and delayed abscission, consolidating a moonlighting role in mitosis.

   Evidence Confocal, live-cell, and STED imaging with siRNA knockdown phenotyping

   PMID:31388347

   Open questions at the time

   • Centrosomal/midbody binding partners of NUP58 not identified
   • Single-lab characterization
8. 2021 Medium

   Demonstrated NUP58 essentiality and the cellular adaptation routes (transcriptome rewiring then focal locus amplification) that buffer its partial loss.

   Evidence CRISPR/base-editing hypomorphs with transcriptome sequencing, copy-number analysis, and clonal evolution tracking in human cells

   PMID:34528284

   Open questions at the time

   • Which essential NUP58 function drives the fitness requirement not pinpointed
   • Single lab
9. 2021 Medium

   Revealed a specialized RNA-pathway role, showing Nup58 (with Nup54) is required in Drosophila follicle cells for flamenco-locus piRNA biogenesis and transposon silencing, distinct from other NPC subunits.

   Evidence RNAi knockdown in Drosophila ovary with small-RNA sequencing and comparison to other NPC subunit depletions

   PMID:33856346

   Open questions at the time

   • Mechanism connecting channel nucleoporins to piRNA biogenesis unknown
   • Conservation of this role in mammals untested
10. 2020 Medium

    Provided in-cell confirmation that NUP58 and its inner-ring partners undergo transport-state-dependent conformational changes, validating the ring-cycle model in living cells.

    Evidence Genetically encoded orientation sensors and fluorescence polarization microscopy under transport perturbation

    PMID:33346731

    Open questions at the time

    • Does not resolve atomic conformations
    • Single method type, single lab
11. 2021 Medium

    Identified an intrinsic biophysical property of NUP58 — conserved amyloidogenic regions that form disulfide-stabilized oligomers and polymers in vitro and in vivo.

    Evidence In vitro and in vivo amyloid formation assays, disulfide-bond biochemistry, and bioinformatic conservation analysis

    PMID:34680573

    Open questions at the time

    • Physiological significance of amyloid forms unclear
    • Relationship to normal NPC function not established
12. 2022 Medium

    Identified the regulatory switch that disassembles the channel complex for mitosis, showing TIP60 acetylation of Nup62 (Lys432) dissolves the Nup62–Nup58–Nup54 complex to allow spindle redistribution and correct chromosome segregation.

    Evidence TIP60 acetyltransferase identification, Lys432 site mapping, Co-IP of the complex before/after acetylation, acetylation-mimetic/deficient mutants, and segregation assays

    PMID:36190325

    Open questions at the time

    • Nup58 participation inferred from complex dissolution rather than direct Nup58 modification
    • Fate and function of released Nup58 not tracked
13. 2024 Medium

    Identified NUP58 as a host substrate of coronavirus 3C-like protease, implicating channel-nucleoporin cleavage in viral disruption of the host nucleocytoplasmic interface.

    Evidence In vitro cleavage assay with recombinant 3CLpro and cleavage-site mutagenesis

    PMID:39454742

    Open questions at the time

    • Cellular and functional consequences of cleavage not demonstrated
    • Cleavage shown in vitro only
14. 2025 Low

    Proposed NUP58 as a position-dependent binding enhancer for HIV capsid translocation, contributing to an FG-affinity gradient across the NPC.

    Evidence Quantitative FG–capsid binding and biophysical/structural analysis (preprint)

    PMID:41256404

    Open questions at the time

    • Preprint; no NUP58-specific mutagenesis or in vivo validation
    • Gradient model not tested by perturbing NUP58 in cells

• It remains unresolved how NUP58's transport-channel conformational cycle is mechanistically linked to its distinct mitotic, DNA-repair, and piRNA-biogenesis roles, and whether these reflect separable functions of the same molecule.
• No structural model of the channel complex within the intact NPC
• Direct in vivo dissection of NUP58 (versus Nup54/Nup62) contributions to each non-transport role lacking
• Disease relevance of NUP58 not established by causative human genetics in this corpus