{"gene":"NUP58","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"Nup58 (along with nup60, nup97, nup153, and nup200) is initially present in a disassembled, soluble form in Xenopus egg cytosol and becomes incorporated into membrane-associated pore complexes (annulate lamellae) in a time- and temperature-dependent manner; GTPγS prevented this incorporation.","method":"Biochemical reconstitution of annulate lamellae from Xenopus egg extracts; immunoblotting; thin-section EM and negative staining; membrane flotation fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cell-free reconstitution with multiple orthogonal methods (immunoblotting, EM, flotation), rigorous pharmacological control (GTPγS), replicated across nucleoporins","pmids":["7790348"],"is_preprint":false},{"year":2015,"finding":"Nup58 forms part of the central channel nucleoporin complex with Nup54 and Nup62. Nup58 and Nup54 cognate coiled-coil segments form interconvertible homo- and hetero-oligomeric rings that underlie a 'ring cycle' model for constriction and dilation of the NPC central transport channel. Crystal structures identified two cognate segments of Nup54, one interacting with Nup58 and one with Nup62, forming crystallographic hetero- or homo-oligomers.","method":"X-ray crystallography of coiled-coil segments; solution analysis (gel filtration, AUC) of full ordered regions; mapping of interactomes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus solution biophysics, consistent with prior crystallographic data from same group, mechanistically validated","pmids":["26025361"],"is_preprint":false},{"year":2015,"finding":"Allosteric coupling exists between the structured coiled-coil domain of Nup58 and its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to disordered domains of Nup58 stabilizes the structured Nup58 domain associated with Nup54, shifting conformational equilibria from Nup58 homo-oligomers to Nup58–Nup54 hetero-oligomers, thereby driving constriction/dilation of the NPC central channel as a function of transport factor occupancy.","method":"Quantitative analysis of multiple equilibria (binding assays); crystallographic data; in vitro reconstitution of Nup58–Nup54–Kapβ1 interactions","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative equilibrium analysis combined with prior crystal structures, rigorous mechanistic framework established in one study","pmids":["26439"],"is_preprint":false},{"year":2015,"finding":"Allosteric coupling exists between the structured coiled-coil domain of Nup58 and its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to disordered domains of Nup58 stabilizes the structured Nup58 domain associated with Nup54, shifting conformational equilibria from Nup58 homo-oligomers to Nup58–Nup54 hetero-oligomers, thereby driving constriction/dilation of the NPC central channel as a function of transport factor occupancy.","method":"Quantitative analysis of multiple equilibria; crystallographic data; in vitro reconstitution of Nup58–Nup54–Kapβ1 interactions","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative equilibrium binding analysis combined with prior crystal structures, multiple orthogonal methods in one rigorous study","pmids":["26046439"],"is_preprint":false},{"year":2014,"finding":"The Nup62 complex (Nup62, Nup54, Nup58) exists in a 1:1:1 stoichiometry in solution, with Nup54 centrally positioned binding both Nup62 and Nup58 directly. At high concentrations the complex forms larger assemblies maintaining this ratio. The same 1:1:1 stoichiometry was determined for the homologous yeast Nsp1 complex, indicating evolutionary conservation. Eliminating one binding partner results in noncanonical stoichiometries in vitro, likely through promiscuous coiled-coil pairing.","method":"Gel filtration chromatography; analytical ultracentrifugation (AUC); in vitro reconstitution","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — two orthogonal quantitative biophysical methods (gel filtration + AUC), in vitro reconstitution, confirmed in yeast ortholog","pmids":["24574455"],"is_preprint":false},{"year":2017,"finding":"In C. elegans and human cells, the channel nucleoporin NPP-1/Nup58 (along with NPP-4/Nup54 and NPP-11/Nup62) physically interacts with the Polo-box domain (PBD) of PLK-1/PLK1, recruiting the kinase to the nuclear pore complex at the nuclear envelope just prior to nuclear envelope breakdown (NEBD). Nup58 and its partners are primed at multiple Polo-docking sites by Cdk1 and PLK-1 itself. This NE localization of PLK-1 is required for efficient NEBD.","method":"Genetic epistasis (C. elegans RNAi/depletion); co-immunoprecipitation; direct physical interaction assays; live-cell imaging of NEBD; human cell validation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal physical interaction assays, epistasis in C. elegans plus human cell validation, live-cell imaging with defined NEBD phenotype, multiple orthogonal methods","pmids":["29065307"],"is_preprint":false},{"year":2018,"finding":"Nup58 depletion (via siRNA) increases radiosensitivity, and Nup58 (identified as a molecular partner of Nup54 and Nup62) is implicated in homologous recombination (HR) repair of DNA double-strand breaks: Nup54 depletion (epistatic with Nup58) decreases HR repair reporter activity, reduces HR-linked DNA synthesis foci and sister chromatid exchanges after IR, and is epistatic with Rad51.","method":"High-throughput siRNA screen; HR repair reporter assays; epistasis analysis with Rad51; measurement of chromosome aberrations, SCEs, and DNA synthesis foci","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established with Rad51, multiple DNA repair readouts; Nup58 identified as molecular partner of Nup54 but primary functional data are for Nup54; single lab","pmids":["29986057"],"is_preprint":false},{"year":2019,"finding":"Nup58 localizes to the nuclear rim during interphase and redistributes to mitotic spindles, centrosomes, and midbodies during mitosis. Depletion of Nup58 results in centrosomal abnormalities and delayed abscission.","method":"Confocal microscopy; live-cell imaging; stimulated emission depletion (STED) nanoscopy; siRNA knockdown with mitotic phenotype readout","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by multiple imaging modalities (confocal, live-cell, STED) combined with loss-of-function phenotype; single lab","pmids":["31388347"],"is_preprint":false},{"year":2019,"finding":"NUP58 knockdown in lung adenocarcinoma cell lines (A549, H1299) inhibits metastasis and invasion in vivo and in vitro, and alters expression of EMT markers; this effect is associated with changes in the GSK-3β/Snail signaling pathway.","method":"Lentiviral shRNA knockdown; in vitro invasion assays; in vivo xenograft; Western blot for EMT markers and GSK-3β/Snail pathway components","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD with phenotypic readout and pathway marker changes, but pathway placement relies on expression changes of downstream markers without direct mechanistic epistasis; single lab","pmids":["30787996"],"is_preprint":false},{"year":2020,"finding":"In living cells, conformational changes in Nup58 (and Nup54, Nup62) within the NPC inner ring occur when nucleocytoplasmic transport is perturbed, while Nups elsewhere in the NPC do not show such changes, indicating that select inner-ring channel nucleoporins are flexible and undergo transport-state-dependent conformational dynamics.","method":"Genetically encoded orientation sensors (mEGFP rigidly conjugated to NPC proteins); fluorescence polarization microscopy in live cells","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo conformational measurement with novel sensor approach, selective to inner ring Nups; single lab, single method type","pmids":["33346731"],"is_preprint":false},{"year":2021,"finding":"Human NUP58 can form amyloid aggregates both in vitro and in vivo, existing as two forms: oligomers and polymers stabilized by disulfide bonds. Bioinformatic analysis shows that all known NUP58 orthologs possess conserved amyloidogenic regions.","method":"In vitro amyloid formation assays; in vivo aggregate detection; biochemical characterization (disulfide bond analysis); bioinformatic prediction","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro and in vivo demonstration with biochemical characterization, but biological significance unclear; single lab","pmids":["34680573"],"is_preprint":false},{"year":2021,"finding":"Nup58 (along with Nup54) is essential in Drosophila ovarian follicle cells for piRNA biogenesis specifically from the flamenco locus; loss of Nup54 and Nup58 results in compromised piRNA production and transposon desilencing, a role distinct from other NPC subunits.","method":"RNAi knockdown of Nup54 and Nup58 in Drosophila ovary; small RNA sequencing; genetic comparison with other NPC subunit knockdowns","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific loss-of-function with defined molecular phenotype (piRNA levels, transposon derepression), comparison to other NPC subunits; single lab","pmids":["33856346"],"is_preprint":false},{"year":2021,"finding":"Hypomorphic alleles of NUP58 trigger early adaptation via transcriptome rewiring and upregulation of NPC-interacting genes, followed by long-term fitness recovery through focal amplification of the NUP58 locus and restoration of mutant protein expression.","method":"Generation of hypomorphic alleles by CRISPR/base editing; transcriptome sequencing; genomic copy number analysis; clonal evolution tracking","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic manipulation with multi-omic readouts in human cells; establishes NUP58 as an essential gene with defined adaptation mechanisms; single lab","pmids":["34528284"],"is_preprint":false},{"year":2022,"finding":"TIP60 acetyltransferase acetylates Nup62 at Lys432, and this acetylation dissolves the Nup62–Nup58–Nup54 complex during mitotic entry, promoting redistribution of Nup62 to the mitotic spindle and enabling correct spindle orientation and chromosome segregation.","method":"Identification of TIP60 as Nup62 acetyltransferase; acetylation site mapping (Lys432); co-immunoprecipitation of Nup62-Nup58-Nup54 complex before/after acetylation; loss-of-function and acetylation-mimetic/deficient mutants; chromosome segregation assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM writer identified with site-specific mutagenesis, complex dissociation demonstrated by Co-IP, functional phenotype readout; Nup58 participation inferred as part of dissolving complex; single lab","pmids":["36190325"],"is_preprint":false},{"year":2014,"finding":"NUPL1 (NUP58) knockdown in MDCK cells causes abnormal cystogenesis, with abnormalities arising primarily from faulty cell divisions including monopolar spindles or spindles with poorly separated poles, indicating a role for NUP58 in bipolar spindle formation.","method":"shRNA knockdown; 3D MDCK cystogenesis assay; confocal microscopy of spindle morphology","journal":"Oncoscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (monopolar spindles) in 3D culture model; single lab, single gene-knockdown approach","pmids":["25621300"],"is_preprint":false},{"year":2024,"finding":"NUP58 is cleaved by the 3C-like protease (3CLpro) of Gammacoronaviruses/Deltacoronaviruses in vitro, as validated by in vitro cleavage experiments and mutational analysis of the cleavage site, identifying NUP58 as a host substrate of coronavirus 3CLpro.","method":"In vitro cleavage assay with recombinant 3CLpro; mutational analysis of cleavage site; PSSM scoring","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic cleavage with mutagenesis validation; single study, limited biological follow-up","pmids":["39454742"],"is_preprint":false},{"year":2025,"finding":"NUP58 acts as a binding enhancer within the NPC channel, enhancing HIV capsid core (CA) binding affinity to FG repeats; NUP58 is positioned in the NPC such that its binding contribution increases with proximity to the nuclear basket, contributing to an affinity gradient that potentiates unidirectional HIV capsid translocation through the NPC.","method":"Biochemical binding assays (quantitative FG-CA interaction measurements); biophysical approaches; structural analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, biochemical binding data but no mutagenesis of NUP58 specifically or in vivo validation of NUP58's role; single study","pmids":["41256404"],"is_preprint":true}],"current_model":"NUP58 is a central channel nucleoporin that forms a 1:1:1 coiled-coil complex with Nup54 and Nup62 at the NPC; its structured domain undergoes allosterically coupled conformational switching between homo- and hetero-oligomers driven by transport factor (Kapβ1) occupancy, thereby mediating constriction and dilation of the NPC central channel; during mitosis, the Nup62–Nup58–Nup54 complex is dissolved by TIP60-mediated acetylation of Nup62 and the complex recruits PLK1 to the nuclear envelope via Polo-box domain interactions primed by Cdk1, facilitating nuclear envelope breakdown; NUP58 itself redistributes to centrosomes and midbodies during mitosis, where its loss causes centrosomal abnormalities and delayed abscission, and contributes to bipolar spindle formation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1995,"claim":"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","pmids":["7790348"],"confidence":"High","gaps":["Did not define the GTPase or assembly machinery responsible","No information on Nup58's partners or position within the assembled pore"]},{"year":2014,"claim":"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","pmids":["24574455"],"confidence":"High","gaps":["Did not address how the complex changes during transport","Higher-order assembly geometry within the intact NPC not resolved"]},{"year":2015,"claim":"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","pmids":["26025361","26046439"],"confidence":"High","gaps":["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"]},{"year":2017,"claim":"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","pmids":["29065307"],"confidence":"High","gaps":["Relative contribution of Nup58 versus Nup54/Nup62 to PLK1 docking not isolated","Structural basis of the PBD–channel-Nup interaction not solved"]},{"year":2018,"claim":"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)","pmids":["29986057"],"confidence":"Medium","gaps":["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"]},{"year":2014,"claim":"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","pmids":["25621300"],"confidence":"Medium","gaps":["Molecular mechanism linking NUP58 to centrosome/pole separation not defined","Single knockdown approach in one model system"]},{"year":2019,"claim":"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","pmids":["31388347"],"confidence":"Medium","gaps":["Centrosomal/midbody binding partners of NUP58 not identified","Single-lab characterization"]},{"year":2021,"claim":"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","pmids":["34528284"],"confidence":"Medium","gaps":["Which essential NUP58 function drives the fitness requirement not pinpointed","Single lab"]},{"year":2021,"claim":"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","pmids":["33856346"],"confidence":"Medium","gaps":["Mechanism connecting channel nucleoporins to piRNA biogenesis unknown","Conservation of this role in mammals untested"]},{"year":2020,"claim":"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","pmids":["33346731"],"confidence":"Medium","gaps":["Does not resolve atomic conformations","Single method type, single lab"]},{"year":2021,"claim":"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","pmids":["34680573"],"confidence":"Medium","gaps":["Physiological significance of amyloid forms unclear","Relationship to normal NPC function not established"]},{"year":2022,"claim":"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","pmids":["36190325"],"confidence":"Medium","gaps":["Nup58 participation inferred from complex dissolution rather than direct Nup58 modification","Fate and function of released Nup58 not tracked"]},{"year":2024,"claim":"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","pmids":["39454742"],"confidence":"Medium","gaps":["Cellular and functional consequences of cleavage not demonstrated","Cleavage shown in vitro only"]},{"year":2025,"claim":"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)","pmids":["41256404"],"confidence":"Low","gaps":["Preprint; no NUP58-specific mutagenesis or in vivo validation","Gradient model not tested by perturbing NUP58 in cells"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,7,13]}],"complexes":["Nup62–Nup58–Nup54 central channel complex","nuclear pore complex"],"partners":["NUP54","NUP62","KPNB1","PLK1","KAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BVL2","full_name":"Nucleoporin p58/p45","aliases":["58 kDa nucleoporin","Nucleoporin-like protein 1"],"length_aa":599,"mass_kda":60.9,"function":"Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q9BVL2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP58","classification":"Common Essential","n_dependent_lines":472,"n_total_lines":1208,"dependency_fraction":0.39072847682119205},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP58","total_profiled":1310},"omim":[{"mim_id":"620427","title":"DYSTONIA 37, EARLY-ONSET, WITH STRIATAL LESIONS; DYT37","url":"https://www.omim.org/entry/620427"},{"mim_id":"607615","title":"NUCLEOPORIN, 58-KD; NUP58","url":"https://www.omim.org/entry/607615"},{"mim_id":"607607","title":"NUCLEOPORIN, 54-KD; NUP54","url":"https://www.omim.org/entry/607607"},{"mim_id":"605815","title":"NUCLEOPORIN, 62-KD; NUP62","url":"https://www.omim.org/entry/605815"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP58"},"hgnc":{"alias_symbol":["KIAA0410","NUP45"],"prev_symbol":["NUPL1"]},"alphafold":{"accession":"Q9BVL2","domains":[{"cath_id":"1.20.5","chopping":"248-333","consensus_level":"medium","plddt":92.735,"start":248,"end":333},{"cath_id":"1.20.5","chopping":"341-378","consensus_level":"medium","plddt":89.2505,"start":341,"end":378},{"cath_id":"1.20.5","chopping":"379-443","consensus_level":"medium","plddt":84.3077,"start":379,"end":443}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVL2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVL2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BVL2-F1-predicted_aligned_error_v6.png","plddt_mean":55.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP58","jax_strain_url":"https://www.jax.org/strain/search?query=NUP58"},"sequence":{"accession":"Q9BVL2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BVL2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BVL2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BVL2"}},"corpus_meta":[{"pmid":"32060001","id":"PMC_32060001","title":"Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice.","date":"2020","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32060001","citation_count":146,"is_preprint":false},{"pmid":"25406947","id":"PMC_25406947","title":"Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns.","date":"2014","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25406947","citation_count":81,"is_preprint":false},{"pmid":"7790348","id":"PMC_7790348","title":"Nuclear pore complex assembly studied with a biochemical assay for annulate lamellae formation.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7790348","citation_count":72,"is_preprint":false},{"pmid":"29065307","id":"PMC_29065307","title":"Channel Nucleoporins Recruit PLK-1 to Nuclear Pore Complexes to Direct Nuclear Envelope Breakdown in C. elegans.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/29065307","citation_count":72,"is_preprint":false},{"pmid":"23319804","id":"PMC_23319804","title":"Genetic amplification of the NOTCH modulator LNX2 upregulates the WNT/β-catenin pathway in colorectal cancer.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23319804","citation_count":70,"is_preprint":false},{"pmid":"26046439","id":"PMC_26046439","title":"Allosteric Regulation in Gating the Central Channel of the Nuclear Pore Complex.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26046439","citation_count":37,"is_preprint":false},{"pmid":"23416983","id":"PMC_23416983","title":"Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23416983","citation_count":34,"is_preprint":false},{"pmid":"25621300","id":"PMC_25621300","title":"Cancer driver candidate genes AVL9, DENND5A and NUPL1 contribute to MDCK cystogenesis.","date":"2014","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/25621300","citation_count":31,"is_preprint":false},{"pmid":"33049985","id":"PMC_33049985","title":"Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington's Disease Status Based on Omics Data.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33049985","citation_count":26,"is_preprint":false},{"pmid":"24574455","id":"PMC_24574455","title":"The stoichiometry of the nucleoporin 62 subcomplex of the nuclear pore in solution.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24574455","citation_count":22,"is_preprint":false},{"pmid":"33856346","id":"PMC_33856346","title":"Channel nuclear pore complex subunits are required for transposon silencing in Drosophila.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33856346","citation_count":20,"is_preprint":false},{"pmid":"29986057","id":"PMC_29986057","title":"Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29986057","citation_count":18,"is_preprint":false},{"pmid":"26025361","id":"PMC_26025361","title":"Ordered Regions of Channel Nucleoporins Nup62, Nup54, and Nup58 Form Dynamic Complexes in Solution.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26025361","citation_count":15,"is_preprint":false},{"pmid":"33346731","id":"PMC_33346731","title":"Conformation of the nuclear pore in living cells is modulated by transport state.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33346731","citation_count":15,"is_preprint":false},{"pmid":"31388347","id":"PMC_31388347","title":"Nucleoporin Nup58 localizes to centrosomes and mid-bodies during mitosis.","date":"2019","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/31388347","citation_count":11,"is_preprint":false},{"pmid":"28406021","id":"PMC_28406021","title":"The Nup62 Coiled-Coil Motif Provides Plasticity for Triple-Helix Bundle Formation.","date":"2017","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28406021","citation_count":11,"is_preprint":false},{"pmid":"36190325","id":"PMC_36190325","title":"Acetylation of Nup62 by TIP60 ensures accurate chromosome segregation in mitosis.","date":"2022","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36190325","citation_count":10,"is_preprint":false},{"pmid":"30787996","id":"PMC_30787996","title":"NUP58 facilitates metastasis and epithelial-mesenchymal transition of lung adenocarcinoma via the GSK-3β/Snail signaling pathway.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/30787996","citation_count":9,"is_preprint":false},{"pmid":"37897949","id":"PMC_37897949","title":"Single-cell transcriptomics uncover hub genes and cell-cell crosstalk in patients with hypertensive nephropathy.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37897949","citation_count":8,"is_preprint":false},{"pmid":"37278318","id":"PMC_37278318","title":"Regulation of FLC nuclear import by coordinated action of the NUP62-subcomplex and importin β SAD2.","date":"2023","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/37278318","citation_count":8,"is_preprint":false},{"pmid":"34680573","id":"PMC_34680573","title":"The Human NUP58 Nucleoporin Can Form Amyloids In Vitro and In Vivo.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34680573","citation_count":6,"is_preprint":false},{"pmid":"34528284","id":"PMC_34528284","title":"Non-genetic and genetic rewiring underlie adaptation to hypomorphic alleles of an essential gene.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/34528284","citation_count":6,"is_preprint":false},{"pmid":"37239918","id":"PMC_37239918","title":"Identification of New FG-Repeat Nucleoporins with Amyloid Properties.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37239918","citation_count":5,"is_preprint":false},{"pmid":"29496964","id":"PMC_29496964","title":"Involvement in surface antigen expression by a moonlighting FG-repeat nucleoporin in trypanosomes.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29496964","citation_count":5,"is_preprint":false},{"pmid":"37198214","id":"PMC_37198214","title":"Indel driven rapid evolution of core nuclear pore protein gene promoters.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37198214","citation_count":4,"is_preprint":false},{"pmid":"38940394","id":"PMC_38940394","title":"Preliminary study of identified novel susceptibility loci for HAPE risk in a Chinese male Han population.","date":"2024","source":"Personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38940394","citation_count":0,"is_preprint":false},{"pmid":"41002397","id":"PMC_41002397","title":"Morphological and Transcriptomic Analyses of the Adrenal Gland in Acomys cahirinus: A Novel Model for Murine Adrenal Physiology.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41002397","citation_count":0,"is_preprint":false},{"pmid":"41256404","id":"PMC_41256404","title":"Translocation of HIV capsid core through the Nuclear Pore Complex by affinity gradient.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41256404","citation_count":0,"is_preprint":false},{"pmid":"39454742","id":"PMC_39454742","title":"Deciphering the cleavage sites of 3C-like protease in Gammacoronaviruses and Deltacoronaviruses.","date":"2024","source":"Biochimica et biophysica acta. Proteins and proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/39454742","citation_count":0,"is_preprint":false},{"pmid":"40865161","id":"PMC_40865161","title":"Histone Deacetylase Inhibitors orchestrate epigenetic signalling and alter the nucleoporins and nuclear envelope in cervical cancer.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40865161","citation_count":0,"is_preprint":false},{"pmid":"41443065","id":"PMC_41443065","title":"Light-exclusion bagging modulates phenylpropanoid metabolism to balance preharvest quality and postharvest granulation in 'Sanhongmiyou' pomelo.","date":"2025","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41443065","citation_count":0,"is_preprint":false},{"pmid":"42155730","id":"PMC_42155730","title":"Proteomic Analysis on Human Islets Suggests Nucleocytoplasmic Transport as a Mechanism of PERK Attenuation Effects in Diabetes.","date":"2026","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/42155730","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17428,"output_tokens":4510,"usd":0.059967,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12515,"output_tokens":4522,"usd":0.087813,"stage2_stop_reason":"end_turn"},"total_usd":0.14778,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Nup58 (along with nup60, nup97, nup153, and nup200) is initially present in a disassembled, soluble form in Xenopus egg cytosol and becomes incorporated into membrane-associated pore complexes (annulate lamellae) in a time- and temperature-dependent manner; GTPγS prevented this incorporation.\",\n      \"method\": \"Biochemical reconstitution of annulate lamellae from Xenopus egg extracts; immunoblotting; thin-section EM and negative staining; membrane flotation fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cell-free reconstitution with multiple orthogonal methods (immunoblotting, EM, flotation), rigorous pharmacological control (GTPγS), replicated across nucleoporins\",\n      \"pmids\": [\"7790348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nup58 forms part of the central channel nucleoporin complex with Nup54 and Nup62. Nup58 and Nup54 cognate coiled-coil segments form interconvertible homo- and hetero-oligomeric rings that underlie a 'ring cycle' model for constriction and dilation of the NPC central transport channel. Crystal structures identified two cognate segments of Nup54, one interacting with Nup58 and one with Nup62, forming crystallographic hetero- or homo-oligomers.\",\n      \"method\": \"X-ray crystallography of coiled-coil segments; solution analysis (gel filtration, AUC) of full ordered regions; mapping of interactomes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus solution biophysics, consistent with prior crystallographic data from same group, mechanistically validated\",\n      \"pmids\": [\"26025361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Allosteric coupling exists between the structured coiled-coil domain of Nup58 and its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to disordered domains of Nup58 stabilizes the structured Nup58 domain associated with Nup54, shifting conformational equilibria from Nup58 homo-oligomers to Nup58–Nup54 hetero-oligomers, thereby driving constriction/dilation of the NPC central channel as a function of transport factor occupancy.\",\n      \"method\": \"Quantitative analysis of multiple equilibria (binding assays); crystallographic data; in vitro reconstitution of Nup58–Nup54–Kapβ1 interactions\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative equilibrium analysis combined with prior crystal structures, rigorous mechanistic framework established in one study\",\n      \"pmids\": [\"26439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Allosteric coupling exists between the structured coiled-coil domain of Nup58 and its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to disordered domains of Nup58 stabilizes the structured Nup58 domain associated with Nup54, shifting conformational equilibria from Nup58 homo-oligomers to Nup58–Nup54 hetero-oligomers, thereby driving constriction/dilation of the NPC central channel as a function of transport factor occupancy.\",\n      \"method\": \"Quantitative analysis of multiple equilibria; crystallographic data; in vitro reconstitution of Nup58–Nup54–Kapβ1 interactions\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative equilibrium binding analysis combined with prior crystal structures, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"26046439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Nup62 complex (Nup62, Nup54, Nup58) exists in a 1:1:1 stoichiometry in solution, with Nup54 centrally positioned binding both Nup62 and Nup58 directly. At high concentrations the complex forms larger assemblies maintaining this ratio. The same 1:1:1 stoichiometry was determined for the homologous yeast Nsp1 complex, indicating evolutionary conservation. Eliminating one binding partner results in noncanonical stoichiometries in vitro, likely through promiscuous coiled-coil pairing.\",\n      \"method\": \"Gel filtration chromatography; analytical ultracentrifugation (AUC); in vitro reconstitution\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal quantitative biophysical methods (gel filtration + AUC), in vitro reconstitution, confirmed in yeast ortholog\",\n      \"pmids\": [\"24574455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans and human cells, the channel nucleoporin NPP-1/Nup58 (along with NPP-4/Nup54 and NPP-11/Nup62) physically interacts with the Polo-box domain (PBD) of PLK-1/PLK1, recruiting the kinase to the nuclear pore complex at the nuclear envelope just prior to nuclear envelope breakdown (NEBD). Nup58 and its partners are primed at multiple Polo-docking sites by Cdk1 and PLK-1 itself. This NE localization of PLK-1 is required for efficient NEBD.\",\n      \"method\": \"Genetic epistasis (C. elegans RNAi/depletion); co-immunoprecipitation; direct physical interaction assays; live-cell imaging of NEBD; human cell validation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal physical interaction assays, epistasis in C. elegans plus human cell validation, live-cell imaging with defined NEBD phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29065307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup58 depletion (via siRNA) increases radiosensitivity, and Nup58 (identified as a molecular partner of Nup54 and Nup62) is implicated in homologous recombination (HR) repair of DNA double-strand breaks: Nup54 depletion (epistatic with Nup58) decreases HR repair reporter activity, reduces HR-linked DNA synthesis foci and sister chromatid exchanges after IR, and is epistatic with Rad51.\",\n      \"method\": \"High-throughput siRNA screen; HR repair reporter assays; epistasis analysis with Rad51; measurement of chromosome aberrations, SCEs, and DNA synthesis foci\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established with Rad51, multiple DNA repair readouts; Nup58 identified as molecular partner of Nup54 but primary functional data are for Nup54; single lab\",\n      \"pmids\": [\"29986057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nup58 localizes to the nuclear rim during interphase and redistributes to mitotic spindles, centrosomes, and midbodies during mitosis. Depletion of Nup58 results in centrosomal abnormalities and delayed abscission.\",\n      \"method\": \"Confocal microscopy; live-cell imaging; stimulated emission depletion (STED) nanoscopy; siRNA knockdown with mitotic phenotype readout\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by multiple imaging modalities (confocal, live-cell, STED) combined with loss-of-function phenotype; single lab\",\n      \"pmids\": [\"31388347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NUP58 knockdown in lung adenocarcinoma cell lines (A549, H1299) inhibits metastasis and invasion in vivo and in vitro, and alters expression of EMT markers; this effect is associated with changes in the GSK-3β/Snail signaling pathway.\",\n      \"method\": \"Lentiviral shRNA knockdown; in vitro invasion assays; in vivo xenograft; Western blot for EMT markers and GSK-3β/Snail pathway components\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with phenotypic readout and pathway marker changes, but pathway placement relies on expression changes of downstream markers without direct mechanistic epistasis; single lab\",\n      \"pmids\": [\"30787996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In living cells, conformational changes in Nup58 (and Nup54, Nup62) within the NPC inner ring occur when nucleocytoplasmic transport is perturbed, while Nups elsewhere in the NPC do not show such changes, indicating that select inner-ring channel nucleoporins are flexible and undergo transport-state-dependent conformational dynamics.\",\n      \"method\": \"Genetically encoded orientation sensors (mEGFP rigidly conjugated to NPC proteins); fluorescence polarization microscopy in live cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo conformational measurement with novel sensor approach, selective to inner ring Nups; single lab, single method type\",\n      \"pmids\": [\"33346731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human NUP58 can form amyloid aggregates both in vitro and in vivo, existing as two forms: oligomers and polymers stabilized by disulfide bonds. Bioinformatic analysis shows that all known NUP58 orthologs possess conserved amyloidogenic regions.\",\n      \"method\": \"In vitro amyloid formation assays; in vivo aggregate detection; biochemical characterization (disulfide bond analysis); bioinformatic prediction\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro and in vivo demonstration with biochemical characterization, but biological significance unclear; single lab\",\n      \"pmids\": [\"34680573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup58 (along with Nup54) is essential in Drosophila ovarian follicle cells for piRNA biogenesis specifically from the flamenco locus; loss of Nup54 and Nup58 results in compromised piRNA production and transposon desilencing, a role distinct from other NPC subunits.\",\n      \"method\": \"RNAi knockdown of Nup54 and Nup58 in Drosophila ovary; small RNA sequencing; genetic comparison with other NPC subunit knockdowns\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific loss-of-function with defined molecular phenotype (piRNA levels, transposon derepression), comparison to other NPC subunits; single lab\",\n      \"pmids\": [\"33856346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hypomorphic alleles of NUP58 trigger early adaptation via transcriptome rewiring and upregulation of NPC-interacting genes, followed by long-term fitness recovery through focal amplification of the NUP58 locus and restoration of mutant protein expression.\",\n      \"method\": \"Generation of hypomorphic alleles by CRISPR/base editing; transcriptome sequencing; genomic copy number analysis; clonal evolution tracking\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic manipulation with multi-omic readouts in human cells; establishes NUP58 as an essential gene with defined adaptation mechanisms; single lab\",\n      \"pmids\": [\"34528284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIP60 acetyltransferase acetylates Nup62 at Lys432, and this acetylation dissolves the Nup62–Nup58–Nup54 complex during mitotic entry, promoting redistribution of Nup62 to the mitotic spindle and enabling correct spindle orientation and chromosome segregation.\",\n      \"method\": \"Identification of TIP60 as Nup62 acetyltransferase; acetylation site mapping (Lys432); co-immunoprecipitation of Nup62-Nup58-Nup54 complex before/after acetylation; loss-of-function and acetylation-mimetic/deficient mutants; chromosome segregation assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM writer identified with site-specific mutagenesis, complex dissociation demonstrated by Co-IP, functional phenotype readout; Nup58 participation inferred as part of dissolving complex; single lab\",\n      \"pmids\": [\"36190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NUPL1 (NUP58) knockdown in MDCK cells causes abnormal cystogenesis, with abnormalities arising primarily from faulty cell divisions including monopolar spindles or spindles with poorly separated poles, indicating a role for NUP58 in bipolar spindle formation.\",\n      \"method\": \"shRNA knockdown; 3D MDCK cystogenesis assay; confocal microscopy of spindle morphology\",\n      \"journal\": \"Oncoscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (monopolar spindles) in 3D culture model; single lab, single gene-knockdown approach\",\n      \"pmids\": [\"25621300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP58 is cleaved by the 3C-like protease (3CLpro) of Gammacoronaviruses/Deltacoronaviruses in vitro, as validated by in vitro cleavage experiments and mutational analysis of the cleavage site, identifying NUP58 as a host substrate of coronavirus 3CLpro.\",\n      \"method\": \"In vitro cleavage assay with recombinant 3CLpro; mutational analysis of cleavage site; PSSM scoring\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic cleavage with mutagenesis validation; single study, limited biological follow-up\",\n      \"pmids\": [\"39454742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP58 acts as a binding enhancer within the NPC channel, enhancing HIV capsid core (CA) binding affinity to FG repeats; NUP58 is positioned in the NPC such that its binding contribution increases with proximity to the nuclear basket, contributing to an affinity gradient that potentiates unidirectional HIV capsid translocation through the NPC.\",\n      \"method\": \"Biochemical binding assays (quantitative FG-CA interaction measurements); biophysical approaches; structural analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, biochemical binding data but no mutagenesis of NUP58 specifically or in vivo validation of NUP58's role; single study\",\n      \"pmids\": [\"41256404\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NUP58 is a central channel nucleoporin that forms a 1:1:1 coiled-coil complex with Nup54 and Nup62 at the NPC; its structured domain undergoes allosterically coupled conformational switching between homo- and hetero-oligomers driven by transport factor (Kapβ1) occupancy, thereby mediating constriction and dilation of the NPC central channel; during mitosis, the Nup62–Nup58–Nup54 complex is dissolved by TIP60-mediated acetylation of Nup62 and the complex recruits PLK1 to the nuclear envelope via Polo-box domain interactions primed by Cdk1, facilitating nuclear envelope breakdown; NUP58 itself redistributes to centrosomes and midbodies during mitosis, where its loss causes centrosomal abnormalities and delayed abscission, and contributes to bipolar spindle formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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) [#4, #1]. 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 [#1, #4]. 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 [#3], and these inner-ring nucleoporins indeed undergo transport-state-dependent conformational changes in living cells [#9]. 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 [#5], while TIP60-mediated acetylation of Nup62 dissolves the complex at mitotic entry to enable correct spindle orientation and chromosome segregation [#13]. 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 [#7, #14]. NUP58 is an essential gene whose hypomorphic loss is buffered by transcriptome rewiring and focal locus amplification [#12], and it is also implicated in homologous-recombination DNA repair as a partner of Nup54 [#6] and, in Drosophila, in flamenco-locus piRNA biogenesis [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cell-free reconstitution of annulate lamellae from Xenopus egg extracts with immunoblotting, EM, and membrane flotation, controlled with GTPγS\",\n      \"pmids\": [\"7790348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the GTPase or assembly machinery responsible\", \"No information on Nup58's partners or position within the assembled pore\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gel filtration and analytical ultracentrifugation of reconstituted complexes, compared to yeast Nsp1 complex\",\n      \"pmids\": [\"24574455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how the complex changes during transport\", \"Higher-order assembly geometry within the intact NPC not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography of coiled-coil segments, solution biophysics, and quantitative multi-equilibrium binding analysis with in vitro Kapβ1 reconstitution\",\n      \"pmids\": [\"26025361\", \"26046439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans epistasis/RNAi, co-immunoprecipitation and direct interaction assays, live-cell NEBD imaging, and human cell validation\",\n      \"pmids\": [\"29065307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of Nup58 versus Nup54/Nup62 to PLK1 docking not isolated\", \"Structural basis of the PBD–channel-Nup interaction not solved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated the channel complex in genome maintenance, linking Nup58 (as a Nup54 partner) to homologous-recombination repair and radiosensitivity.\",\n      \"evidence\": \"siRNA screen, HR reporter assays, Rad51 epistasis, and IR-induced SCE/foci measurements (primary functional data on Nup54)\",\n      \"pmids\": [\"29986057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed NUP58 is required for bipolar spindle formation, with its loss producing monopolar or poorly separated spindle poles during cell division.\",\n      \"evidence\": \"shRNA knockdown in a 3D MDCK cystogenesis model with confocal spindle morphology analysis\",\n      \"pmids\": [\"25621300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking NUP58 to centrosome/pole separation not defined\", \"Single knockdown approach in one model system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Confocal, live-cell, and STED imaging with siRNA knockdown phenotyping\",\n      \"pmids\": [\"31388347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Centrosomal/midbody binding partners of NUP58 not identified\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated NUP58 essentiality and the cellular adaptation routes (transcriptome rewiring then focal locus amplification) that buffer its partial loss.\",\n      \"evidence\": \"CRISPR/base-editing hypomorphs with transcriptome sequencing, copy-number analysis, and clonal evolution tracking in human cells\",\n      \"pmids\": [\"34528284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which essential NUP58 function drives the fitness requirement not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi knockdown in Drosophila ovary with small-RNA sequencing and comparison to other NPC subunit depletions\",\n      \"pmids\": [\"33856346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting channel nucleoporins to piRNA biogenesis unknown\", \"Conservation of this role in mammals untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetically encoded orientation sensors and fluorescence polarization microscopy under transport perturbation\",\n      \"pmids\": [\"33346731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve atomic conformations\", \"Single method type, single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified an intrinsic biophysical property of NUP58 — conserved amyloidogenic regions that form disulfide-stabilized oligomers and polymers in vitro and in vivo.\",\n      \"evidence\": \"In vitro and in vivo amyloid formation assays, disulfide-bond biochemistry, and bioinformatic conservation analysis\",\n      \"pmids\": [\"34680573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of amyloid forms unclear\", \"Relationship to normal NPC function not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"TIP60 acetyltransferase identification, Lys432 site mapping, Co-IP of the complex before/after acetylation, acetylation-mimetic/deficient mutants, and segregation assays\",\n      \"pmids\": [\"36190325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nup58 participation inferred from complex dissolution rather than direct Nup58 modification\", \"Fate and function of released Nup58 not tracked\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified NUP58 as a host substrate of coronavirus 3C-like protease, implicating channel-nucleoporin cleavage in viral disruption of the host nucleocytoplasmic interface.\",\n      \"evidence\": \"In vitro cleavage assay with recombinant 3CLpro and cleavage-site mutagenesis\",\n      \"pmids\": [\"39454742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular and functional consequences of cleavage not demonstrated\", \"Cleavage shown in vitro only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed NUP58 as a position-dependent binding enhancer for HIV capsid translocation, contributing to an FG-affinity gradient across the NPC.\",\n      \"evidence\": \"Quantitative FG–capsid binding and biophysical/structural analysis (preprint)\",\n      \"pmids\": [\"41256404\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; no NUP58-specific mutagenesis or in vivo validation\", \"Gradient model not tested by perturbing NUP58 in cells\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 7, 13]}\n    ],\n    \"complexes\": [\"Nup62–Nup58–Nup54 central channel complex\", \"nuclear pore complex\"],\n    \"partners\": [\"NUP54\", \"NUP62\", \"KPNB1\", \"PLK1\", \"KAT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}