{"gene":"NUP58","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1995,"finding":"NUP58 (nup58) is a soluble nucleoporin that assembles into nuclear pore complexes (annulate lamellae) in a time- and temperature-dependent manner in a Xenopus egg extract reconstitution system. Assembly of nup58 into membranes was inhibited by GTPγS, indicating a GTP-dependent step in nuclear pore assembly.","method":"Biochemical reconstitution of annulate lamellae in Xenopus egg extracts; immunoblotting of membrane fractions; electron microscopy; flotation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with multiple orthogonal methods (EM, biochemistry, pharmacological inhibition)","pmids":["7790348"],"is_preprint":false},{"year":2001,"finding":"The Nup62 complex (containing NUP58) resides in the central channel of the NPC and binds importin β with intermediate affinity, between the lower-affinity cytoplasmic Nup358 and the higher-affinity nuclear Nup153, establishing a gradient of increasing affinity along the import pathway.","method":"Quantitative solid-phase binding analysis; antibody inhibition of nuclear import in permeabilized cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding assay with functional antibody inhibition corroborating directionality","pmids":["11266456"],"is_preprint":false},{"year":2002,"finding":"HIV-1 Vpr interacts with the nucleoporin hCG1 (NUP58) via the N-terminal region of hCG1 (not the FG repeat domain), and this interaction mediates docking of Vpr at the nuclear envelope, as demonstrated by yeast two-hybrid, in vitro binding, co-immunoprecipitation in transfected cells, and nuclear import assays.","method":"Yeast two-hybrid; in vitro pulldown; co-immunoprecipitation; FRAP in living cells; digitonin-permeabilized cell nuclear import assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, in vitro, co-IP, functional import assay) in single study","pmids":["12228227"],"is_preprint":false},{"year":2013,"finding":"Integrated cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry placed the Nup62 subcomplex (including NUP58) within the central channel of the human NPC scaffold, revealing its position relative to the Nup107 subcomplex rings.","method":"Electron tomography; single-particle EM; crosslinking mass spectrometry","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — integrated structural approach with multiple orthogonal methods","pmids":["24315095"],"is_preprint":false},{"year":2014,"finding":"The Nup62 complex (Nup62, Nup54, NUP58) forms a 1:1:1 stoichiometric heterotrimer in solution, with Nup54 as the central scaffold that directly binds both Nup62 and NUP58 via coiled-coil segments. The same 1:1:1 stoichiometry is conserved in the yeast Nsp1 complex. At high concentration the complex forms larger assemblies while maintaining this ratio.","method":"Analytical ultracentrifugation; gel filtration; in vitro reconstitution","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — quantitative in vitro reconstitution with multiple biophysical methods, evolutionarily validated","pmids":["24574455"],"is_preprint":false},{"year":2015,"finding":"Crystallographic and solution analyses demonstrated that NUP58 and Nup54 cognate segments can form either homo-oligomers or hetero-oligomers, enabling inter-convertible 'mid-plane' ring structures that model dilation and constriction of the NPC central transport channel. The full ordered regions of Nup62, Nup54, and NUP58 form a dynamic triple complex in solution consistent with a 4:2:1 (Nup62:Nup54:NUP58) copy-number stoichiometry.","method":"X-ray crystallography; size exclusion chromatography; analytical ultracentrifugation; solution binding analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures combined with quantitative solution biophysics, consistent across methods","pmids":["26025361"],"is_preprint":false},{"year":2015,"finding":"A structured domain of NUP58 is allosterically coupled to its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to disordered domains of NUP58 stabilizes the adjacent structured domain associated with Nup54, shifting conformational equilibria from NUP58 homo-oligomers to Nup54–NUP58 hetero-oligomers. This allosteric mechanism provides a quantitative framework for constriction and dilation of the NPC central channel as a function of transport factor occupancy.","method":"Analysis of multiple binding equilibria; crystallography-based structural framework; in vitro binding assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — quantitative equilibrium analysis combined with prior crystallographic data, mechanistic framework established","pmids":["26046439"],"is_preprint":false},{"year":2017,"finding":"The channel nucleoporins NPP-1/Nup58, NPP-4/Nup54, and NPP-11/Nup62 in C. elegans recruit Polo-like kinase 1 (PLK-1) to the nuclear pore complex via the PLK-1 Polo-box domain (PBD) just prior to nuclear envelope breakdown (NEBD). Cdk1 and PLK-1 itself prime multiple Polo-docking sites on these nucleoporins, and this NE-localized PLK-1 pool is required for efficient NEBD and proper chromosome segregation.","method":"Genetic epistasis (C. elegans); RNAi knockdown; live imaging; co-immunoprecipitation; phosphorylation site mapping; PLK-1 localization assays in human cells","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional genetics and biochemistry in two organisms with defined mechanistic pathway","pmids":["29065307"],"is_preprint":false},{"year":2018,"finding":"NUP58 (as part of the Nup54–Nup62–NUP58 central channel complex) was identified by siRNA screen as a novel factor in radiosensitivity. Nup54 (and concomitantly NUP58) depletion impaired homologous recombination (HR) repair, decreased Rad51 focus formation, reduced sister chromatid exchanges, and caused mitotic catastrophe after ionizing radiation. Nup54 is epistatic with the HR factor Rad51.","method":"High-throughput siRNA screen; clonogenic survival assay; HR repair reporter assay; immunofluorescence for DNA damage foci; epistasis analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — functional screen with mechanistic follow-up; NUP58 identified as co-depleted partner of Nup54, direct NUP58 role inferred but not individually validated","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 causes centrosomal abnormalities and delayed abscission, establishing a role for NUP58 in centrosome homeostasis and cytokinetic abscission.","method":"Confocal microscopy; live-cell imaging; STED (stimulated emission depletion) nanoscopy; siRNA depletion with phenotypic readout","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by super-resolution imaging with functional KD phenotype; single lab","pmids":["31388347"],"is_preprint":false},{"year":2019,"finding":"NUP58 knockdown in lung adenocarcinoma cell lines (A549, H1299) inhibited metastasis and invasion in vitro and in vivo. Silencing NUP58 altered expression of EMT markers and suppressed GSK-3β/Snail pathway activity, indicating NUP58 promotes EMT-driven metastasis through the GSK-3β/Snail signaling axis.","method":"Lentiviral shRNA knockdown; invasion/migration assays; in vivo xenograft; Western blotting for EMT markers and pathway components","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method class; pathway placement inferred from expression changes without direct mechanistic reconstitution","pmids":["30787996"],"is_preprint":false},{"year":2020,"finding":"In vivo conformational sensors (mEGFP rigidly conjugated to NPC proteins) showed that NUP58 and its inner-ring neighbors Nup54 and Nup62 undergo conformational changes when nucleocytoplasmic transport is perturbed, while Nups elsewhere in the NPC do not, demonstrating that the central channel nucleoporins are the flexible, transport-responsive elements of the NPC.","method":"Live-cell imaging with orientation-sensitive fluorescent sensors; transport perturbation assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo structural measurement with functional perturbation; single lab","pmids":["33346731"],"is_preprint":false},{"year":2021,"finding":"Hypomorphic alleles of NUP58 in human cells trigger early transcriptome rewiring (upregulation of NPC-interacting genes) as a non-genetic adaptation, followed by focal genomic amplification of the NUP58 locus to restore protein expression as a long-term genetic adaptation, establishing NUP58 as an essential NPC gene whose impairment drives ordered adaptive evolution.","method":"Generation of hypomorphic alleles by CRISPR; RNA-seq; genomic copy number analysis; clonal fitness assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — systematic genetic dissection with transcriptomic and genomic readouts; single lab","pmids":["34528284"],"is_preprint":false},{"year":2021,"finding":"Drosophila Nup54 and Nup58 (channel nucleoporins) are essential for piRNA-mediated transposon silencing in ovarian follicle cells, specifically from the flamenco locus, while knockdown of other NPC subunits has broader consequences. This demonstrates tissue-specific, locus-specific gene regulatory roles for NUP58 beyond its canonical transport function.","method":"Drosophila RNAi knockdown in ovarian follicle cells; small RNA sequencing; transposon derepression assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with specific molecular readout in defined tissue; single lab","pmids":["33856346"],"is_preprint":false},{"year":2021,"finding":"Human NUP58 can form amyloid aggregates both in vitro and in vivo (in bacterial and yeast systems), existing as both oligomers and polymers stabilized by disulfide bonds. Bioinformatic analysis identified conserved amyloidogenic regions across all known NUP58 orthologs, suggesting an intrinsic aggregation propensity of NUP58 related to its phase-separation capacity.","method":"In vitro amyloid formation assays; Congo red/ThT fluorescence; electron microscopy of fibrils; in vivo expression in bacteria and yeast; bioinformatic amyloid prediction","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro and in vivo aggregation demonstrated with multiple methods; single lab","pmids":["34680573"],"is_preprint":false},{"year":2022,"finding":"TIP60 acetyltransferase acetylates Nup62 at Lys432, which dissolves the Nup62–NUP58–Nup54 complex during mitotic entry, promoting redistribution of Nup62 to the mitotic spindle for correct spindle orientation and accurate chromosome segregation.","method":"Mass spectrometry identification of acetylation; mutagenesis of acetylation site; co-immunoprecipitation; immunofluorescence; siRNA knockdown with mitotic phenotype readout","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — PTM identified by MS with site-specific mutagenesis and functional consequence on NUP58 complex dissolution; single lab","pmids":["36190325"],"is_preprint":false},{"year":2024,"finding":"NUP58 is a host substrate of coronavirus 3C-like protease (3CLpro): in vitro cleavage experiments and mutational analysis validated NUP58 as a high-scoring cleavage target of Gammacoronavirus/Deltacoronavirus 3CLpro, suggesting 3CLpro may modulate nucleo-cytoplasmic transport by cleaving NUP58.","method":"PSSM-based computational prediction; in vitro cleavage assay; mutational analysis of cleavage site","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Low","confidence_rationale":"Tier 3 — in vitro cleavage validated but functional consequence in cells not established; single study","pmids":["39454742"],"is_preprint":false},{"year":2025,"finding":"NUP58 acts as a binding enhancer for HIV capsid core within the NPC central channel: biochemical and biophysical analyses showed that FG/FxFG motifs of NUP58 bind HIV capsid (CA) with enhanced affinity compared to canonical FxFG motifs, contributing to an avidity gradient along the cytoplasmic-nuclear axis that promotes unidirectional HIV capsid translocation into the nucleus.","method":"Biochemical binding assays; biophysical affinity measurements; structural analyses (AlphaFold-guided); mutational analysis of FG motifs","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint; in vitro binding data without cellular validation of NUP58-specific contribution","pmids":["41256404"],"is_preprint":true}],"current_model":"NUP58 is a central channel nucleoporin that forms a dynamic 1:1:1 heterotrimer with Nup54 and Nup62 via coiled-coil interactions; its structured domain is allosterically coupled to FG-repeat domains, enabling Kapβ1-driven conformational shifts between homo- and hetero-oligomeric ring states that dilate or constrict the NPC transport channel, while during mitosis NUP58 is mobilized to centrosomes and midbodies (regulated in part by TIP60-mediated acetylation of the Nup62 complex), where it recruits PLK-1 to facilitate nuclear envelope breakdown and accurate chromosome segregation, and additionally participates in homologous recombination repair and tissue-specific gene regulation including piRNA-mediated transposon silencing."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that NUP58 is a soluble nucleoporin whose integration into nuclear pore complexes requires a GTP-dependent step resolved the basic question of how central channel components are assembled into membranes.","evidence":"Biochemical reconstitution of annulate lamellae in Xenopus egg extracts with GTPγS inhibition, EM, and flotation assays","pmids":["7790348"],"confidence":"High","gaps":["Identity of the GTPase required for NUP58 pore incorporation was not determined","Whether NUP58 assembly is co-translational or post-translational was not resolved"]},{"year":2001,"claim":"Demonstrating that the Nup62 complex (containing NUP58) binds importin β at intermediate affinity between cytoplasmic and nuclear FG-nucleoporins established the affinity gradient model for directional transport through the central channel.","evidence":"Quantitative solid-phase binding assays and antibody inhibition of nuclear import in permeabilized cells","pmids":["11266456"],"confidence":"High","gaps":["Individual contribution of NUP58 versus Nup62 and Nup54 FG domains to importin β binding not dissected","In vivo validation of the affinity gradient not performed"]},{"year":2002,"claim":"Identification of NUP58 as a direct binding partner of HIV-1 Vpr through its N-terminal (non-FG) domain revealed the NPC central channel as a viral docking platform distinct from canonical FG-mediated transport.","evidence":"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, and digitonin-permeabilized cell nuclear import assays","pmids":["12228227"],"confidence":"High","gaps":["Structural basis of the Vpr–NUP58 interaction not resolved","Functional consequence for viral replication not fully demonstrated in this study"]},{"year":2013,"claim":"Integrated structural mapping of the human NPC placed the Nup62 subcomplex (including NUP58) within the central transport channel relative to the scaffold rings, answering where NUP58 sits in the intact pore architecture.","evidence":"Cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry of human NPCs","pmids":["24315095"],"confidence":"High","gaps":["Atomic-resolution structure of NUP58 within the intact NPC not achieved","Conformational dynamics of NUP58 in situ not captured"]},{"year":2014,"claim":"Quantitative demonstration that Nup62, Nup54, and NUP58 form a 1:1:1 heterotrimer with Nup54 as the central scaffold resolved the subunit stoichiometry and architecture of the channel nucleoporin complex.","evidence":"Analytical ultracentrifugation and gel filtration of recombinant complex; evolutionary conservation validated with yeast Nsp1 complex","pmids":["24574455"],"confidence":"High","gaps":["Whether the 1:1:1 trimer is the only relevant stoichiometry in the assembled NPC was debated"]},{"year":2015,"claim":"Crystal structures and binding equilibria revealed that NUP58 segments can switch between homo-oligomeric and NUP58–Nup54 hetero-oligomeric ring conformations, and that Kapβ1 binding to NUP58's FG domains allosterically drives this switch—providing the first mechanistic model for how transport factor occupancy modulates central channel diameter.","evidence":"X-ray crystallography, analytical ultracentrifugation, and quantitative equilibrium binding analyses","pmids":["26025361","26046439"],"confidence":"High","gaps":["In vivo validation that the homo-to-hetero switch occurs during active transport not directly demonstrated","Contribution of post-translational modifications to the conformational equilibrium unknown"]},{"year":2017,"claim":"Discovery that NUP58 and other channel nucleoporins recruit PLK-1 via Polo-box domain docking sites primed by Cdk1 established a mitotic signaling function for NUP58 at the nuclear envelope, required for efficient NEBD and chromosome segregation.","evidence":"C. elegans RNAi epistasis, live imaging, co-immunoprecipitation, phosphorylation site mapping; confirmed in human cells","pmids":["29065307"],"confidence":"High","gaps":["Which specific phosphosites on human NUP58 are essential for PLK-1 recruitment not fully mapped","Whether NUP58's mitotic role is independent of its transport function not resolved"]},{"year":2018,"claim":"A radiosensitivity siRNA screen implicated the Nup54–NUP58 complex in homologous recombination repair, linking central channel nucleoporins to DNA damage response for the first time.","evidence":"High-throughput siRNA screen, HR reporter assay, Rad51 foci quantification, and epistasis analysis with Rad51","pmids":["29986057"],"confidence":"Medium","gaps":["NUP58 was identified as co-depleted partner of Nup54; individual NUP58 knockdown phenotype in HR not separately validated","Mechanism by which channel nucleoporins promote HR (e.g. mRNA export of repair factors versus direct nuclear role) not determined"]},{"year":2019,"claim":"Super-resolution imaging demonstrated that NUP58 redistributes from the nuclear rim to centrosomes, spindle poles, and midbodies during mitosis, and its depletion causes centrosomal defects and delayed abscission, broadening its mitotic role beyond NEBD to cytokinesis.","evidence":"STED nanoscopy, confocal and live-cell imaging, siRNA depletion with phenotypic scoring","pmids":["31388347"],"confidence":"Medium","gaps":["Molecular partners of NUP58 at centrosomes and midbodies not identified","Whether NUP58's cytokinetic function depends on the Nup62 complex or is independent unknown"]},{"year":2020,"claim":"In vivo conformational sensors confirmed that NUP58, Nup54, and Nup62 are the flexible, transport-responsive elements of the NPC, validating the earlier in vitro allosteric dilation model in living cells.","evidence":"Live-cell imaging with orientation-sensitive mEGFP sensors under transport perturbation","pmids":["33346731"],"confidence":"Medium","gaps":["Sensor reports on orientation, not directly on ring diameter or stoichiometry changes","Magnitude of conformational change and its relationship to cargo flux not quantified"]},{"year":2021,"claim":"Three parallel studies expanded NUP58's biology: (1) hypomorphic alleles showed NUP58 is essential and its impairment drives ordered adaptive evolution via focal gene amplification; (2) Drosophila genetics revealed a tissue-specific role in piRNA-mediated transposon silencing; (3) in vitro studies showed NUP58 can form amyloid aggregates, suggesting intrinsic phase-separation capacity.","evidence":"CRISPR hypomorphic alleles with RNA-seq and copy-number analysis; Drosophila RNAi with small-RNA sequencing; in vitro amyloid assays with Congo red/ThT and EM","pmids":["34528284","33856346","34680573"],"confidence":"Medium","gaps":["Whether amyloid formation is physiologically relevant or an artifact of overexpression unknown","How NUP58 selectively regulates the flamenco piRNA locus versus other loci not mechanistically explained","Whether the adaptive amplification mechanism operates in tumors in vivo not tested"]},{"year":2022,"claim":"Identification of TIP60-mediated acetylation of Nup62-K432 as the signal that dissolves the Nup62–NUP58–Nup54 complex during mitotic entry provided a PTM-based mechanism coupling interphase NPC disassembly to spindle orientation and chromosome segregation.","evidence":"Mass spectrometry, site-directed mutagenesis of K432, co-immunoprecipitation of complex dissolution, and mitotic phenotyping after TIP60 or Nup62 perturbation","pmids":["36190325"],"confidence":"Medium","gaps":["Whether NUP58 itself is acetylated during mitosis not examined","Temporal coordination between K432 acetylation and PLK-1 recruitment to NUP58 not resolved"]},{"year":null,"claim":"Key unresolved questions include: (1) the atomic-resolution structure of NUP58 within an intact NPC; (2) how NUP58 mechanistically contributes to homologous recombination independently of its transport role; (3) the physiological relevance of NUP58 amyloid formation; and (4) whether NUP58 cleavage by viral proteases disrupts transport in infected cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution in situ structure of NUP58 in the intact human NPC","Mechanism linking NUP58 to HR repair pathway not established","In vivo relevance of NUP58 amyloid aggregation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,11]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,2,3,9]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[7,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[9,15]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,6,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,9,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]}],"complexes":["Nup62 complex (Nup62–Nup54–NUP58)"],"partners":["NUP54","NUP62","KPNB1","PLK1","KAT5"],"other_free_text":[]},"mechanistic_narrative":"NUP58 is a central channel nucleoporin that, together with Nup54 and Nup62, forms the dynamic core of the nuclear pore complex transport channel and participates in mitotic regulation and gene control. The Nup62–Nup54–NUP58 heterotrimer assembles via coiled-coil interactions with Nup54 as the central scaffold, and multivalent binding of the transport factor Kapβ1 to NUP58's disordered FG-repeat domains allosterically shifts the structured domain between homo- and hetero-oligomeric ring states, providing a mechanism for transport-responsive dilation and constriction of the NPC channel [PMID:26046439, PMID:24574455, PMID:26025361]. During mitosis, NUP58 redistributes from the nuclear envelope to centrosomes, spindles, and midbodies—regulated in part by TIP60-mediated acetylation of Nup62 that dissolves the heterotrimer—where it recruits PLK-1 to promote nuclear envelope breakdown and accurate chromosome segregation [PMID:29065307, PMID:31388347, PMID:36190325]. Beyond nucleocytoplasmic transport, NUP58 contributes to homologous recombination repair, tissue-specific piRNA-mediated transposon silencing, and serves as a docking site for HIV-1 Vpr at the nuclear envelope [PMID:29986057, PMID:33856346, PMID:12228227]."},"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":"21189294","id":"PMC_21189294","title":"Identification and characterization of nuclear pore complex components in Arabidopsis thaliana.","date":"2010","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/21189294","citation_count":239,"is_preprint":false,"source_track":"pubmed_title"},{"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":141,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"pmid":"7790348","id":"PMC_7790348","title":"Nuclear pore complex assembly studied with a biochemical assay 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reconstitution system; this assembly is blocked by GTPγS.\",\n      \"method\": \"Biochemical reconstitution of annulate lamellae formation from Xenopus egg extracts, immunoblotting, flotation/sedimentation assay, electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal methods (biochemical assay, EM, flotation)\",\n      \"pmids\": [\"7790348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nup58 forms a 1:1:1 stoichiometric complex with Nup54 and Nup62 in solution; Nup54 is the central component binding both Nup62 and Nup58, and at high concentrations the complex assembles into larger oligomers while maintaining the same ratio.\",\n      \"method\": \"In vitro reconstitution, gel filtration, analytical ultracentrifugation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with multiple biophysical methods\",\n      \"pmids\": [\"24574455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The ordered (structured) region of Nup58 engages in dynamic homo- and hetero-oligomeric interactions with Nup54's cognate segment; these interconvertible oligomers (homo-tetramers vs. hetero-dodecamers) underlie a 'ring cycle' model for dilation and constriction of the nuclear pore central transport channel.\",\n      \"method\": \"Crystal structure analysis of cognate segments combined with solution studies (SEC, cross-linking); structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures plus solution biophysics, consistent with prior structural data\",\n      \"pmids\": [\"26025361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Allosteric coupling exists between the structured domain of Nup58 and its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to Nup58's disordered domains stabilizes the adjacent structured domain bound to Nup54, shifting equilibria from Nup58 homo-oligomers to Nup54–Nup58 hetero-oligomers, thereby driving conformational changes (constriction/dilation) of the central channel.\",\n      \"method\": \"Multi-equilibrium binding analysis, crystallography (prior data cited), in vitro binding assays with Kapβ1\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative multi-equilibrium analysis plus crystallographic data, published in high-impact journal\",\n      \"pmids\": [\"26046439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, the central channel nucleoporin NPP-1/Nup58 (together with NPP-4/Nup54 and NPP-11/Nup62) recruits PLK-1 to the nuclear pore complex via direct physical interaction with PLK-1's Polo-box domain; priming phosphorylation by Cdk1 and PLK-1 itself at multiple sites on these nucleoporins is required, and this recruitment is necessary for efficient nuclear envelope breakdown.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis (C. elegans loss-of-function), live-cell imaging, phosphorylation assays, pull-down with PLK-1 PBD\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, epistasis, and functional rescue across two organisms (C. elegans and human cells)\",\n      \"pmids\": [\"29065307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup58 (along with Nup54 and Nup62) is identified as a factor implicated in radiosensitivity and homologous recombination (HR) repair; Nup54 is epistatic with Rad51 in HR, and Nup58 depletion leads to increased chromosome aberrations and reduced HR-linked DNA synthesis foci, placing the Nup62 subcomplex in the HR pathway.\",\n      \"method\": \"siRNA knockdown, HR reporter assay, epistasis with Rad51, γH2AX and RAD51 focus formation, SCE assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis and functional HR reporters, but Nup58 findings are secondary to primary Nup54 focus\",\n      \"pmids\": [\"29986057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nup58 localizes to nuclear rim during interphase and redistributes to centrosomes, mitotic spindles, and midbodies during mitosis; Nup58 depletion causes centrosomal abnormalities and delayed abscission.\",\n      \"method\": \"Confocal microscopy, live-cell imaging, STED (STORM) nanoscopy, siRNA knockdown with phenotypic readout\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by super-resolution imaging tied to functional consequence (abscission delay, centrosome defects) via KD\",\n      \"pmids\": [\"31388347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of NUP58 inhibits metastasis and invasion of lung adenocarcinoma cells and alters EMT marker expression via the GSK-3β/Snail signaling pathway.\",\n      \"method\": \"Lentiviral shRNA knockdown, in vitro invasion/migration assays, in vivo xenograft, western blotting of GSK-3β/Snail pathway components\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway placement inferred from marker expression changes without direct mechanistic epistasis\",\n      \"pmids\": [\"30787996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conformational changes occur specifically in Nup58 (and Nup54, Nup62) within the NPC inner ring when nucleocytoplasmic transport is perturbed, while nucleoporins outside the central channel show no such conformational changes, demonstrating that Nup58 is a dynamic, flexible component of the transport channel.\",\n      \"method\": \"FRET-based conformational sensor (mEGFP rigidly conjugated to NPC proteins), live-cell imaging with pharmacological transport perturbation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo conformational measurement with engineered sensors and functional perturbation\",\n      \"pmids\": [\"33346731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hypomorphic alleles of NUP58 generated by CRISPR cause early non-genetic adaptation (transcriptome rewiring, upregulation of NPC-interacting genes) followed by long-term genetic adaptation via focal amplification of the NUP58 locus and restoration of mutant protein expression, demonstrating that NUP58 is an essential gene in human cells.\",\n      \"method\": \"CRISPR-generated hypomorphic alleles, RNA-seq, copy number analysis, clonal evolution experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined genetic manipulation with multi-omic readouts in human cells\",\n      \"pmids\": [\"34528284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup54 and Nup58 (central channel nucleoporins) are specifically required for piRNA biogenesis from the flamenco locus in Drosophila ovarian follicle cells; knockdown of these but not other NPC subunits selectively compromises this transposon-silencing pathway.\",\n      \"method\": \"siRNA/RNAi knockdown in Drosophila ovary, piRNA sequencing, transposon derepression assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific tissue-specific phenotype; ortholog in Drosophila consistent with mammalian Nup58\",\n      \"pmids\": [\"33856346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human NUP58 can form amyloid aggregates both in vitro and in vivo; two forms of aggregates are observed—oligomers and polymers stabilized by disulfide bonds—and bioinformatic analysis identifies conserved amyloidogenic regions across NUP58 orthologs.\",\n      \"method\": \"Thioflavin T fluorescence, electron microscopy, SDS-PAGE under reducing/non-reducing conditions, in vivo aggregation assay in yeast\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro biophysical characterization with multiple orthogonal methods, though biological significance unclear\",\n      \"pmids\": [\"34680573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIP60 acetylates Nup62 at Lys432, which 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\": \"Co-immunoprecipitation, acetylation site mutagenesis, in vitro acetyltransferase assay, immunofluorescence, RNAi knockdown with chromosome segregation phenotype\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — acetylation writer identified with mutagenesis and functional phenotype, though primary focus is Nup62; Nup58 complex dissolution is directly demonstrated\",\n      \"pmids\": [\"36190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP58 is cleaved by the 3C-like protease (3CLpro) of Gammacoronaviruses/Deltacoronaviruses; the cleavage site was identified and validated by in vitro cleavage experiments and mutational analysis.\",\n      \"method\": \"In vitro cleavage assay, PSSM-based site prediction, mutagenesis of cleavage site, AlphaFold2 structural analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis validation, single study\",\n      \"pmids\": [\"39454742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP58 acts as a binding enhancer for HIV capsid core interaction with the nuclear pore complex; NUP58's FG/FxFG motifs contribute to an affinity gradient that increases toward the nuclear basket, proposed to drive unidirectional translocation of the HIV capsid core through the NPC.\",\n      \"method\": \"Biochemical binding assays, biophysical quantitation of FG–capsid affinities, structural analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, NUP58 role is secondary/supporting in broader HIV capsid study\",\n      \"pmids\": [\"41256404\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NUP58 is a central channel nucleoporin that forms a dynamic 1:1:1 complex with Nup54 and Nup62 via coiled-coil interactions; its structured domain undergoes allosterically regulated homo-to-hetero-oligomeric transitions driven by transport factor (Kapβ1) binding, enabling constriction and dilation of the NPC transport channel, while during mitosis it redistributes to centrosomes and midbodies (dissolution of the Nup62–Nup58–Nup54 complex triggered by TIP60-mediated Nup62 acetylation), recruits PLK-1 to the nuclear envelope to facilitate nuclear envelope breakdown, and is required for bipolar spindle formation and abscission.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n- Papers 1, 21, 29 (corpus): Plant NUP58/NUP62 or Arabidopsis — EXCLUDE (plant symbol collision or off-target)\n- Papers 2, 3, 5, 8, 9, 10, 31, 32: About NUPL1 (NUP88/NUP214 family), not NUP58 — EXCLUDE (alias collision)\n- Paper 20: ZmNUP58 in maize, stress response — EXCLUDE (plant symbol collision)\n- Paper 29 (corpus): pomelo MYB78/bHLH25/NUP58 module — EXCLUDE (plant symbol collision)\n- Papers 4, 6, 7, 11, 12, 13, 14, 15, 16, 17, 18, 19, 23, 24, 25, 26, 27, 28, 33: About canonical NUP58 — KEEP\n- Curated papers: Most are large interactome/proteome screens that detect NUP58 as part of the NPC — relevant interactions noted; also paper 23 (Nup62 complex), paper 29 (hCG1/NUP58 Vpr interaction) — KEEP relevant ones\n\nLet me now extract mechanistic discoveries from KEEP papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"NUP58 (nup58) is a soluble nucleoporin that assembles into nuclear pore complexes (annulate lamellae) in a time- and temperature-dependent manner in a Xenopus egg extract reconstitution system. Assembly of nup58 into membranes was inhibited by GTPγS, indicating a GTP-dependent step in nuclear pore assembly.\",\n      \"method\": \"Biochemical reconstitution of annulate lamellae in Xenopus egg extracts; immunoblotting of membrane fractions; electron microscopy; flotation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with multiple orthogonal methods (EM, biochemistry, pharmacological inhibition)\",\n      \"pmids\": [\"7790348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Nup62 complex (containing NUP58) resides in the central channel of the NPC and binds importin β with intermediate affinity, between the lower-affinity cytoplasmic Nup358 and the higher-affinity nuclear Nup153, establishing a gradient of increasing affinity along the import pathway.\",\n      \"method\": \"Quantitative solid-phase binding analysis; antibody inhibition of nuclear import in permeabilized cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding assay with functional antibody inhibition corroborating directionality\",\n      \"pmids\": [\"11266456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HIV-1 Vpr interacts with the nucleoporin hCG1 (NUP58) via the N-terminal region of hCG1 (not the FG repeat domain), and this interaction mediates docking of Vpr at the nuclear envelope, as demonstrated by yeast two-hybrid, in vitro binding, co-immunoprecipitation in transfected cells, and nuclear import assays.\",\n      \"method\": \"Yeast two-hybrid; in vitro pulldown; co-immunoprecipitation; FRAP in living cells; digitonin-permeabilized cell nuclear import assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, in vitro, co-IP, functional import assay) in single study\",\n      \"pmids\": [\"12228227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Integrated cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry placed the Nup62 subcomplex (including NUP58) within the central channel of the human NPC scaffold, revealing its position relative to the Nup107 subcomplex rings.\",\n      \"method\": \"Electron tomography; single-particle EM; crosslinking mass spectrometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — integrated structural approach with multiple orthogonal methods\",\n      \"pmids\": [\"24315095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Nup62 complex (Nup62, Nup54, NUP58) forms a 1:1:1 stoichiometric heterotrimer in solution, with Nup54 as the central scaffold that directly binds both Nup62 and NUP58 via coiled-coil segments. The same 1:1:1 stoichiometry is conserved in the yeast Nsp1 complex. At high concentration the complex forms larger assemblies while maintaining this ratio.\",\n      \"method\": \"Analytical ultracentrifugation; gel filtration; in vitro reconstitution\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro reconstitution with multiple biophysical methods, evolutionarily validated\",\n      \"pmids\": [\"24574455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystallographic and solution analyses demonstrated that NUP58 and Nup54 cognate segments can form either homo-oligomers or hetero-oligomers, enabling inter-convertible 'mid-plane' ring structures that model dilation and constriction of the NPC central transport channel. The full ordered regions of Nup62, Nup54, and NUP58 form a dynamic triple complex in solution consistent with a 4:2:1 (Nup62:Nup54:NUP58) copy-number stoichiometry.\",\n      \"method\": \"X-ray crystallography; size exclusion chromatography; analytical ultracentrifugation; solution binding analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures combined with quantitative solution biophysics, consistent across methods\",\n      \"pmids\": [\"26025361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A structured domain of NUP58 is allosterically coupled to its neighboring disordered FG domain: multivalent binding of the transport factor Kapβ1 to disordered domains of NUP58 stabilizes the adjacent structured domain associated with Nup54, shifting conformational equilibria from NUP58 homo-oligomers to Nup54–NUP58 hetero-oligomers. This allosteric mechanism provides a quantitative framework for constriction and dilation of the NPC central channel as a function of transport factor occupancy.\",\n      \"method\": \"Analysis of multiple binding equilibria; crystallography-based structural framework; in vitro binding assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative equilibrium analysis combined with prior crystallographic data, mechanistic framework established\",\n      \"pmids\": [\"26046439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The channel nucleoporins NPP-1/Nup58, NPP-4/Nup54, and NPP-11/Nup62 in C. elegans recruit Polo-like kinase 1 (PLK-1) to the nuclear pore complex via the PLK-1 Polo-box domain (PBD) just prior to nuclear envelope breakdown (NEBD). Cdk1 and PLK-1 itself prime multiple Polo-docking sites on these nucleoporins, and this NE-localized PLK-1 pool is required for efficient NEBD and proper chromosome segregation.\",\n      \"method\": \"Genetic epistasis (C. elegans); RNAi knockdown; live imaging; co-immunoprecipitation; phosphorylation site mapping; PLK-1 localization assays in human cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional genetics and biochemistry in two organisms with defined mechanistic pathway\",\n      \"pmids\": [\"29065307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUP58 (as part of the Nup54–Nup62–NUP58 central channel complex) was identified by siRNA screen as a novel factor in radiosensitivity. Nup54 (and concomitantly NUP58) depletion impaired homologous recombination (HR) repair, decreased Rad51 focus formation, reduced sister chromatid exchanges, and caused mitotic catastrophe after ionizing radiation. Nup54 is epistatic with the HR factor Rad51.\",\n      \"method\": \"High-throughput siRNA screen; clonogenic survival assay; HR repair reporter assay; immunofluorescence for DNA damage foci; epistasis analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional screen with mechanistic follow-up; NUP58 identified as co-depleted partner of Nup54, direct NUP58 role inferred but not individually validated\",\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 causes centrosomal abnormalities and delayed abscission, establishing a role for NUP58 in centrosome homeostasis and cytokinetic abscission.\",\n      \"method\": \"Confocal microscopy; live-cell imaging; STED (stimulated emission depletion) nanoscopy; siRNA depletion with phenotypic readout\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by super-resolution imaging with functional KD 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) inhibited metastasis and invasion in vitro and in vivo. Silencing NUP58 altered expression of EMT markers and suppressed GSK-3β/Snail pathway activity, indicating NUP58 promotes EMT-driven metastasis through the GSK-3β/Snail signaling axis.\",\n      \"method\": \"Lentiviral shRNA knockdown; invasion/migration assays; in vivo xenograft; Western blotting for EMT markers and pathway components\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method class; pathway placement inferred from expression changes without direct mechanistic reconstitution\",\n      \"pmids\": [\"30787996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vivo conformational sensors (mEGFP rigidly conjugated to NPC proteins) showed that NUP58 and its inner-ring neighbors Nup54 and Nup62 undergo conformational changes when nucleocytoplasmic transport is perturbed, while Nups elsewhere in the NPC do not, demonstrating that the central channel nucleoporins are the flexible, transport-responsive elements of the NPC.\",\n      \"method\": \"Live-cell imaging with orientation-sensitive fluorescent sensors; transport perturbation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo structural measurement with functional perturbation; single lab\",\n      \"pmids\": [\"33346731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hypomorphic alleles of NUP58 in human cells trigger early transcriptome rewiring (upregulation of NPC-interacting genes) as a non-genetic adaptation, followed by focal genomic amplification of the NUP58 locus to restore protein expression as a long-term genetic adaptation, establishing NUP58 as an essential NPC gene whose impairment drives ordered adaptive evolution.\",\n      \"method\": \"Generation of hypomorphic alleles by CRISPR; RNA-seq; genomic copy number analysis; clonal fitness assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic genetic dissection with transcriptomic and genomic readouts; single lab\",\n      \"pmids\": [\"34528284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Drosophila Nup54 and Nup58 (channel nucleoporins) are essential for piRNA-mediated transposon silencing in ovarian follicle cells, specifically from the flamenco locus, while knockdown of other NPC subunits has broader consequences. This demonstrates tissue-specific, locus-specific gene regulatory roles for NUP58 beyond its canonical transport function.\",\n      \"method\": \"Drosophila RNAi knockdown in ovarian follicle cells; small RNA sequencing; transposon derepression assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific molecular readout in defined tissue; single lab\",\n      \"pmids\": [\"33856346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human NUP58 can form amyloid aggregates both in vitro and in vivo (in bacterial and yeast systems), existing as both oligomers and polymers stabilized by disulfide bonds. Bioinformatic analysis identified conserved amyloidogenic regions across all known NUP58 orthologs, suggesting an intrinsic aggregation propensity of NUP58 related to its phase-separation capacity.\",\n      \"method\": \"In vitro amyloid formation assays; Congo red/ThT fluorescence; electron microscopy of fibrils; in vivo expression in bacteria and yeast; bioinformatic amyloid prediction\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro and in vivo aggregation demonstrated with multiple methods; single lab\",\n      \"pmids\": [\"34680573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIP60 acetyltransferase acetylates Nup62 at Lys432, which dissolves the Nup62–NUP58–Nup54 complex during mitotic entry, promoting redistribution of Nup62 to the mitotic spindle for correct spindle orientation and accurate chromosome segregation.\",\n      \"method\": \"Mass spectrometry identification of acetylation; mutagenesis of acetylation site; co-immunoprecipitation; immunofluorescence; siRNA knockdown with mitotic phenotype readout\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — PTM identified by MS with site-specific mutagenesis and functional consequence on NUP58 complex dissolution; single lab\",\n      \"pmids\": [\"36190325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP58 is a host substrate of coronavirus 3C-like protease (3CLpro): in vitro cleavage experiments and mutational analysis validated NUP58 as a high-scoring cleavage target of Gammacoronavirus/Deltacoronavirus 3CLpro, suggesting 3CLpro may modulate nucleo-cytoplasmic transport by cleaving NUP58.\",\n      \"method\": \"PSSM-based computational prediction; in vitro cleavage assay; mutational analysis of cleavage site\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vitro cleavage validated but functional consequence in cells not established; single study\",\n      \"pmids\": [\"39454742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP58 acts as a binding enhancer for HIV capsid core within the NPC central channel: biochemical and biophysical analyses showed that FG/FxFG motifs of NUP58 bind HIV capsid (CA) with enhanced affinity compared to canonical FxFG motifs, contributing to an avidity gradient along the cytoplasmic-nuclear axis that promotes unidirectional HIV capsid translocation into the nucleus.\",\n      \"method\": \"Biochemical binding assays; biophysical affinity measurements; structural analyses (AlphaFold-guided); mutational analysis of FG motifs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint; in vitro binding data without cellular validation of NUP58-specific contribution\",\n      \"pmids\": [\"41256404\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NUP58 is a central channel nucleoporin that forms a dynamic 1:1:1 heterotrimer with Nup54 and Nup62 via coiled-coil interactions; its structured domain is allosterically coupled to FG-repeat domains, enabling Kapβ1-driven conformational shifts between homo- and hetero-oligomeric ring states that dilate or constrict the NPC transport channel, while during mitosis NUP58 is mobilized to centrosomes and midbodies (regulated in part by TIP60-mediated acetylation of the Nup62 complex), where it recruits PLK-1 to facilitate nuclear envelope breakdown and accurate chromosome segregation, and additionally participates in homologous recombination repair and tissue-specific gene regulation including piRNA-mediated transposon silencing.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP58 is a central channel nucleoporin that functions in nucleocytoplasmic transport and mitotic progression. It forms a 1:1:1 stoichiometric complex with Nup54 and Nup62 via coiled-coil interactions, and its structured domain undergoes dynamic homo-to-hetero-oligomeric transitions with Nup54 that are allosterically driven by transport factor (Kapβ1) binding to adjacent FG domains, thereby mediating constriction and dilation of the NPC transport channel [PMID:24574455, PMID:26025361, PMID:26046439, PMID:33346731]. During mitosis, TIP60-mediated acetylation of Nup62 dissolves the Nup62–Nup58–Nup54 complex, and Nup58 redistributes to centrosomes, spindles, and midbodies where it recruits PLK-1 to facilitate nuclear envelope breakdown and is required for bipolar spindle formation and cytokinetic abscission [PMID:29065307, PMID:31388347, PMID:36190325]. NUP58 is essential in human cells, as hypomorphic CRISPR alleles trigger transcriptome rewiring and compensatory focal amplification of the NUP58 locus [PMID:34528284].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that Nup58 is a soluble nucleoporin whose incorporation into nuclear pore complexes is GTP-dependent resolved how this protein reaches the NPC and placed it within the regulated pore assembly pathway.\",\n      \"evidence\": \"Biochemical reconstitution of annulate lamellae from Xenopus egg extracts with GTPγS block, flotation assay, and electron microscopy\",\n      \"pmids\": [\"7790348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Assembly pathway intermediates not identified\", \"Identity of the GTPase required for incorporation unknown\", \"No information on stoichiometry within the assembled pore\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Determining that Nup58, Nup54, and Nup62 form a 1:1:1 complex with Nup54 as the central scaffold defined the subunit architecture of the central channel subcomplex.\",\n      \"evidence\": \"In vitro reconstitution with gel filtration and analytical ultracentrifugation\",\n      \"pmids\": [\"24574455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Higher-order oligomeric arrangement within the intact NPC not resolved\", \"No information on post-translational regulation of complex assembly\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of Nup58's structured domain revealed interconvertible homo-tetrameric and hetero-dodecameric states with Nup54, providing a structural basis for the 'ring cycle' model of central channel dilation and constriction, and showing that Kapβ1 binding to FG domains allosterically shifts the equilibrium toward hetero-oligomers.\",\n      \"evidence\": \"X-ray crystallography of cognate segments, SEC, cross-linking, and multi-equilibrium binding analysis with Kapβ1\",\n      \"pmids\": [\"26025361\", \"26046439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational transitions not directly observed in situ in intact NPCs\", \"Whether other transport factors exert similar allosteric effects is untested\", \"Structural model lacks the FG domain itself\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that the Nup62–Nup58–Nup54 subcomplex directly recruits PLK-1 via Polo-box domain interactions, primed by Cdk1 phosphorylation, established a mitotic function for central channel nucleoporins in nuclear envelope breakdown.\",\n      \"evidence\": \"Reciprocal Co-IP, PLK-1 PBD pull-down, genetic epistasis in C. elegans, live-cell imaging, phosphorylation assays\",\n      \"pmids\": [\"29065307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites on Nup58 that prime PLK-1 binding not fully mapped in mammalian cells\", \"Whether PLK-1 recruitment feeds back on NPC disassembly kinetics unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking Nup58 depletion to increased chromosome aberrations and reduced homologous recombination broadened Nup58's roles beyond transport to include genome maintenance.\",\n      \"evidence\": \"siRNA knockdown with HR reporter assay, epistasis with Rad51, γH2AX/RAD51 foci quantification\",\n      \"pmids\": [\"29986057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nup58's contribution is secondary to the primary Nup54 epistasis data\", \"Whether the HR role is transport-dependent or direct is unresolved\", \"No biochemical interaction between Nup58 and HR factors demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Super-resolution imaging showed Nup58 redistributes from the nuclear rim to centrosomes, spindles, and midbodies during mitosis, and its depletion causes centrosomal abnormalities and delayed abscission, establishing a direct mitotic role beyond NPC function.\",\n      \"evidence\": \"STED/STORM nanoscopy, confocal and live-cell imaging, siRNA knockdown in human cells\",\n      \"pmids\": [\"31388347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Nup58 recruitment to centrosomes unknown\", \"Whether Nup58's mitotic functions are separable from Nup62/Nup54 not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo FRET sensors demonstrated that Nup58 (together with Nup54 and Nup62) undergoes conformational changes when nucleocytoplasmic transport is perturbed, whereas outer ring nucleoporins do not, validating the dynamic flexibility model specifically for central channel nucleoporins in living cells.\",\n      \"evidence\": \"FRET-based conformational sensors with mEGFP rigid conjugation, pharmacological transport perturbation, live-cell imaging\",\n      \"pmids\": [\"33346731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FRET reports ensemble conformational change; individual pore dynamics not resolved\", \"Correlation with specific cargo passage events not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three independent studies expanded the functional landscape: CRISPR hypomorphic alleles proved NUP58 essentiality in human cells with compensatory gene amplification; Drosophila Nup58 was shown to be specifically required for piRNA biogenesis from the flamenco locus; and Nup58 was found capable of forming amyloid aggregates in vitro.\",\n      \"evidence\": \"CRISPR mutagenesis with RNA-seq and copy number analysis; RNAi in Drosophila ovary with piRNA sequencing; ThT fluorescence, EM, and SDS-PAGE aggregation assays\",\n      \"pmids\": [\"34528284\", \"33856346\", \"34680573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Essentiality mechanism (transport vs. mitotic vs. gene expression) not dissected\", \"Whether piRNA role is conserved in mammals unknown\", \"Physiological relevance of amyloid aggregation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of TIP60-mediated Nup62 acetylation at Lys432 as the trigger for Nup62–Nup58–Nup54 complex dissolution at mitotic entry provided the first post-translational mechanism governing subcomplex disassembly and spindle function.\",\n      \"evidence\": \"In vitro acetyltransferase assay, acetylation site mutagenesis, Co-IP, RNAi with chromosome segregation phenotype\",\n      \"pmids\": [\"36190325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Nup58 itself is acetylated or modified at mitotic entry not addressed\", \"Temporal coordination with PLK-1 recruitment not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that Gammacoronavirus/Deltacoronavirus 3CLpro cleaves NUP58 at a defined site revealed a viral strategy targeting the central transport channel.\",\n      \"evidence\": \"In vitro cleavage assay with purified 3CLpro, mutagenesis of cleavage site, AlphaFold2 modeling\",\n      \"pmids\": [\"39454742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage not demonstrated during live viral infection\", \"Functional consequence of cleavage on NPC transport not tested\", \"Relevance to human-pathogenic coronaviruses (SARS-CoV-2) not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the in situ structural arrangement of Nup58 oligomeric transitions within intact NPCs, whether its mitotic and DNA repair functions are transport-dependent or autonomous, and how its roles in piRNA biogenesis and viral interactions integrate with central channel dynamics.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution cryo-ET structure of Nup58 transitions within the intact human NPC\", \"Separation-of-function alleles for transport vs. mitotic roles not generated\", \"Mammalian conservation of the piRNA biogenesis role untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 3, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 6, 12]}\n    ],\n    \"complexes\": [\n      \"Nup62–Nup58–Nup54 central channel subcomplex\"\n    ],\n    \"partners\": [\n      \"NUP54\",\n      \"NUP62\",\n      \"PLK1\",\n      \"KPNB1\",\n      \"TIP60\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP58 is a central channel nucleoporin that, together with Nup54 and Nup62, forms the dynamic core of the nuclear pore complex transport channel and participates in mitotic regulation and gene control. The Nup62–Nup54–NUP58 heterotrimer assembles via coiled-coil interactions with Nup54 as the central scaffold, and multivalent binding of the transport factor Kapβ1 to NUP58's disordered FG-repeat domains allosterically shifts the structured domain between homo- and hetero-oligomeric ring states, providing a mechanism for transport-responsive dilation and constriction of the NPC channel [PMID:26046439, PMID:24574455, PMID:26025361]. During mitosis, NUP58 redistributes from the nuclear envelope to centrosomes, spindles, and midbodies—regulated in part by TIP60-mediated acetylation of Nup62 that dissolves the heterotrimer—where it recruits PLK-1 to promote nuclear envelope breakdown and accurate chromosome segregation [PMID:29065307, PMID:31388347, PMID:36190325]. Beyond nucleocytoplasmic transport, NUP58 contributes to homologous recombination repair, tissue-specific piRNA-mediated transposon silencing, and serves as a docking site for HIV-1 Vpr at the nuclear envelope [PMID:29986057, PMID:33856346, PMID:12228227].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that NUP58 is a soluble nucleoporin whose integration into nuclear pore complexes requires a GTP-dependent step resolved the basic question of how central channel components are assembled into membranes.\",\n      \"evidence\": \"Biochemical reconstitution of annulate lamellae in Xenopus egg extracts with GTPγS inhibition, EM, and flotation assays\",\n      \"pmids\": [\"7790348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the GTPase required for NUP58 pore incorporation was not determined\", \"Whether NUP58 assembly is co-translational or post-translational was not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that the Nup62 complex (containing NUP58) binds importin β at intermediate affinity between cytoplasmic and nuclear FG-nucleoporins established the affinity gradient model for directional transport through the central channel.\",\n      \"evidence\": \"Quantitative solid-phase binding assays and antibody inhibition of nuclear import in permeabilized cells\",\n      \"pmids\": [\"11266456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of NUP58 versus Nup62 and Nup54 FG domains to importin β binding not dissected\", \"In vivo validation of the affinity gradient not performed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of NUP58 as a direct binding partner of HIV-1 Vpr through its N-terminal (non-FG) domain revealed the NPC central channel as a viral docking platform distinct from canonical FG-mediated transport.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, and digitonin-permeabilized cell nuclear import assays\",\n      \"pmids\": [\"12228227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Vpr–NUP58 interaction not resolved\", \"Functional consequence for viral replication not fully demonstrated in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Integrated structural mapping of the human NPC placed the Nup62 subcomplex (including NUP58) within the central transport channel relative to the scaffold rings, answering where NUP58 sits in the intact pore architecture.\",\n      \"evidence\": \"Cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry of human NPCs\",\n      \"pmids\": [\"24315095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of NUP58 within the intact NPC not achieved\", \"Conformational dynamics of NUP58 in situ not captured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Quantitative demonstration that Nup62, Nup54, and NUP58 form a 1:1:1 heterotrimer with Nup54 as the central scaffold resolved the subunit stoichiometry and architecture of the channel nucleoporin complex.\",\n      \"evidence\": \"Analytical ultracentrifugation and gel filtration of recombinant complex; evolutionary conservation validated with yeast Nsp1 complex\",\n      \"pmids\": [\"24574455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the 1:1:1 trimer is the only relevant stoichiometry in the assembled NPC was debated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures and binding equilibria revealed that NUP58 segments can switch between homo-oligomeric and NUP58–Nup54 hetero-oligomeric ring conformations, and that Kapβ1 binding to NUP58's FG domains allosterically drives this switch—providing the first mechanistic model for how transport factor occupancy modulates central channel diameter.\",\n      \"evidence\": \"X-ray crystallography, analytical ultracentrifugation, and quantitative equilibrium binding analyses\",\n      \"pmids\": [\"26025361\", \"26046439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation that the homo-to-hetero switch occurs during active transport not directly demonstrated\", \"Contribution of post-translational modifications to the conformational equilibrium unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that NUP58 and other channel nucleoporins recruit PLK-1 via Polo-box domain docking sites primed by Cdk1 established a mitotic signaling function for NUP58 at the nuclear envelope, required for efficient NEBD and chromosome segregation.\",\n      \"evidence\": \"C. elegans RNAi epistasis, live imaging, co-immunoprecipitation, phosphorylation site mapping; confirmed in human cells\",\n      \"pmids\": [\"29065307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific phosphosites on human NUP58 are essential for PLK-1 recruitment not fully mapped\", \"Whether NUP58's mitotic role is independent of its transport function not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A radiosensitivity siRNA screen implicated the Nup54–NUP58 complex in homologous recombination repair, linking central channel nucleoporins to DNA damage response for the first time.\",\n      \"evidence\": \"High-throughput siRNA screen, HR reporter assay, Rad51 foci quantification, and epistasis analysis with Rad51\",\n      \"pmids\": [\"29986057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NUP58 was identified as co-depleted partner of Nup54; individual NUP58 knockdown phenotype in HR not separately validated\", \"Mechanism by which channel nucleoporins promote HR (e.g. mRNA export of repair factors versus direct nuclear role) not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Super-resolution imaging demonstrated that NUP58 redistributes from the nuclear rim to centrosomes, spindle poles, and midbodies during mitosis, and its depletion causes centrosomal defects and delayed abscission, broadening its mitotic role beyond NEBD to cytokinesis.\",\n      \"evidence\": \"STED nanoscopy, confocal and live-cell imaging, siRNA depletion with phenotypic scoring\",\n      \"pmids\": [\"31388347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners of NUP58 at centrosomes and midbodies not identified\", \"Whether NUP58's cytokinetic function depends on the Nup62 complex or is independent unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo conformational sensors confirmed that NUP58, Nup54, and Nup62 are the flexible, transport-responsive elements of the NPC, validating the earlier in vitro allosteric dilation model in living cells.\",\n      \"evidence\": \"Live-cell imaging with orientation-sensitive mEGFP sensors under transport perturbation\",\n      \"pmids\": [\"33346731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sensor reports on orientation, not directly on ring diameter or stoichiometry changes\", \"Magnitude of conformational change and its relationship to cargo flux not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three parallel studies expanded NUP58's biology: (1) hypomorphic alleles showed NUP58 is essential and its impairment drives ordered adaptive evolution via focal gene amplification; (2) Drosophila genetics revealed a tissue-specific role in piRNA-mediated transposon silencing; (3) in vitro studies showed NUP58 can form amyloid aggregates, suggesting intrinsic phase-separation capacity.\",\n      \"evidence\": \"CRISPR hypomorphic alleles with RNA-seq and copy-number analysis; Drosophila RNAi with small-RNA sequencing; in vitro amyloid assays with Congo red/ThT and EM\",\n      \"pmids\": [\"34528284\", \"33856346\", \"34680573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether amyloid formation is physiologically relevant or an artifact of overexpression unknown\", \"How NUP58 selectively regulates the flamenco piRNA locus versus other loci not mechanistically explained\", \"Whether the adaptive amplification mechanism operates in tumors in vivo not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of TIP60-mediated acetylation of Nup62-K432 as the signal that dissolves the Nup62–NUP58–Nup54 complex during mitotic entry provided a PTM-based mechanism coupling interphase NPC disassembly to spindle orientation and chromosome segregation.\",\n      \"evidence\": \"Mass spectrometry, site-directed mutagenesis of K432, co-immunoprecipitation of complex dissolution, and mitotic phenotyping after TIP60 or Nup62 perturbation\",\n      \"pmids\": [\"36190325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP58 itself is acetylated during mitosis not examined\", \"Temporal coordination between K432 acetylation and PLK-1 recruitment to NUP58 not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the atomic-resolution structure of NUP58 within an intact NPC; (2) how NUP58 mechanistically contributes to homologous recombination independently of its transport role; (3) the physiological relevance of NUP58 amyloid formation; and (4) whether NUP58 cleavage by viral proteases disrupts transport in infected cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution in situ structure of NUP58 in the intact human NPC\", \"Mechanism linking NUP58 to HR repair pathway not established\", \"In vivo relevance of NUP58 amyloid aggregation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 6, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 9, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"Nup62 complex (Nup62–Nup54–NUP58)\"\n    ],\n    \"partners\": [\n      \"NUP54\",\n      \"NUP62\",\n      \"KPNB1\",\n      \"PLK1\",\n      \"KAT5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}