{"gene":"NUP188","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1996,"finding":"Yeast Nup188p is a major constituent of the nuclear pore complex (NPC) that localizes to both the cytoplasmic and nucleoplasmic faces of the NPC core, physically interacts with the pore membrane protein Pom152p and nucleoporin Nic96p, and is required for normal nuclear envelope and NPC morphology; null mutants appear normal but certain alleles cause dominant NPC-associated nuclear envelope herniations.","method":"Biochemical fractionation of NPCs, immunofluorescence, immunoelectron microscopy, genetic deletion and allelic analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunoEM, genetics) in a focused mechanistic study, replicated across two concurrent papers (PMIDs 8682855, 8682854)","pmids":["8682855"],"is_preprint":false},{"year":1996,"finding":"The C-terminal domain of Nic96p functionally and physically interacts with Nup188p in an allele-specific fashion; affinity purification of Nup188p co-purifies a fraction of Nic96p, placing Nup188p in a direct protein–protein interaction with Nic96p within the NPC scaffold.","method":"Allele-specific genetic interaction, affinity purification (ProtA-Nup188p pull-down), co-fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical evidence for the Nic96p–Nup188p interaction, replicated independently (PMIDs 8682854, 8682855)","pmids":["8682854"],"is_preprint":false},{"year":1995,"finding":"Genetic epistasis in yeast shows that deletion of NUP188 is not lethal alone, but pairwise deletion with POM152 or NUP170 is synthetically lethal, placing Nup188p in a functionally redundant inner-ring scaffold substructure of the NPC together with Pom152p and Nup170p.","method":"Synthetic lethal genetic screen, pairwise deletion analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple gene pairs, consistent with concurrent structural characterization papers","pmids":["8522578"],"is_preprint":false},{"year":2000,"finding":"Deletion of NUP188 (nup188-Δ) in yeast increases passive nuclear envelope permeability: passive export rates of NLS-GFP reporters are significantly faster and the equilibrium sieving limit of the diffusion channel is greater than wild-type, indicating that Nup188p contributes to establishing the functional resting diameter of the NPC central transport channel.","method":"In vivo passive permeability assay using NLS-GFP and NES-GFP reporters of defined molecular weights in nup188-Δ cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple reporters of different sizes, clean deletion mutant, specific functional readout on channel diameter","pmids":["10831607"],"is_preprint":false},{"year":2000,"finding":"Vertebrate (Xenopus) Nup188 exists in a complex with Nup93 (xNup93) and Nup205 (xNup205) at the nuclear pore; the Nup93-Nup188-Nup205 complex does not bind WGA directly but associates indirectly via N-acetylglucosamine-modified nucleoporins, and Nup188 assembles into annulate lamellae pore structures.","method":"WGA-affinity chromatography of Xenopus egg extracts, organelle trap (annulate lamellae assembly) assay, identification of human NUP188 gene","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two-step biochemical assay (affinity selection + in vitro assembly) with identification of complex composition","pmids":["11029043"],"is_preprint":false},{"year":2013,"finding":"The structure of Nup188 was determined: it folds into an extended stack of helices where an N-terminal ~130 kDa segment forms an intricate closed ring and the C-terminal region is a superhelical structure with distant similarity to flexible S-shaped nuclear transport receptors (NTRs). Both Nup188 and Nup192 specifically bind FG-repeats and can translocate through NPCs by facilitated diffusion, suggesting an evolutionary relationship between NPC scaffold and soluble transport machinery.","method":"X-ray crystallography (structure determination), FG-repeat binding assay, facilitated diffusion assay through NPCs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus multiple functional assays (FG binding, translocation) in one focused study","pmids":["23795296"],"is_preprint":false},{"year":2013,"finding":"Human Nup188 localizes to spindle poles during mitosis via its C-terminal region; depletion of Nup188 causes failure of chromosome alignment at the metaphase plate, impairs robust K-fiber (kinetochore microtubule bundle) formation, and perturbs NuMA localization to spindle poles. Nup188 directly interacts with NuMA.","method":"siRNA depletion, immunofluorescence, co-immunoprecipitation (Nup188–NuMA interaction), live-cell imaging","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean depletion with defined phenotypic readouts and co-IP for the NuMA interaction, single lab","pmids":["23551833"],"is_preprint":false},{"year":2016,"finding":"Nup188 (as part of the Nup93 sub-complex) associates with the HOXA gene cluster promoters and is required for tethering the HOXA locus to the nuclear periphery and repressing HOXA gene expression; depletion of the Nup93/Nup188/Nup205 sub-complex upregulates HOXA genes, increases active histone marks (H3K9ac), and decreases repressive marks (H3K27me3) at the HOXA1 promoter.","method":"ChIP, siRNA knockdown, 3D-FISH, histone mark analysis by ChIP","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, FISH, histone marks), single lab; Nup188 role is partially inferred from sub-complex depletion","pmids":["27980680"],"is_preprint":false},{"year":2017,"finding":"GLFG repeats of Nup116 function redundantly with Nup188, a non-essential scaffold nucleoporin, to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly; GLFG repeats directly bind multiple scaffold Nups including Nup188 in vitro.","method":"In vitro FG-repeat binding assay, genetic redundancy analysis (nup116Δ/nup188 synthetic interactions), NPC assembly assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding plus genetic epistasis with clear assembly phenotype, published in high-tier journal","pmids":["29033133"],"is_preprint":false},{"year":2018,"finding":"The integral membrane protein Brl1 physically interacts with Nup188 (by immunoprecipitation) at NPC assembly sites, indicating a direct role for Brl1 in NPC biogenesis through contact with this inner-ring scaffold component.","method":"Immunoprecipitation (Brl1–Nup188 co-IP), split-YFP analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP supported by split-YFP, single lab","pmids":["29439116"],"is_preprint":false},{"year":2018,"finding":"Quantitative fluorescence microscopy in intact yeast NPCs reveals that Nup188 and its paralog Nup192 form a paralog pair whose altered expression leads to significant changes in NPC stoichiometry, inducing voids in NPC structure or substitution of one paralog by the other, demonstrating compositional plasticity of the NPC.","method":"Quantitative fluorescence microscopy (NuRIM pipeline), genetic manipulation of Nup expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative in vivo imaging with genetic manipulation, single lab","pmids":["29632211"],"is_preprint":false},{"year":2019,"finding":"TDP-43 controls mRNA splicing of NUP188; complete loss of TDP-43 in human cells results in aberrant NUP188 splicing and nuclear envelope morphological defects.","method":"TDP-43 knockout human cells, transcriptomic analysis, cell biological phenotyping","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with transcriptomic and morphological readouts, single lab","pmids":["31527135"],"is_preprint":false},{"year":2020,"finding":"Nup188 localizes to the pericentriolar material (PCM) of centrosomes independently of NPCs: pulse-chase labeling shows centrosomal Nup188 is newly synthesized and does not exchange with NPC-resident Nup188 even after mitotic NPC breakdown. The centrosomal pool is subject to proteasomal degradation (unlike the NPC pool). Nup188 directly binds Cep152 (by co-IP/proximity labeling), and depletion of Nup188 impairs centriole duplication at or upstream of Sas6 loading.","method":"Pulse-chase fluorescent labeling, super-resolution microscopy, proximity labeling (BioID), proteasome inhibition, co-immunoprecipitation (Nup188–Cep152), siRNA depletion with centriole duplication readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pulse-chase, proximity labeling, co-IP, super-resolution, functional depletion) in a focused mechanistic study","pmids":["32211895"],"is_preprint":false},{"year":2022,"finding":"Near-atomic composite structures of the human and S. cerevisiae NPC were determined by combining crystal structures and cryo-EM structures of Nup188 and Nup192 scaffold hubs bound to Nic96, Nup145N, and Nup53 linker nucleoporin binding regions, revealing that Nup188 forms a question mark-shaped keystone of a hetero-octameric inner ring complex. Linkers bind scaffold surface pockets of Nup188 through short defined motifs. Structure-guided mutagenesis in yeast confirmed the physiological relevance of linker-scaffold interactions. Nup188 is positioned exclusively in the inner ring (not the outer rings) in the intact NPC.","method":"X-ray crystallography, single-particle cryo-EM, cryo-ET docking, biochemical reconstitution, structure-guided mutagenesis in S. cerevisiae","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures + cryo-EM + reconstitution + mutagenesis + in situ cryo-ET validation, multiple orthogonal methods in one rigorous study","pmids":["35679425"],"is_preprint":false},{"year":2022,"finding":"NUP188 was identified as a new binding partner of Nesprin-2 (LINC complex component) at the nuclear envelope; this interaction positions the NPC to capture SV40 virus upon its release from Nesprin-2, enabling NPC-mediated nuclear translocation of the virus.","method":"Co-immunoprecipitation (NUP188–Nesprin-2 interaction), siRNA depletion, viral infection assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and depletion experiments, single lab, mechanistic context provided by viral entry assay","pmids":["36067270"],"is_preprint":false},{"year":2011,"finding":"Morpholino knockdown of NUP188 in Xenopus strongly disrupts morphological left-right development and expression of pitx2, a molecular marker of left-right patterning, placing NUP188 as a functional gene required for left-right organizer activity.","method":"Morpholino knockdown in Xenopus, in situ hybridization for pitx2, morphological scoring of LR defects","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with molecular and morphological readouts, validated against 13 control genes","pmids":["21282601"],"is_preprint":false},{"year":1997,"finding":"The N-terminal GLFG domain of Nup145p (N-Nup145p), generated by in vivo cleavage, becomes essential in a nup188 mutant background, and generation of a free N-domain is a prerequisite for complementation of this synthetic lethal interaction, placing Nup188p in a functional relationship with the GLFG-containing transport domain of Nup145p.","method":"Genetic synthetic lethality analysis, in vivo cleavage domain dissection","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with domain dissection, single lab","pmids":["9305650"],"is_preprint":false},{"year":1999,"finding":"Full-length Pom152p (including its lumenal C-terminal domain) is uniquely required to rescue nup188 mutations, whereas N-terminal or transmembrane segments alone are insufficient, indicating that the lumenal structures of Pom152p play an important role in functional interactions with Nup188p on the pore-side of the NPC.","method":"Domain deletion/truncation complementation assay in synthetic lethal nup188 strains","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain dissection of Pom152p in defined genetic background, single lab","pmids":["9988776"],"is_preprint":false},{"year":1999,"finding":"Elevated levels of SSA1 (but not SSB1) suppress NLS-GFP nuclear localization defects in nup188-Δ cells; NES-less Ssb1p also stimulates nuclear transport in nup188-Δ cells, demonstrating a genetic interaction between NUP188 and Hsp70 chaperones in the NLS-directed import pathway.","method":"Genetic suppression assay, GFP reporter localization in nup188-Δ cells, Ssa1p/Ssb1p overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppression with multiple Hsp70 variants and reporters, single lab","pmids":["10347213"],"is_preprint":false},{"year":2018,"finding":"A cold-sensitive nup188-brr7 allele causes defects in both select protein import pathways and mRNA export in S. cerevisiae, linking Nup188p (as part of the Nic96 nucleoporin complex) to bidirectional nucleocytoplasmic transport.","method":"Cold-sensitive mutant screen, dT50 in situ hybridization assay (poly-A RNA export), NLS-GFP import assay","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual functional assays (import and export) in a defined mutant allele, single lab","pmids":["30021831"],"is_preprint":false},{"year":2025,"finding":"In a genome-wide screen for yeast genes involved in break-induced replication (BIR), Nup188 was identified as functioning after DNA synthesis to support BIR repair completion, acting sequentially after Nup84 (which acts before DNA synthesis).","method":"Genome-wide deletion screen for BIR defects, epistasis ordering of Nup84 vs. Nup188 in BIR","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genome-wide screen with limited mechanistic follow-up specific to Nup188, single study","pmids":["41398407"],"is_preprint":false},{"year":2026,"finding":"NUP188 promotes liver cancer stem cell (LCSC) stemness through two mechanisms: (1) facilitating importin-β-mediated nuclear import of OCT4 (POU5F1), and (2) stabilizing SOX2 by preventing its lysosome-dependent degradation. A NUP188-targeting peptide suppressed tumor sphere formation and inhibited tumor growth in vivo.","method":"siRNA/KO functional assays, co-immunoprecipitation (NUP188–importin-β), lysosome inhibition rescue, in vitro and in vivo tumor assays, NUP188-targeting peptide","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and mechanistic experiments (co-IP, rescue), single lab","pmids":["42119810"],"is_preprint":false}],"current_model":"NUP188 encodes a large scaffold nucleoporin that forms a question mark-shaped keystone of the inner ring of the nuclear pore complex (NPC), where it interacts with Nic96/Nup93, Nup145N, Nup53, and Pom152 through defined surface pockets to maintain NPC integrity and channel diameter; beyond its NPC role, Nup188 independently localizes to the pericentriolar material where it binds Cep152 and is required for centriole duplication, localizes to spindle poles during mitosis where it recruits NuMA to promote K-fiber formation and chromosome alignment, participates in transcriptional repression of the HOXA gene cluster by tethering it to the nuclear periphery, facilitates importin-β-mediated nuclear import of specific cargoes (e.g., OCT4) and SOX2 stabilization in cancer stem cells, and is required for left-right body patterning via a cilia-related mechanism."},"narrative":{"mechanistic_narrative":"NUP188 encodes a large scaffold nucleoporin that is a core structural element of the inner ring of the nuclear pore complex (NPC), where it functions as a question mark-shaped keystone of a hetero-octameric inner ring complex and engages the linker nucleoporins Nic96, Nup145N, and Nup53 through defined surface pockets [PMID:35679425]. It was first identified in yeast as a major NPC constituent that interacts with the pore membrane protein Pom152p and the nucleoporin Nic96p and is required for normal nuclear envelope and NPC morphology [PMID:8682855, PMID:8682854, PMID:9988776]. Although Nup188 is individually non-essential, it operates within a functionally redundant inner-ring substructure: loss is synthetically lethal with POM152 or NUP170 and genetically intertwined with the GLFG transport domains of Nup145p and Nup116 needed for late NPC assembly [PMID:8522578, PMID:29033133, PMID:9305650]. Functionally, Nup188 helps set the resting diameter of the central transport channel, as its deletion increases passive nuclear envelope permeability [PMID:10831607], and structural work shows it binds FG-repeats and can itself translocate through NPCs by facilitated diffusion, indicating an evolutionary kinship between scaffold and soluble transport machinery [PMID:23795296]. Beyond the pore, Nup188 has independent, spatially distinct roles: a centrosomal pool localizes to the pericentriolar material where it binds Cep152 and is required for centriole duplication upstream of Sas6 loading [PMID:32211895]; during mitosis it localizes to spindle poles, directly interacts with NuMA, and promotes K-fiber formation and chromosome alignment [PMID:23551833]; and as part of the Nup93/Nup188/Nup205 sub-complex it tethers the HOXA cluster to the nuclear periphery to repress its expression [PMID:27980680]. Additional roles include facilitating importin-β-mediated nuclear import of OCT4 and stabilizing SOX2 to drive liver cancer stem cell stemness [PMID:42119810] and supporting left-right body patterning in vertebrate development [PMID:21282601].","teleology":[{"year":1995,"claim":"Established that Nup188 is a non-essential NPC component embedded within a functionally redundant inner-ring substructure, framing it as a scaffold buffer rather than a single critical pore subunit.","evidence":"Synthetic lethal genetic screen with pairwise NUP188/POM152/NUP170 deletions in yeast","pmids":["8522578"],"confidence":"High","gaps":["Does not define the physical architecture of the redundant substructure","Mechanism of redundancy at the molecular level unresolved"]},{"year":1996,"claim":"Identified Nup188 as a major NPC constituent and placed it in direct contact with Pom152p and Nic96p, defining its first physical partners within the pore scaffold.","evidence":"Biochemical NPC fractionation, immunoEM, allele-specific genetics, and ProtA-Nup188p affinity purification in yeast","pmids":["8682855","8682854"],"confidence":"High","gaps":["No atomic-resolution interface for the Nic96 or Pom152 contacts","Stoichiometry within the NPC not determined"]},{"year":1997,"claim":"Linked Nup188 function to the FG/GLFG transport domains by showing the free N-Nup145p domain becomes essential in a nup188 mutant background.","evidence":"Genetic synthetic lethality and in vivo cleavage domain dissection in yeast","pmids":["9305650"],"confidence":"Medium","gaps":["Direct physical interaction between Nup188 and N-Nup145p not shown here","Functional consequence on transport not directly measured"]},{"year":1999,"claim":"Refined the Pom152p interaction to its lumenal C-terminal domain and connected NUP188 genetically to the Hsp70-dependent NLS import pathway.","evidence":"Domain truncation complementation in synthetic lethal strains and SSA1/SSB1 overexpression suppression of nup188-Δ import defects","pmids":["9988776","10347213"],"confidence":"Medium","gaps":["Direct biochemical Pom152 lumenal-domain binding not demonstrated","Hsp70 link is genetic, not a physical interaction"]},{"year":2000,"claim":"Demonstrated that Nup188 contributes to setting the functional diameter of the NPC central transport channel and is part of a conserved vertebrate Nup93–Nup188–Nup205 complex.","evidence":"Passive permeability assays with sized NLS/NES-GFP reporters in nup188-Δ yeast; WGA-affinity chromatography and annulate lamellae assembly in Xenopus extracts","pmids":["10831607","11029043"],"confidence":"High","gaps":["Structural basis for channel-diameter control unknown","How the sub-complex assembles into the ring not resolved"]},{"year":2013,"claim":"Provided the first crystal structure of Nup188 and showed it binds FG-repeats and translocates through NPCs, suggesting an evolutionary relationship between scaffold and soluble transport receptors.","evidence":"X-ray crystallography, FG-repeat binding, and facilitated diffusion assays","pmids":["23795296"],"confidence":"High","gaps":["Physiological significance of facilitated diffusion in vivo unclear","Full-length architecture in the assembled NPC not resolved at this stage"]},{"year":2013,"claim":"Revealed a moonlighting mitotic role: human Nup188 localizes to spindle poles, binds NuMA, and is required for K-fiber formation and chromosome alignment.","evidence":"siRNA depletion, immunofluorescence, co-IP, and live-cell imaging in human cells","pmids":["23551833"],"confidence":"Medium","gaps":["Mechanism of spindle-pole targeting not defined","NuMA interaction not validated by orthogonal structural or reciprocal methods"]},{"year":2016,"claim":"Connected the Nup93/Nup188/Nup205 sub-complex to gene regulation by showing it tethers and represses the HOXA cluster at the nuclear periphery.","evidence":"ChIP, siRNA knockdown, 3D-FISH, and histone-mark profiling in human cells","pmids":["27980680"],"confidence":"Medium","gaps":["Nup188-specific contribution inferred from sub-complex depletion","Direct DNA or chromatin contact by Nup188 not shown"]},{"year":2017,"claim":"Showed Nup116 GLFG repeats act redundantly with Nup188 to stabilize scaffold interactions during late NPC assembly, with direct in vitro binding.","evidence":"In vitro FG-repeat binding, genetic redundancy analysis, and NPC assembly assay in yeast","pmids":["29033133"],"confidence":"High","gaps":["Precise assembly step Nup188 stabilizes not pinpointed","Quantitative kinetics of assembly contribution unknown"]},{"year":2018,"claim":"Extended Nup188's assembly role by identifying Brl1 as an NPC-biogenesis partner and demonstrating compositional plasticity through the Nup188/Nup192 paralog pair.","evidence":"Brl1 co-IP and split-YFP; quantitative fluorescence microscopy (NuRIM) with genetic manipulation of Nup expression in yeast","pmids":["29439116","29632211"],"confidence":"Medium","gaps":["Brl1 link rests on a single co-IP supported by split-YFP","Functional consequence of paralog substitution for transport unknown"]},{"year":2018,"claim":"Linked Nup188 to bidirectional nucleocytoplasmic transport via a cold-sensitive allele affecting both protein import and mRNA export.","evidence":"Cold-sensitive nup188-brr7 mutant with poly-A RNA in situ export and NLS-GFP import assays in yeast","pmids":["30021831"],"confidence":"Medium","gaps":["Whether transport defects are direct or secondary to scaffold disruption unclear","Cargo selectivity not fully mapped"]},{"year":2019,"claim":"Placed NUP188 downstream of TDP-43, showing its mRNA splicing is TDP-43-dependent and its mis-splicing causes nuclear envelope defects.","evidence":"TDP-43 knockout human cells with transcriptomic and morphological phenotyping","pmids":["31527135"],"confidence":"Medium","gaps":["Disease relevance of NUP188 mis-splicing not established","Functional NUP188 isoform consequences not characterized"]},{"year":2020,"claim":"Defined an NPC-independent centrosomal pool of Nup188 that binds Cep152 and is required for centriole duplication, establishing a distinct moonlighting function.","evidence":"Pulse-chase labeling, super-resolution microscopy, BioID, proteasome inhibition, co-IP, and siRNA centriole-duplication readout in human cells","pmids":["32211895"],"confidence":"High","gaps":["How centrosomal versus NPC targeting is partitioned mechanistically unknown","Structural basis of Cep152 binding undefined"]},{"year":2022,"claim":"Delivered the near-atomic architecture of Nup188 as a question mark-shaped inner-ring keystone engaging linker nucleoporins through defined surface pockets, validated functionally.","evidence":"X-ray crystallography, cryo-EM, cryo-ET docking, reconstitution, and structure-guided mutagenesis of human and yeast NPCs","pmids":["35679425"],"confidence":"High","gaps":["Dynamics of linker-scaffold engagement during assembly not captured","Does not address moonlighting localizations outside the NPC"]},{"year":2022,"claim":"Identified NUP188 as a Nesprin-2 (LINC complex) partner positioning the NPC for SV40 viral nuclear translocation.","evidence":"Co-IP, siRNA depletion, and viral infection assays in human cells","pmids":["36067270"],"confidence":"Medium","gaps":["Single-lab co-IP without reciprocal structural validation","Generality beyond SV40 entry unknown"]},{"year":2025,"claim":"Implicated Nup188 in DNA repair by placing it after DNA synthesis in break-induced replication, downstream of Nup84.","evidence":"Genome-wide deletion screen for BIR defects with epistasis ordering in yeast","pmids":["41398407"],"confidence":"Low","gaps":["Genome-wide screen with limited Nup188-specific mechanistic follow-up","Direct role versus indirect transport/scaffold effect not distinguished"]},{"year":2026,"claim":"Defined a pro-stemness role in liver cancer through importin-β-mediated OCT4 import and lysosome-protective SOX2 stabilization, with a targeting peptide showing therapeutic potential.","evidence":"siRNA/KO assays, co-IP, lysosome inhibition rescue, tumor sphere and in vivo tumor assays, and a NUP188-targeting peptide","pmids":["42119810"],"confidence":"Medium","gaps":["Whether OCT4/SOX2 effects depend on NPC-resident or moonlighting Nup188 unclear","Mechanism of SOX2 protection from lysosomal degradation not defined"]},{"year":null,"claim":"How a single scaffold nucleoporin is partitioned among its NPC, centrosomal, spindle-pole, and chromatin-tethering roles, and how these moonlighting activities are regulated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism for targeting Nup188 to distinct compartments","Structural basis for non-NPC partner interactions (NuMA, Cep152, Nesprin-2) undefined","Regulation switching between pore and moonlighting pools unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,6,12]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,19]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,12]}],"complexes":["NPC inner ring complex","Nup93-Nup188-Nup205 sub-complex"],"partners":["NIC96/NUP93","POM152","NUP205","NUMA1","CEP152","NESPRIN-2","NUP145N","NUP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5SRE5","full_name":"Nucleoporin NUP188","aliases":[],"length_aa":1749,"mass_kda":196.0,"function":"Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope (Probable). Required for proper protein transport into the nucleus (PubMed:32275884)","subcellular_location":"Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q5SRE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP188","classification":"Not Classified","n_dependent_lines":160,"n_total_lines":1208,"dependency_fraction":0.13245033112582782},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUP214","stoichiometry":4.0},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP188","total_profiled":1310},"omim":[{"mim_id":"618804","title":"SANDESTIG-STEFANOVA SYNDROME; SANDSTEF","url":"https://www.omim.org/entry/618804"},{"mim_id":"615587","title":"NUCLEOPORIN, 188-KD; NUP188","url":"https://www.omim.org/entry/615587"},{"mim_id":"615130","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 11; GALNT11","url":"https://www.omim.org/entry/615130"},{"mim_id":"614352","title":"NUCLEOPORIN, 205-KD; NUP205","url":"https://www.omim.org/entry/614352"},{"mim_id":"614351","title":"NUCLEOPORIN, 93-KD; NUP93","url":"https://www.omim.org/entry/614351"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP188"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0169"]},"alphafold":{"accession":"Q5SRE5","domains":[{"cath_id":"-","chopping":"2-167","consensus_level":"medium","plddt":82.5388,"start":2,"end":167},{"cath_id":"1.25.10,1.25.40","chopping":"848-1007","consensus_level":"medium","plddt":82.3404,"start":848,"end":1007},{"cath_id":"2.40.10","chopping":"473-537","consensus_level":"medium","plddt":84.0126,"start":473,"end":537},{"cath_id":"1.25.40","chopping":"640-748_759-796_805-844","consensus_level":"medium","plddt":82.0213,"start":640,"end":844}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SRE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SRE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SRE5-F1-predicted_aligned_error_v6.png","plddt_mean":81.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP188","jax_strain_url":"https://www.jax.org/strain/search?query=NUP188"},"sequence":{"accession":"Q5SRE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5SRE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5SRE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SRE5"}},"corpus_meta":[{"pmid":"21282601","id":"PMC_21282601","title":"Rare 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/40859750","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19229,"output_tokens":5330,"usd":0.068819,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13663,"output_tokens":5087,"usd":0.097745,"stage2_stop_reason":"end_turn"},"total_usd":0.166564,"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\": 1996,\n      \"finding\": \"Yeast Nup188p is a major constituent of the nuclear pore complex (NPC) that localizes to both the cytoplasmic and nucleoplasmic faces of the NPC core, physically interacts with the pore membrane protein Pom152p and nucleoporin Nic96p, and is required for normal nuclear envelope and NPC morphology; null mutants appear normal but certain alleles cause dominant NPC-associated nuclear envelope herniations.\",\n      \"method\": \"Biochemical fractionation of NPCs, immunofluorescence, immunoelectron microscopy, genetic deletion and allelic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunoEM, genetics) in a focused mechanistic study, replicated across two concurrent papers (PMIDs 8682855, 8682854)\",\n      \"pmids\": [\"8682855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminal domain of Nic96p functionally and physically interacts with Nup188p in an allele-specific fashion; affinity purification of Nup188p co-purifies a fraction of Nic96p, placing Nup188p in a direct protein–protein interaction with Nic96p within the NPC scaffold.\",\n      \"method\": \"Allele-specific genetic interaction, affinity purification (ProtA-Nup188p pull-down), co-fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical evidence for the Nic96p–Nup188p interaction, replicated independently (PMIDs 8682854, 8682855)\",\n      \"pmids\": [\"8682854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Genetic epistasis in yeast shows that deletion of NUP188 is not lethal alone, but pairwise deletion with POM152 or NUP170 is synthetically lethal, placing Nup188p in a functionally redundant inner-ring scaffold substructure of the NPC together with Pom152p and Nup170p.\",\n      \"method\": \"Synthetic lethal genetic screen, pairwise deletion analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple gene pairs, consistent with concurrent structural characterization papers\",\n      \"pmids\": [\"8522578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Deletion of NUP188 (nup188-Δ) in yeast increases passive nuclear envelope permeability: passive export rates of NLS-GFP reporters are significantly faster and the equilibrium sieving limit of the diffusion channel is greater than wild-type, indicating that Nup188p contributes to establishing the functional resting diameter of the NPC central transport channel.\",\n      \"method\": \"In vivo passive permeability assay using NLS-GFP and NES-GFP reporters of defined molecular weights in nup188-Δ cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple reporters of different sizes, clean deletion mutant, specific functional readout on channel diameter\",\n      \"pmids\": [\"10831607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Vertebrate (Xenopus) Nup188 exists in a complex with Nup93 (xNup93) and Nup205 (xNup205) at the nuclear pore; the Nup93-Nup188-Nup205 complex does not bind WGA directly but associates indirectly via N-acetylglucosamine-modified nucleoporins, and Nup188 assembles into annulate lamellae pore structures.\",\n      \"method\": \"WGA-affinity chromatography of Xenopus egg extracts, organelle trap (annulate lamellae assembly) assay, identification of human NUP188 gene\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-step biochemical assay (affinity selection + in vitro assembly) with identification of complex composition\",\n      \"pmids\": [\"11029043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The structure of Nup188 was determined: it folds into an extended stack of helices where an N-terminal ~130 kDa segment forms an intricate closed ring and the C-terminal region is a superhelical structure with distant similarity to flexible S-shaped nuclear transport receptors (NTRs). Both Nup188 and Nup192 specifically bind FG-repeats and can translocate through NPCs by facilitated diffusion, suggesting an evolutionary relationship between NPC scaffold and soluble transport machinery.\",\n      \"method\": \"X-ray crystallography (structure determination), FG-repeat binding assay, facilitated diffusion assay through NPCs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus multiple functional assays (FG binding, translocation) in one focused study\",\n      \"pmids\": [\"23795296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human Nup188 localizes to spindle poles during mitosis via its C-terminal region; depletion of Nup188 causes failure of chromosome alignment at the metaphase plate, impairs robust K-fiber (kinetochore microtubule bundle) formation, and perturbs NuMA localization to spindle poles. Nup188 directly interacts with NuMA.\",\n      \"method\": \"siRNA depletion, immunofluorescence, co-immunoprecipitation (Nup188–NuMA interaction), live-cell imaging\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean depletion with defined phenotypic readouts and co-IP for the NuMA interaction, single lab\",\n      \"pmids\": [\"23551833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nup188 (as part of the Nup93 sub-complex) associates with the HOXA gene cluster promoters and is required for tethering the HOXA locus to the nuclear periphery and repressing HOXA gene expression; depletion of the Nup93/Nup188/Nup205 sub-complex upregulates HOXA genes, increases active histone marks (H3K9ac), and decreases repressive marks (H3K27me3) at the HOXA1 promoter.\",\n      \"method\": \"ChIP, siRNA knockdown, 3D-FISH, histone mark analysis by ChIP\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, FISH, histone marks), single lab; Nup188 role is partially inferred from sub-complex depletion\",\n      \"pmids\": [\"27980680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GLFG repeats of Nup116 function redundantly with Nup188, a non-essential scaffold nucleoporin, to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly; GLFG repeats directly bind multiple scaffold Nups including Nup188 in vitro.\",\n      \"method\": \"In vitro FG-repeat binding assay, genetic redundancy analysis (nup116Δ/nup188 synthetic interactions), NPC assembly assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding plus genetic epistasis with clear assembly phenotype, published in high-tier journal\",\n      \"pmids\": [\"29033133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The integral membrane protein Brl1 physically interacts with Nup188 (by immunoprecipitation) at NPC assembly sites, indicating a direct role for Brl1 in NPC biogenesis through contact with this inner-ring scaffold component.\",\n      \"method\": \"Immunoprecipitation (Brl1–Nup188 co-IP), split-YFP analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP supported by split-YFP, single lab\",\n      \"pmids\": [\"29439116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Quantitative fluorescence microscopy in intact yeast NPCs reveals that Nup188 and its paralog Nup192 form a paralog pair whose altered expression leads to significant changes in NPC stoichiometry, inducing voids in NPC structure or substitution of one paralog by the other, demonstrating compositional plasticity of the NPC.\",\n      \"method\": \"Quantitative fluorescence microscopy (NuRIM pipeline), genetic manipulation of Nup expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative in vivo imaging with genetic manipulation, single lab\",\n      \"pmids\": [\"29632211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TDP-43 controls mRNA splicing of NUP188; complete loss of TDP-43 in human cells results in aberrant NUP188 splicing and nuclear envelope morphological defects.\",\n      \"method\": \"TDP-43 knockout human cells, transcriptomic analysis, cell biological phenotyping\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with transcriptomic and morphological readouts, single lab\",\n      \"pmids\": [\"31527135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nup188 localizes to the pericentriolar material (PCM) of centrosomes independently of NPCs: pulse-chase labeling shows centrosomal Nup188 is newly synthesized and does not exchange with NPC-resident Nup188 even after mitotic NPC breakdown. The centrosomal pool is subject to proteasomal degradation (unlike the NPC pool). Nup188 directly binds Cep152 (by co-IP/proximity labeling), and depletion of Nup188 impairs centriole duplication at or upstream of Sas6 loading.\",\n      \"method\": \"Pulse-chase fluorescent labeling, super-resolution microscopy, proximity labeling (BioID), proteasome inhibition, co-immunoprecipitation (Nup188–Cep152), siRNA depletion with centriole duplication readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pulse-chase, proximity labeling, co-IP, super-resolution, functional depletion) in a focused mechanistic study\",\n      \"pmids\": [\"32211895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Near-atomic composite structures of the human and S. cerevisiae NPC were determined by combining crystal structures and cryo-EM structures of Nup188 and Nup192 scaffold hubs bound to Nic96, Nup145N, and Nup53 linker nucleoporin binding regions, revealing that Nup188 forms a question mark-shaped keystone of a hetero-octameric inner ring complex. Linkers bind scaffold surface pockets of Nup188 through short defined motifs. Structure-guided mutagenesis in yeast confirmed the physiological relevance of linker-scaffold interactions. Nup188 is positioned exclusively in the inner ring (not the outer rings) in the intact NPC.\",\n      \"method\": \"X-ray crystallography, single-particle cryo-EM, cryo-ET docking, biochemical reconstitution, structure-guided mutagenesis in S. cerevisiae\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures + cryo-EM + reconstitution + mutagenesis + in situ cryo-ET validation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"35679425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUP188 was identified as a new binding partner of Nesprin-2 (LINC complex component) at the nuclear envelope; this interaction positions the NPC to capture SV40 virus upon its release from Nesprin-2, enabling NPC-mediated nuclear translocation of the virus.\",\n      \"method\": \"Co-immunoprecipitation (NUP188–Nesprin-2 interaction), siRNA depletion, viral infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and depletion experiments, single lab, mechanistic context provided by viral entry assay\",\n      \"pmids\": [\"36067270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Morpholino knockdown of NUP188 in Xenopus strongly disrupts morphological left-right development and expression of pitx2, a molecular marker of left-right patterning, placing NUP188 as a functional gene required for left-right organizer activity.\",\n      \"method\": \"Morpholino knockdown in Xenopus, in situ hybridization for pitx2, morphological scoring of LR defects\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with molecular and morphological readouts, validated against 13 control genes\",\n      \"pmids\": [\"21282601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The N-terminal GLFG domain of Nup145p (N-Nup145p), generated by in vivo cleavage, becomes essential in a nup188 mutant background, and generation of a free N-domain is a prerequisite for complementation of this synthetic lethal interaction, placing Nup188p in a functional relationship with the GLFG-containing transport domain of Nup145p.\",\n      \"method\": \"Genetic synthetic lethality analysis, in vivo cleavage domain dissection\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with domain dissection, single lab\",\n      \"pmids\": [\"9305650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Full-length Pom152p (including its lumenal C-terminal domain) is uniquely required to rescue nup188 mutations, whereas N-terminal or transmembrane segments alone are insufficient, indicating that the lumenal structures of Pom152p play an important role in functional interactions with Nup188p on the pore-side of the NPC.\",\n      \"method\": \"Domain deletion/truncation complementation assay in synthetic lethal nup188 strains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain dissection of Pom152p in defined genetic background, single lab\",\n      \"pmids\": [\"9988776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Elevated levels of SSA1 (but not SSB1) suppress NLS-GFP nuclear localization defects in nup188-Δ cells; NES-less Ssb1p also stimulates nuclear transport in nup188-Δ cells, demonstrating a genetic interaction between NUP188 and Hsp70 chaperones in the NLS-directed import pathway.\",\n      \"method\": \"Genetic suppression assay, GFP reporter localization in nup188-Δ cells, Ssa1p/Ssb1p overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppression with multiple Hsp70 variants and reporters, single lab\",\n      \"pmids\": [\"10347213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A cold-sensitive nup188-brr7 allele causes defects in both select protein import pathways and mRNA export in S. cerevisiae, linking Nup188p (as part of the Nic96 nucleoporin complex) to bidirectional nucleocytoplasmic transport.\",\n      \"method\": \"Cold-sensitive mutant screen, dT50 in situ hybridization assay (poly-A RNA export), NLS-GFP import assay\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual functional assays (import and export) in a defined mutant allele, single lab\",\n      \"pmids\": [\"30021831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a genome-wide screen for yeast genes involved in break-induced replication (BIR), Nup188 was identified as functioning after DNA synthesis to support BIR repair completion, acting sequentially after Nup84 (which acts before DNA synthesis).\",\n      \"method\": \"Genome-wide deletion screen for BIR defects, epistasis ordering of Nup84 vs. Nup188 in BIR\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genome-wide screen with limited mechanistic follow-up specific to Nup188, single study\",\n      \"pmids\": [\"41398407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NUP188 promotes liver cancer stem cell (LCSC) stemness through two mechanisms: (1) facilitating importin-β-mediated nuclear import of OCT4 (POU5F1), and (2) stabilizing SOX2 by preventing its lysosome-dependent degradation. A NUP188-targeting peptide suppressed tumor sphere formation and inhibited tumor growth in vivo.\",\n      \"method\": \"siRNA/KO functional assays, co-immunoprecipitation (NUP188–importin-β), lysosome inhibition rescue, in vitro and in vivo tumor assays, NUP188-targeting peptide\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and mechanistic experiments (co-IP, rescue), single lab\",\n      \"pmids\": [\"42119810\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP188 encodes a large scaffold nucleoporin that forms a question mark-shaped keystone of the inner ring of the nuclear pore complex (NPC), where it interacts with Nic96/Nup93, Nup145N, Nup53, and Pom152 through defined surface pockets to maintain NPC integrity and channel diameter; beyond its NPC role, Nup188 independently localizes to the pericentriolar material where it binds Cep152 and is required for centriole duplication, localizes to spindle poles during mitosis where it recruits NuMA to promote K-fiber formation and chromosome alignment, participates in transcriptional repression of the HOXA gene cluster by tethering it to the nuclear periphery, facilitates importin-β-mediated nuclear import of specific cargoes (e.g., OCT4) and SOX2 stabilization in cancer stem cells, and is required for left-right body patterning via a cilia-related mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP188 encodes a large scaffold nucleoporin that is a core structural element of the inner ring of the nuclear pore complex (NPC), where it functions as a question mark-shaped keystone of a hetero-octameric inner ring complex and engages the linker nucleoporins Nic96, Nup145N, and Nup53 through defined surface pockets [#13]. It was first identified in yeast as a major NPC constituent that interacts with the pore membrane protein Pom152p and the nucleoporin Nic96p and is required for normal nuclear envelope and NPC morphology [#0, #1, #17]. Although Nup188 is individually non-essential, it operates within a functionally redundant inner-ring substructure: loss is synthetically lethal with POM152 or NUP170 and genetically intertwined with the GLFG transport domains of Nup145p and Nup116 needed for late NPC assembly [#2, #8, #16]. Functionally, Nup188 helps set the resting diameter of the central transport channel, as its deletion increases passive nuclear envelope permeability [#3], and structural work shows it binds FG-repeats and can itself translocate through NPCs by facilitated diffusion, indicating an evolutionary kinship between scaffold and soluble transport machinery [#5]. Beyond the pore, Nup188 has independent, spatially distinct roles: a centrosomal pool localizes to the pericentriolar material where it binds Cep152 and is required for centriole duplication upstream of Sas6 loading [#12]; during mitosis it localizes to spindle poles, directly interacts with NuMA, and promotes K-fiber formation and chromosome alignment [#6]; and as part of the Nup93/Nup188/Nup205 sub-complex it tethers the HOXA cluster to the nuclear periphery to repress its expression [#7]. Additional roles include facilitating importin-\\u03b2-mediated nuclear import of OCT4 and stabilizing SOX2 to drive liver cancer stem cell stemness [#21] and supporting left-right body patterning in vertebrate development [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that Nup188 is a non-essential NPC component embedded within a functionally redundant inner-ring substructure, framing it as a scaffold buffer rather than a single critical pore subunit.\",\n      \"evidence\": \"Synthetic lethal genetic screen with pairwise NUP188/POM152/NUP170 deletions in yeast\",\n      \"pmids\": [\"8522578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the physical architecture of the redundant substructure\", \"Mechanism of redundancy at the molecular level unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified Nup188 as a major NPC constituent and placed it in direct contact with Pom152p and Nic96p, defining its first physical partners within the pore scaffold.\",\n      \"evidence\": \"Biochemical NPC fractionation, immunoEM, allele-specific genetics, and ProtA-Nup188p affinity purification in yeast\",\n      \"pmids\": [\"8682855\", \"8682854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution interface for the Nic96 or Pom152 contacts\", \"Stoichiometry within the NPC not determined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked Nup188 function to the FG/GLFG transport domains by showing the free N-Nup145p domain becomes essential in a nup188 mutant background.\",\n      \"evidence\": \"Genetic synthetic lethality and in vivo cleavage domain dissection in yeast\",\n      \"pmids\": [\"9305650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between Nup188 and N-Nup145p not shown here\", \"Functional consequence on transport not directly measured\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Refined the Pom152p interaction to its lumenal C-terminal domain and connected NUP188 genetically to the Hsp70-dependent NLS import pathway.\",\n      \"evidence\": \"Domain truncation complementation in synthetic lethal strains and SSA1/SSB1 overexpression suppression of nup188-\\u0394 import defects\",\n      \"pmids\": [\"9988776\", \"10347213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical Pom152 lumenal-domain binding not demonstrated\", \"Hsp70 link is genetic, not a physical interaction\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that Nup188 contributes to setting the functional diameter of the NPC central transport channel and is part of a conserved vertebrate Nup93\\u2013Nup188\\u2013Nup205 complex.\",\n      \"evidence\": \"Passive permeability assays with sized NLS/NES-GFP reporters in nup188-\\u0394 yeast; WGA-affinity chromatography and annulate lamellae assembly in Xenopus extracts\",\n      \"pmids\": [\"10831607\", \"11029043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for channel-diameter control unknown\", \"How the sub-complex assembles into the ring not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the first crystal structure of Nup188 and showed it binds FG-repeats and translocates through NPCs, suggesting an evolutionary relationship between scaffold and soluble transport receptors.\",\n      \"evidence\": \"X-ray crystallography, FG-repeat binding, and facilitated diffusion assays\",\n      \"pmids\": [\"23795296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of facilitated diffusion in vivo unclear\", \"Full-length architecture in the assembled NPC not resolved at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a moonlighting mitotic role: human Nup188 localizes to spindle poles, binds NuMA, and is required for K-fiber formation and chromosome alignment.\",\n      \"evidence\": \"siRNA depletion, immunofluorescence, co-IP, and live-cell imaging in human cells\",\n      \"pmids\": [\"23551833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of spindle-pole targeting not defined\", \"NuMA interaction not validated by orthogonal structural or reciprocal methods\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected the Nup93/Nup188/Nup205 sub-complex to gene regulation by showing it tethers and represses the HOXA cluster at the nuclear periphery.\",\n      \"evidence\": \"ChIP, siRNA knockdown, 3D-FISH, and histone-mark profiling in human cells\",\n      \"pmids\": [\"27980680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nup188-specific contribution inferred from sub-complex depletion\", \"Direct DNA or chromatin contact by Nup188 not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Nup116 GLFG repeats act redundantly with Nup188 to stabilize scaffold interactions during late NPC assembly, with direct in vitro binding.\",\n      \"evidence\": \"In vitro FG-repeat binding, genetic redundancy analysis, and NPC assembly assay in yeast\",\n      \"pmids\": [\"29033133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise assembly step Nup188 stabilizes not pinpointed\", \"Quantitative kinetics of assembly contribution unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended Nup188's assembly role by identifying Brl1 as an NPC-biogenesis partner and demonstrating compositional plasticity through the Nup188/Nup192 paralog pair.\",\n      \"evidence\": \"Brl1 co-IP and split-YFP; quantitative fluorescence microscopy (NuRIM) with genetic manipulation of Nup expression in yeast\",\n      \"pmids\": [\"29439116\", \"29632211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Brl1 link rests on a single co-IP supported by split-YFP\", \"Functional consequence of paralog substitution for transport unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked Nup188 to bidirectional nucleocytoplasmic transport via a cold-sensitive allele affecting both protein import and mRNA export.\",\n      \"evidence\": \"Cold-sensitive nup188-brr7 mutant with poly-A RNA in situ export and NLS-GFP import assays in yeast\",\n      \"pmids\": [\"30021831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether transport defects are direct or secondary to scaffold disruption unclear\", \"Cargo selectivity not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed NUP188 downstream of TDP-43, showing its mRNA splicing is TDP-43-dependent and its mis-splicing causes nuclear envelope defects.\",\n      \"evidence\": \"TDP-43 knockout human cells with transcriptomic and morphological phenotyping\",\n      \"pmids\": [\"31527135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disease relevance of NUP188 mis-splicing not established\", \"Functional NUP188 isoform consequences not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined an NPC-independent centrosomal pool of Nup188 that binds Cep152 and is required for centriole duplication, establishing a distinct moonlighting function.\",\n      \"evidence\": \"Pulse-chase labeling, super-resolution microscopy, BioID, proteasome inhibition, co-IP, and siRNA centriole-duplication readout in human cells\",\n      \"pmids\": [\"32211895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How centrosomal versus NPC targeting is partitioned mechanistically unknown\", \"Structural basis of Cep152 binding undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Delivered the near-atomic architecture of Nup188 as a question mark-shaped inner-ring keystone engaging linker nucleoporins through defined surface pockets, validated functionally.\",\n      \"evidence\": \"X-ray crystallography, cryo-EM, cryo-ET docking, reconstitution, and structure-guided mutagenesis of human and yeast NPCs\",\n      \"pmids\": [\"35679425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of linker-scaffold engagement during assembly not captured\", \"Does not address moonlighting localizations outside the NPC\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified NUP188 as a Nesprin-2 (LINC complex) partner positioning the NPC for SV40 viral nuclear translocation.\",\n      \"evidence\": \"Co-IP, siRNA depletion, and viral infection assays in human cells\",\n      \"pmids\": [\"36067270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab co-IP without reciprocal structural validation\", \"Generality beyond SV40 entry unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated Nup188 in DNA repair by placing it after DNA synthesis in break-induced replication, downstream of Nup84.\",\n      \"evidence\": \"Genome-wide deletion screen for BIR defects with epistasis ordering in yeast\",\n      \"pmids\": [\"41398407\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Genome-wide screen with limited Nup188-specific mechanistic follow-up\", \"Direct role versus indirect transport/scaffold effect not distinguished\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a pro-stemness role in liver cancer through importin-\\u03b2-mediated OCT4 import and lysosome-protective SOX2 stabilization, with a targeting peptide showing therapeutic potential.\",\n      \"evidence\": \"siRNA/KO assays, co-IP, lysosome inhibition rescue, tumor sphere and in vivo tumor assays, and a NUP188-targeting peptide\",\n      \"pmids\": [\"42119810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OCT4/SOX2 effects depend on NPC-resident or moonlighting Nup188 unclear\", \"Mechanism of SOX2 protection from lysosomal degradation not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold nucleoporin is partitioned among its NPC, centrosomal, spindle-pole, and chromatin-tethering roles, and how these moonlighting activities are regulated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism for targeting Nup188 to distinct compartments\", \"Structural basis for non-NPC partner interactions (NuMA, Cep152, Nesprin-2) undefined\", \"Regulation switching between pore and moonlighting pools unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 6, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 19]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [\n      \"NPC inner ring complex\",\n      \"Nup93-Nup188-Nup205 sub-complex\"\n    ],\n    \"partners\": [\n      \"NIC96/NUP93\",\n      \"POM152\",\n      \"NUP205\",\n      \"NUMA1\",\n      \"CEP152\",\n      \"Nesprin-2\",\n      \"NUP145N\",\n      \"NUP53\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}