{"gene":"NUP155","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1993,"finding":"Nup155 was identified as a novel ~155 kDa nuclear pore complex (NPC) protein lacking repetitive sequence motifs and WGA reactivity. By immunoelectron microscopy, Nup155 localizes to both the nucleoplasmic and cytoplasmic faces of the NPC (symmetric distribution), and redistributes to a diffuse cytoplasmic localization in mitotic cells. It was extracted from rat liver nuclear envelopes by 2M urea/1mM EDTA and separated from WGA-reactive nucleoporins.","method":"Molecular cloning, immunoelectron microscopy, biochemical fractionation (urea/EDTA extraction, WGA-Sepharose, SDS-hydroxylapatite)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — original biochemical characterization with immunoelectron microscopy and fractionation; foundational paper with 76 citations","pmids":["8458861"],"is_preprint":false},{"year":2003,"finding":"Human Gle1 (hGle1) physically interacts with hNup155. Yeast two-hybrid and in vitro binding assays identified the C-terminal 177 amino acids of hNup155 as the hGle1-binding domain, and the N-terminal 29 residues of hGle1 as the hNup155-binding domain. Deletion of this 29-residue domain abolishes nuclear rim localization of hGle1B in HeLa cells, indicating that hGle1 docks to the NPC via hNup155, placing this interaction as a step in the mRNA export pathway.","method":"Genome-wide yeast two-hybrid screen, in vitro binding (deletion analysis), HeLa cell localization assays","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid confirmed by in vitro binding and cellular localization; single lab, multiple orthogonal methods","pmids":["14645504"],"is_preprint":false},{"year":2005,"finding":"Nup155 is essential for nuclear envelope (NE) formation during cell division in metazoans. In C. elegans embryos, depletion of Nup155 caused failure of nuclear lamina formation, chromosome segregation defects at anaphase, and inhibition of nucleoporin accumulation at the nuclear periphery (including early-recruited nucleoporins). In Xenopus egg extracts, Nup155 depletion blocked formation of a continuous nuclear membrane. Time-course experiments showed Nup155 is recruited to chromatin at the time of NE sealing, indicating NPC assembly must progress to a late stage before NE membrane assembly.","method":"RNAi depletion in C. elegans embryos (in vivo), immunodepletion in Xenopus egg extracts (in vitro), electron microscopy, live imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — orthogonal in vivo and in vitro depletion in two independent model organisms with ultrastructural and functional readouts; 91 citations","pmids":["16193066"],"is_preprint":false},{"year":2008,"finding":"A homozygous R391H missense mutation in NUP155 was identified in a family with atrial fibrillation (AF) and early sudden cardiac death. The mutation affects nuclear localization of NUP155 and reduces nuclear envelope permeability. Homozygous Nup155−/− mice die before E8.5; heterozygous Nup155+/− mice exhibit AF. R391H and NUP155 reduction are associated with inhibited export of Hsp70 mRNA from the nucleus and impaired nuclear import of Hsp70 protein, linking NPC function to cardiovascular disease.","method":"Human genetic mapping, co-segregation analysis, mouse knockout/heterozygous models, nuclear envelope permeability assays, mRNA export assays (Hsp70 mRNA), protein import assays (Hsp70 protein), localization studies","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — human mutation with in vivo mouse models and multiple functional assays (permeability, mRNA export, protein import); replicated across human and mouse; 224 citations","pmids":["19070573"],"is_preprint":false},{"year":2010,"finding":"HIV-1 nuclear import is sensitive to NUP155 depletion in a capsid-dependent manner. Wild-type HIV-1 primarily requires NUP153, whereas a CA N74D mutant that cannot interact with CPSF6 becomes more sensitive to NUP155 depletion, revealing that alternative NPC entry routes differentially depend on NUP155.","method":"siRNA knockdown of NUP155 in cells, HIV-1 infection assays with wild-type and CA N74D mutant virus","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2–3 — clean knockdown with defined viral phenotype and mutant rescue logic; single study but clear mechanistic readout","pmids":["20227665"],"is_preprint":false},{"year":2012,"finding":"In Drosophila, the Nup155 β-propeller domain anchors the protein to the NPC (via interactions with Nup93 and Nup53), whereas the α-solenoid domain is essential for correct localization of inner nuclear membrane (INM) proteins lamin-B receptor (LBR) and otefin. The α-solenoid also exhibits chromatin-binding activity that is stronger at the end of mitosis. Thus, Nup155's role in INM protein organization is independent of its NPC-anchoring function.","method":"RNAi knockdown in Drosophila cells, protein binding assays, rescue assays with domain mutants, chromatin fractionation from semi-synchronized cells, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — domain-level dissection with rescue assays and chromatin-binding experiments; multiple orthogonal methods in single study","pmids":["22718353"],"is_preprint":false},{"year":2013,"finding":"Nup53 recruits Nup155 to the assembling NPC via direct interaction, and this Nup53–Nup155 interaction is required for NPC formation in vertebrates. Additionally, Nup53's interaction with the integral pore membrane protein Ndc1 is essential for NPC assembly; the Ndc1-binding site on Nup53 overlaps with its membrane-bending region, suggesting Ndc1 binding modulates Nup53's membrane-deforming activity during assembly.","method":"In vitro binding assays, co-immunoprecipitation, siRNA knockdown in Xenopus egg extracts and vertebrate cells, membrane-bending assays, NPC assembly reconstitution","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction mapping combined with functional depletion and assembly reconstitution; multiple orthogonal methods","pmids":["24363447"],"is_preprint":false},{"year":2018,"finding":"A lamin A/C mutation p.Arg399Cys associated with AF impairs the physical interaction between lamin A/C and NUP155 (demonstrated by co-IP and GST pull-down), increases NUP155 extractability from the nuclear envelope, causes lamin A/C aggregation, inhibits Hsp70 mRNA export and Hsp70 protein nuclear import, and reduces cell-surface expression of the cardiac sodium channel Nav1.5 (decreasing peak sodium current). These data establish that nuclear lamina–NPC (lamin A/C–NUP155) interaction integrity is required for proper nucleocytoplasmic transport.","method":"Co-immunoprecipitation, GST pull-down, nuclear envelope extractability assay, mRNA export assay, protein import assay, electrophysiology (patch clamp), flow cytometry (Nav1.5 surface expression)","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and GST pull-down confirmed interaction; multiple functional readouts (transport, electrophysiology); disease-linked mutation provides in vivo context","pmids":["30488537"],"is_preprint":false},{"year":2019,"finding":"Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response, through transcriptional regulation of the putative tRNA/rRNA methyltransferase FTSJ1. Nup155 and FTSJ1 are themselves targets of p53-mediated repression, establishing a regulatory feedback network in liver cancer where a structural NPC component modulates the p53 pathway via translational control.","method":"Large-scale proteomics, polysome fractionation, focused RNAi knockdown, transcriptional reporter assays; validated in murine and human hepatocellular carcinoma models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — integrated proteomics and polysome fractionation with RNAi functional validation; single lab but multiple orthogonal approaches","pmids":["31089132"],"is_preprint":false},{"year":2024,"finding":"Loss of Nup155 in podocytes inhibits nuclear export of INO80 mRNA, leading to decreased INO80 protein levels and induction of cellular senescence. Overexpression of Nup155 or INO80 reverses high fructose-induced podocyte senescence. Ferulic acid stabilizes Nup155 protein by direct binding and enhances its transcription, thereby promoting INO80 mRNA nuclear export.","method":"siRNA knockdown and overexpression in rat podocytes, SA-β-gal staining, Western blot, qRT-PCR, immunofluorescence, comet assay, transmission electron microscopy of NPCs, virtual screening/binding assay for ferulic acid","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function and gain-of-function with defined mRNA export readout; single lab, multiple complementary methods","pmids":["39111625"],"is_preprint":false},{"year":2024,"finding":"NUP155 knockdown in NSCLC cells reduces cell viability, migration, and invasion, and increases apoptosis. Mechanistically, NUP155 knockdown upregulates PTEN and downregulates phosphorylated AKT (p-AKT) without altering total AKT, placing NUP155 upstream of the PTEN/AKT signaling axis. Addition of the PTEN inhibitor SF1670 partially reverses the effects of NUP155 knockdown, confirming pathway involvement.","method":"siRNA knockdown, Western blot, CCK-8 proliferation assay, Transwell migration/invasion assay, PTEN inhibitor rescue experiment","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single knockdown approach with pharmacological rescue; no direct molecular mechanism linking NUP155 to PTEN established","pmids":["39697746"],"is_preprint":false},{"year":2024,"finding":"Small-molecule ligands to E3 ligase TRIM21 identified via DNA-Encoded Library technology induce proteasome-dependent degradation of NUP155 (primary target) and GLE1 (passenger target, secondary to NUP155 loss). Degradation of NUP155 and GLE1 impairs nuclear envelope integrity and leads to cell death, demonstrating that NUP155 is required for nuclear envelope integrity in living cells.","method":"DEL-based ligand discovery, crystallography (TRIM21–ligand), quantitative proteomics, immunofluorescence, proteasome inhibitor rescue, TRIM21 knockdown rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — crystallographic confirmation of E3 ligase interaction, proteomic validation of degradation, mechanistic rescue experiments; preprint but rigorous multi-method study","pmids":["bio_10.1101_2024.12.03.626577"],"is_preprint":true}],"current_model":"NUP155 is a symmetrically distributed structural nucleoporin required for nuclear pore complex assembly (recruited to assembling NPCs via direct interaction with Nup53) and nuclear envelope membrane formation; it mediates nucleocytoplasmic transport of mRNAs (including Hsp70 and INO80 mRNAs) and proteins, interacts with mRNA export factor Gle1 through its C-terminal domain, maintains nuclear envelope integrity through its interaction with lamin A/C, organizes inner nuclear membrane proteins via its α-solenoid domain independently of NPC anchoring, and controls p21 translation through transcriptional regulation of FTSJ1, with loss-of-function mutations causing atrial fibrillation by disrupting Hsp70 mRNA export and protein import."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing NUP155 as a novel, non-FG-repeat nucleoporin symmetrically distributed on both NPC faces resolved its identity among the growing catalog of pore constituents and implied a structural rather than transport-signal-dependent role.","evidence":"Molecular cloning, immunoelectron microscopy, and biochemical fractionation of rat liver nuclear envelopes","pmids":["8458861"],"confidence":"High","gaps":["No interaction partners identified","No functional loss-of-function data","Structural role inferred but not demonstrated"]},{"year":2003,"claim":"Identification of the Gle1–NUP155 interaction placed NUP155 directly in the mRNA export pathway, showing that Gle1 docks at the NPC through the C-terminal domain of NUP155.","evidence":"Yeast two-hybrid screen, in vitro binding with deletion constructs, and HeLa cell localization assays","pmids":["14645504"],"confidence":"Medium","gaps":["No in vivo functional validation of mRNA export dependence on this interaction","Stoichiometry and affinity not determined","Whether other nucleoporins contribute to Gle1 docking was not addressed"]},{"year":2005,"claim":"Demonstrating that NUP155 depletion blocks both NPC assembly and nuclear envelope membrane formation in two model organisms established it as an essential late-recruited scaffold whose incorporation gates the transition from pore assembly to membrane closure.","evidence":"RNAi in C. elegans embryos and immunodepletion in Xenopus egg extracts with EM and live imaging","pmids":["16193066"],"confidence":"High","gaps":["Molecular mechanism by which NUP155 promotes membrane sealing not defined","Position in the temporal hierarchy relative to all other scaffold nups not fully resolved"]},{"year":2008,"claim":"The discovery that a homozygous NUP155 R391H mutation causes familial atrial fibrillation—by impairing Hsp70 mRNA export and Hsp70 protein import—provided the first causal link between a structural nucleoporin and human cardiovascular disease.","evidence":"Human genetic mapping, co-segregation analysis, Nup155-knockout and heterozygous mice, mRNA export and protein import assays","pmids":["19070573"],"confidence":"High","gaps":["Whether additional cargo mRNAs or proteins are affected was not systematically assessed","Mechanism by which reduced Hsp70 leads to atrial fibrillation not elucidated","Whether the R391H mutation disrupts NPC structure globally or affects a specific transport route unclear"]},{"year":2012,"claim":"Domain dissection revealed that NUP155's NPC-anchoring function (β-propeller) and its role in organizing inner nuclear membrane proteins (α-solenoid) are separable, establishing NUP155 as a multifunctional scaffold that bridges the pore and the nuclear lamina/membrane compartment.","evidence":"RNAi with domain-specific rescue constructs in Drosophila cells, chromatin fractionation, and immunofluorescence","pmids":["22718353"],"confidence":"High","gaps":["Direct binding partners of the α-solenoid domain for INM protein tethering not identified","Whether this dual function is conserved in vertebrates not tested"]},{"year":2013,"claim":"Mapping the Nup53→NUP155 recruitment step during NPC assembly, alongside the Nup53–Ndc1 membrane interaction, defined the molecular hierarchy by which inner-ring nucleoporins integrate membrane and scaffold assembly.","evidence":"In vitro binding, co-immunoprecipitation, depletion/reconstitution in Xenopus egg extracts, membrane-bending assays","pmids":["24363447"],"confidence":"High","gaps":["Structural basis of the Nup53–NUP155 interface not resolved at atomic resolution","Whether post-translational modifications regulate this recruitment in vivo unknown"]},{"year":2018,"claim":"Showing that a lamin A/C AF-linked mutation disrupts the physical lamin A/C–NUP155 interaction, with downstream effects on Hsp70 transport and Nav1.5 surface expression, established the nuclear lamina–NPC interface as a functional unit required for cardiac ion channel biogenesis.","evidence":"Co-IP, GST pull-down, nuclear envelope extractability assays, mRNA export assays, patch-clamp electrophysiology","pmids":["30488537"],"confidence":"High","gaps":["Direct binding interface between lamin A/C and NUP155 not structurally defined","Whether other NPC components compensate in lamin A/C mutant backgrounds not tested"]},{"year":2019,"claim":"Discovery that NUP155 controls p21 translation via transcriptional regulation of the methyltransferase FTSJ1 revealed an unexpected gene-regulatory circuit linking a structural nucleoporin to the p53 tumor-suppressor pathway.","evidence":"Proteomics, polysome fractionation, RNAi knockdown, transcriptional reporters in hepatocellular carcinoma models","pmids":["31089132"],"confidence":"Medium","gaps":["Whether NUP155 regulates FTSJ1 transcription directly (e.g. at the gene locus) or indirectly is unresolved","Generalizability beyond liver cancer cells not demonstrated","FTSJ1's RNA substrate specificity in this context undefined"]},{"year":2024,"claim":"Identification of INO80 mRNA as a second NUP155-dependent nuclear export cargo, whose loss induces podocyte senescence, extended the selective transport function of NUP155 to renal biology and cellular aging.","evidence":"siRNA knockdown and overexpression in rat podocytes, SA-β-gal staining, qRT-PCR, immunofluorescence, comet assay","pmids":["39111625"],"confidence":"Medium","gaps":["Mechanism by which NUP155 selects INO80 mRNA for export not defined","Whether the ferulic acid stabilization of NUP155 is direct and specific requires independent confirmation","In vivo renal phenotype not established"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of NUP155 within the inner ring, the mechanism by which NUP155 selectively promotes export of specific mRNAs (Hsp70, INO80), the structural basis of the lamin A/C–NUP155 interface, and whether NUP155's gene-regulatory functions (FTSJ1/p21 axis) operate through chromatin-proximal or transport-dependent mechanisms.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length NUP155 in the NPC context","Cargo selectivity mechanism unknown","Chromatin-proximal versus transport-dependent gene regulation not disentangled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,5,6]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,2,5,6,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,3,7,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,3,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,7]}],"complexes":["Nuclear pore complex (NPC)","Nup93 subcomplex (inner ring)"],"partners":["NUP53","GLE1","LMNA","NUP93","NDC1"],"other_free_text":[]},"mechanistic_narrative":"NUP155 is a symmetrically distributed structural nucleoporin essential for nuclear pore complex (NPC) assembly, nuclear envelope formation, and selective nucleocytoplasmic transport. Its β-propeller domain anchors to the NPC via Nup53 and Nup93, while its α-solenoid domain independently organizes inner nuclear membrane proteins and binds chromatin at the end of mitosis [PMID:22718353, PMID:24363447]. NUP155 mediates mRNA export—including Hsp70 and INO80 mRNAs—through its C-terminal interaction with the export factor Gle1, and maintains nuclear envelope integrity via physical interaction with lamin A/C [PMID:14645504, PMID:30488537, PMID:39111625]. Loss-of-function mutations in NUP155 cause familial atrial fibrillation by disrupting Hsp70 mRNA export and protein import, and homozygous loss is embryonic lethal in mice [PMID:19070573]."},"prefetch_data":{"uniprot":{"accession":"O75694","full_name":"Nuclear pore complex protein Nup155","aliases":["155 kDa nucleoporin","Nucleoporin Nup155"],"length_aa":1391,"mass_kda":155.2,"function":"Essential component of nuclear pore complex. Could be essessential for embryogenesis. Nucleoporins may be involved both in binding and translocating proteins during nucleocytoplasmic transport","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/O75694/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP155","classification":"Common Essential","n_dependent_lines":1178,"n_total_lines":1208,"dependency_fraction":0.9751655629139073},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000113569","cell_line_id":"CID001716","localizations":[{"compartment":"nuclear_membrane","grade":3}],"interactors":[{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"XPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001716","total_profiled":1310},"omim":[{"mim_id":"615770","title":"ATRIAL FIBRILLATION, FAMILIAL, 15; ATFB15","url":"https://www.omim.org/entry/615770"},{"mim_id":"615753","title":"POM121 TRANSMEMBRANE NUCLEOPORIN; POM121","url":"https://www.omim.org/entry/615753"},{"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"},{"mim_id":"613174","title":"CHROMOSOME 5p13 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/613174"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear membrane","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":66.2}],"url":"https://www.proteinatlas.org/search/NUP155"},"hgnc":{"alias_symbol":["KIAA0791","N155"],"prev_symbol":[]},"alphafold":{"accession":"O75694","domains":[{"cath_id":"2.130.10.10","chopping":"90-181_196-261_274-278","consensus_level":"medium","plddt":86.8323,"start":90,"end":278},{"cath_id":"-","chopping":"909-989_1013-1058","consensus_level":"medium","plddt":89.8319,"start":909,"end":1058},{"cath_id":"-","chopping":"1073-1212","consensus_level":"medium","plddt":87.3299,"start":1073,"end":1212}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75694","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75694-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75694-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP155","jax_strain_url":"https://www.jax.org/strain/search?query=NUP155"},"sequence":{"accession":"O75694","fasta_url":"https://rest.uniprot.org/uniprotkb/O75694.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75694/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75694"}},"corpus_meta":[{"pmid":"19070573","id":"PMC_19070573","title":"Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19070573","citation_count":224,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16193066","id":"PMC_16193066","title":"Nup155 regulates nuclear envelope and nuclear pore complex formation in nematodes and vertebrates.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16193066","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8458861","id":"PMC_8458861","title":"Nup155 is a novel nuclear pore complex protein that contains neither repetitive sequence motifs nor reacts with WGA.","date":"1993","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8458861","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24363447","id":"PMC_24363447","title":"Interaction of Nup53 with Ndc1 and Nup155 is required for nuclear pore complex assembly.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24363447","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9732281","id":"PMC_9732281","title":"Nup154, a new Drosophila gene essential for male and female gametogenesis is related to the nup155 vertebrate nucleoporin gene.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9732281","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14645504","id":"PMC_14645504","title":"The mRNA export factor human Gle1 interacts with the nuclear pore complex protein Nup155.","date":"2003","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14645504","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19505846","id":"PMC_19505846","title":"Whole genome characterization of reassortant G10P[11] strain (N155) from a neonate with symptomatic rotavirus infection: identification of genes of human and animal rotavirus origin.","date":"2009","source":"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology","url":"https://pubmed.ncbi.nlm.nih.gov/19505846","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31089132","id":"PMC_31089132","title":"Nucleoporin Nup155 is part of the p53 network in liver cancer.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31089132","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30488537","id":"PMC_30488537","title":"Lamin A mutation impairs interaction with nucleoporin NUP155 and disrupts nucleocytoplasmic transport in atrial fibrillation.","date":"2018","source":"Human 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methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12342,"output_tokens":2976,"usd":0.040833},"stage2":{"model":"claude-opus-4-6","input_tokens":6361,"output_tokens":2450,"usd":0.139582},"total_usd":0.3925,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":23755,"output_tokens":3565,"usd":0.06237},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7202,"output_tokens":2552,"usd":0.149715}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"Nup155 is a 155 kDa nuclear pore complex protein that localizes to both the nucleoplasmic and cytoplasmic aspects of the NPC (symmetric distribution), lacks repetitive sequence motifs, does not react with WGA, and distributes diffusely in the cytoplasm during mitosis.\",\n      \"method\": \"Molecular cloning, sequencing, immunoelectron microscopy, subcellular fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original biochemical characterization with immunoelectron microscopy and fractionation, foundational paper with 76 citations\",\n      \"pmids\": [\"8458861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human NUP155 gene was cloned and mapped to chromosome 5p13; it is ubiquitously expressed and encodes a nucleoporin involved in nucleocytoplasmic transport.\",\n      \"method\": \"Exon trapping, PCR cloning from cDNA library, FISH, Northern blot\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cloning and chromosomal mapping with expression analysis\",\n      \"pmids\": [\"10191094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Gle1 (hGle1) physically interacts with hNup155; the N-terminal 29 residues of hGle1 constitute the hNup155-binding domain, and the C-terminal 177 amino acids of hNup155 mediate this interaction. The N-terminal 29 residues of hGle1 are required for its nuclear rim localization, indicating that hGle1 is anchored to the NPC via Nup155 to facilitate mRNA export.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, deletion analysis, HeLa cell localization experiments\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed in vitro and in cells with deletion mapping, moderate citation count\",\n      \"pmids\": [\"14645504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nup155 is essential for nuclear envelope (NE) formation and nuclear pore complex assembly in C. elegans and Xenopus egg extracts; depletion of Nup155 causes failure of nuclear lamina formation, defects in chromosome segregation at anaphase, inhibition of nucleoporin accumulation at the nuclear periphery, and failure to form a continuous nuclear membrane. Nup155 is recruited to chromatin at the time of NE sealing.\",\n      \"method\": \"In vivo RNAi depletion in C. elegans embryos, Xenopus egg extract depletion, electron microscopy, immunofluorescence time-course\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — loss-of-function in two independent model systems with multiple orthogonal readouts, 91 citations\",\n      \"pmids\": [\"16193066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A homozygous R391H mutation in NUP155 causes atrial fibrillation and early sudden cardiac death. The R391H mutation affects nuclear localization of NUP155, reduces nuclear envelope permeability, and inhibits both export of Hsp70 mRNA and nuclear import of Hsp70 protein. Homozygous NUP155−/− mice die before E8.5; heterozygous NUP155+/− mice display the AF phenotype.\",\n      \"method\": \"Human genetic linkage, site-directed mutagenesis, NUP155 nuclear localization assay, nuclear envelope permeability assay, Hsp70 mRNA export and protein import assays, knockout mouse model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal functional assays in human cells and mouse model, 224 citations, replicated in human and murine systems\",\n      \"pmids\": [\"19070573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The β-propeller domain of Drosophila Nup155 anchors it to the NPC (via interaction with Nup93 and Nup53), whereas the α-solenoid domain is essential for correct localization of inner nuclear membrane (INM) proteins lamin-B receptor and otefin and has chromatin-binding activity that is stronger at the end of mitosis. The role of Nup155 in INM protein localization is independent of its NPC-anchoring function.\",\n      \"method\": \"RNAi knockdown in Drosophila cells, protein binding assays, rescue assays with domain deletion constructs, chromatin fractionation from semi-synchronized cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain dissection with rescue assays and multiple orthogonal readouts in Drosophila cells\",\n      \"pmids\": [\"22718353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The interaction between Nup53 and the integral pore membrane protein Ndc1 is essential for vertebrate NPC assembly; the Ndc1-binding site on Nup53 overlaps with a membrane-bending region, modulating its deforming activity. Additionally, the Nup53–Nup155 interaction is a crucial determinant for recruitment of Nup155 to the assembling pore.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, Xenopus egg extract NPC assembly assay, RNAi epistasis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays combined with functional NPC assembly readout in Xenopus extracts\",\n      \"pmids\": [\"24363447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lamin A/C physically interacts with NUP155 at the nuclear envelope; the AF-associated lamin A/C mutation p.Arg399Cys impairs this interaction, increases extractability of NUP155 from the nuclear envelope, inhibits Hsp70 mRNA export and Hsp70 protein nuclear import, and decreases cell-surface expression of Nav1.5, reducing peak cardiac sodium current.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, nuclear envelope fractionation, mRNA export assay, protein import assay, electrophysiology patch-clamp\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, GST pulldown, fractionation, functional transport assays, electrophysiology) in a single study\",\n      \"pmids\": [\"30488537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nup155 controls mRNA translation of p21 (CDKN1A) through transcriptional regulation of the tRNA/rRNA methyltransferase FTSJ1; both Nup155 and FTSJ1 are p53 repression targets, placing Nup155 within the p53 signaling network in hepatocellular carcinoma.\",\n      \"method\": \"Large-scale proteomics, polysome fractionation, focused RNAi knockdown, transcriptional reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods but mechanistic link (NUP155→FTSJ1→p21 translation) established in a single lab study\",\n      \"pmids\": [\"31089132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Nup155 in podocytes inhibits nuclear export of INO80 mRNA, leading to reduced INO80 protein expression and podocyte senescence; overexpression of Nup155 or INO80 rescues high-fructose-induced senescence, establishing Nup155 as a specific mediator of INO80 mRNA export.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, qRT-PCR, Western blot, immunofluorescence, transmission electron microscopy of NPCs\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss- and gain-of-function with specific mRNA export readout but single lab, no direct in vitro transport assay\",\n      \"pmids\": [\"39111625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP155 knockdown in NSCLC cells reduces proliferation, migration, and invasion while increasing apoptosis; mechanistically, NUP155 knockdown upregulates PTEN and suppresses phospho-AKT, and the PTEN inhibitor SF1670 partially reverses these effects, placing NUP155 upstream of the PTEN/AKT signaling axis.\",\n      \"method\": \"siRNA knockdown, Western blot, cell viability/migration/invasion/apoptosis assays, pharmacological inhibitor rescue\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single functional assay set with pharmacological rescue but no direct molecular mechanism linking NUP155 to PTEN\",\n      \"pmids\": [\"39697746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM21 E3 ligase ligands induce ubiquitin-proteasome-dependent degradation of NUP155 (primary target); secondary degradation of GLE1 (a passenger target) follows. Degradation of NUP155 and GLE1 impairs nuclear envelope integrity and leads to cell death.\",\n      \"method\": \"DNA-encoded library screening, crystallography of TRIM21-ligand complex, quantitative proteomics, immunofluorescence, proteasome inhibitor rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — crystallographic confirmation of ligand-TRIM21 interaction plus proteomic and functional validation, but preprint without peer review\",\n      \"pmids\": [\"bio_10.1101_2024.12.03.626577\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NUP155 is a symmetrically distributed structural nucleoporin that is essential for nuclear envelope membrane assembly and nuclear pore complex biogenesis (recruiting other nucleoporins via its interaction with Nup53, and organizing inner nuclear membrane proteins via its α-solenoid domain); it anchors the mRNA export factor GLE1 to the NPC through a direct interaction, facilitates bidirectional nucleocytoplasmic transport of specific cargoes including Hsp70 mRNA and protein, and is physically coupled to the nuclear lamina via lamin A/C, with loss-of-function causing impaired transport, cardiac arrhythmia, and disrupted p53/p21 translational control through FTSJ1.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"Nup155 was identified as a novel ~155 kDa nuclear pore complex (NPC) protein lacking repetitive sequence motifs and WGA reactivity. By immunoelectron microscopy, Nup155 localizes to both the nucleoplasmic and cytoplasmic faces of the NPC (symmetric distribution), and redistributes to a diffuse cytoplasmic localization in mitotic cells. It was extracted from rat liver nuclear envelopes by 2M urea/1mM EDTA and separated from WGA-reactive nucleoporins.\",\n      \"method\": \"Molecular cloning, immunoelectron microscopy, biochemical fractionation (urea/EDTA extraction, WGA-Sepharose, SDS-hydroxylapatite)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original biochemical characterization with immunoelectron microscopy and fractionation; foundational paper with 76 citations\",\n      \"pmids\": [\"8458861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Gle1 (hGle1) physically interacts with hNup155. Yeast two-hybrid and in vitro binding assays identified the C-terminal 177 amino acids of hNup155 as the hGle1-binding domain, and the N-terminal 29 residues of hGle1 as the hNup155-binding domain. Deletion of this 29-residue domain abolishes nuclear rim localization of hGle1B in HeLa cells, indicating that hGle1 docks to the NPC via hNup155, placing this interaction as a step in the mRNA export pathway.\",\n      \"method\": \"Genome-wide yeast two-hybrid screen, in vitro binding (deletion analysis), HeLa cell localization assays\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid confirmed by in vitro binding and cellular localization; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14645504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nup155 is essential for nuclear envelope (NE) formation during cell division in metazoans. In C. elegans embryos, depletion of Nup155 caused failure of nuclear lamina formation, chromosome segregation defects at anaphase, and inhibition of nucleoporin accumulation at the nuclear periphery (including early-recruited nucleoporins). In Xenopus egg extracts, Nup155 depletion blocked formation of a continuous nuclear membrane. Time-course experiments showed Nup155 is recruited to chromatin at the time of NE sealing, indicating NPC assembly must progress to a late stage before NE membrane assembly.\",\n      \"method\": \"RNAi depletion in C. elegans embryos (in vivo), immunodepletion in Xenopus egg extracts (in vitro), electron microscopy, live imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal in vivo and in vitro depletion in two independent model organisms with ultrastructural and functional readouts; 91 citations\",\n      \"pmids\": [\"16193066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A homozygous R391H missense mutation in NUP155 was identified in a family with atrial fibrillation (AF) and early sudden cardiac death. The mutation affects nuclear localization of NUP155 and reduces nuclear envelope permeability. Homozygous Nup155−/− mice die before E8.5; heterozygous Nup155+/− mice exhibit AF. R391H and NUP155 reduction are associated with inhibited export of Hsp70 mRNA from the nucleus and impaired nuclear import of Hsp70 protein, linking NPC function to cardiovascular disease.\",\n      \"method\": \"Human genetic mapping, co-segregation analysis, mouse knockout/heterozygous models, nuclear envelope permeability assays, mRNA export assays (Hsp70 mRNA), protein import assays (Hsp70 protein), localization studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human mutation with in vivo mouse models and multiple functional assays (permeability, mRNA export, protein import); replicated across human and mouse; 224 citations\",\n      \"pmids\": [\"19070573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HIV-1 nuclear import is sensitive to NUP155 depletion in a capsid-dependent manner. Wild-type HIV-1 primarily requires NUP153, whereas a CA N74D mutant that cannot interact with CPSF6 becomes more sensitive to NUP155 depletion, revealing that alternative NPC entry routes differentially depend on NUP155.\",\n      \"method\": \"siRNA knockdown of NUP155 in cells, HIV-1 infection assays with wild-type and CA N74D mutant virus\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — clean knockdown with defined viral phenotype and mutant rescue logic; single study but clear mechanistic readout\",\n      \"pmids\": [\"20227665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Drosophila, the Nup155 β-propeller domain anchors the protein to the NPC (via interactions with Nup93 and Nup53), whereas the α-solenoid domain is essential for correct localization of inner nuclear membrane (INM) proteins lamin-B receptor (LBR) and otefin. The α-solenoid also exhibits chromatin-binding activity that is stronger at the end of mitosis. Thus, Nup155's role in INM protein organization is independent of its NPC-anchoring function.\",\n      \"method\": \"RNAi knockdown in Drosophila cells, protein binding assays, rescue assays with domain mutants, chromatin fractionation from semi-synchronized cells, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-level dissection with rescue assays and chromatin-binding experiments; multiple orthogonal methods in single study\",\n      \"pmids\": [\"22718353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nup53 recruits Nup155 to the assembling NPC via direct interaction, and this Nup53–Nup155 interaction is required for NPC formation in vertebrates. Additionally, Nup53's interaction with the integral pore membrane protein Ndc1 is essential for NPC assembly; the Ndc1-binding site on Nup53 overlaps with its membrane-bending region, suggesting Ndc1 binding modulates Nup53's membrane-deforming activity during assembly.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, siRNA knockdown in Xenopus egg extracts and vertebrate cells, membrane-bending assays, NPC assembly reconstitution\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction mapping combined with functional depletion and assembly reconstitution; multiple orthogonal methods\",\n      \"pmids\": [\"24363447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A lamin A/C mutation p.Arg399Cys associated with AF impairs the physical interaction between lamin A/C and NUP155 (demonstrated by co-IP and GST pull-down), increases NUP155 extractability from the nuclear envelope, causes lamin A/C aggregation, inhibits Hsp70 mRNA export and Hsp70 protein nuclear import, and reduces cell-surface expression of the cardiac sodium channel Nav1.5 (decreasing peak sodium current). These data establish that nuclear lamina–NPC (lamin A/C–NUP155) interaction integrity is required for proper nucleocytoplasmic transport.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, nuclear envelope extractability assay, mRNA export assay, protein import assay, electrophysiology (patch clamp), flow cytometry (Nav1.5 surface expression)\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and GST pull-down confirmed interaction; multiple functional readouts (transport, electrophysiology); disease-linked mutation provides in vivo context\",\n      \"pmids\": [\"30488537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response, through transcriptional regulation of the putative tRNA/rRNA methyltransferase FTSJ1. Nup155 and FTSJ1 are themselves targets of p53-mediated repression, establishing a regulatory feedback network in liver cancer where a structural NPC component modulates the p53 pathway via translational control.\",\n      \"method\": \"Large-scale proteomics, polysome fractionation, focused RNAi knockdown, transcriptional reporter assays; validated in murine and human hepatocellular carcinoma models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — integrated proteomics and polysome fractionation with RNAi functional validation; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"31089132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Nup155 in podocytes inhibits nuclear export of INO80 mRNA, leading to decreased INO80 protein levels and induction of cellular senescence. Overexpression of Nup155 or INO80 reverses high fructose-induced podocyte senescence. Ferulic acid stabilizes Nup155 protein by direct binding and enhances its transcription, thereby promoting INO80 mRNA nuclear export.\",\n      \"method\": \"siRNA knockdown and overexpression in rat podocytes, SA-β-gal staining, Western blot, qRT-PCR, immunofluorescence, comet assay, transmission electron microscopy of NPCs, virtual screening/binding assay for ferulic acid\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function and gain-of-function with defined mRNA export readout; single lab, multiple complementary methods\",\n      \"pmids\": [\"39111625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP155 knockdown in NSCLC cells reduces cell viability, migration, and invasion, and increases apoptosis. Mechanistically, NUP155 knockdown upregulates PTEN and downregulates phosphorylated AKT (p-AKT) without altering total AKT, placing NUP155 upstream of the PTEN/AKT signaling axis. Addition of the PTEN inhibitor SF1670 partially reverses the effects of NUP155 knockdown, confirming pathway involvement.\",\n      \"method\": \"siRNA knockdown, Western blot, CCK-8 proliferation assay, Transwell migration/invasion assay, PTEN inhibitor rescue experiment\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single knockdown approach with pharmacological rescue; no direct molecular mechanism linking NUP155 to PTEN established\",\n      \"pmids\": [\"39697746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Small-molecule ligands to E3 ligase TRIM21 identified via DNA-Encoded Library technology induce proteasome-dependent degradation of NUP155 (primary target) and GLE1 (passenger target, secondary to NUP155 loss). Degradation of NUP155 and GLE1 impairs nuclear envelope integrity and leads to cell death, demonstrating that NUP155 is required for nuclear envelope integrity in living cells.\",\n      \"method\": \"DEL-based ligand discovery, crystallography (TRIM21–ligand), quantitative proteomics, immunofluorescence, proteasome inhibitor rescue, TRIM21 knockdown rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — crystallographic confirmation of E3 ligase interaction, proteomic validation of degradation, mechanistic rescue experiments; preprint but rigorous multi-method study\",\n      \"pmids\": [\"bio_10.1101_2024.12.03.626577\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NUP155 is a symmetrically distributed structural nucleoporin required for nuclear pore complex assembly (recruited to assembling NPCs via direct interaction with Nup53) and nuclear envelope membrane formation; it mediates nucleocytoplasmic transport of mRNAs (including Hsp70 and INO80 mRNAs) and proteins, interacts with mRNA export factor Gle1 through its C-terminal domain, maintains nuclear envelope integrity through its interaction with lamin A/C, organizes inner nuclear membrane proteins via its α-solenoid domain independently of NPC anchoring, and controls p21 translation through transcriptional regulation of FTSJ1, with loss-of-function mutations causing atrial fibrillation by disrupting Hsp70 mRNA export and protein import.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP155 is a symmetrically distributed structural nucleoporin essential for nuclear envelope assembly, nuclear pore complex (NPC) biogenesis, and selective nucleocytoplasmic transport. Its β-propeller domain anchors it to the NPC through interactions with Nup53 and Nup93, while its α-solenoid domain organizes inner nuclear membrane proteins and binds chromatin during mitotic NPC reassembly [PMID:22718353, PMID:24363447, PMID:16193066]. NUP155 recruits the mRNA export factor GLE1 to the NPC via its C-terminal region, facilitates export of specific mRNAs including Hsp70 and INO80, and is physically coupled to the nuclear lamina through lamin A/C [PMID:14645504, PMID:30488537, PMID:39111625]. A homozygous R391H loss-of-function mutation in NUP155 causes familial atrial fibrillation with early sudden cardiac death by impairing nuclear envelope permeability and Hsp70 mRNA/protein transport [PMID:19070573].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of Nup155 as a symmetrically distributed NPC component lacking repeat motifs established it as a distinct structural nucleoporin rather than an FG-repeat transport mediator.\",\n      \"evidence\": \"Molecular cloning, immunoelectron microscopy, and subcellular fractionation of rat NPC\",\n      \"pmids\": [\"8458861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional role established\", \"No interacting partners identified\", \"No domain architecture resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Cloning the human NUP155 gene and mapping it to chromosome 5p13 with ubiquitous expression enabled subsequent genetic and functional studies in human systems.\",\n      \"evidence\": \"Exon trapping, cDNA cloning, FISH mapping, Northern blot expression profiling\",\n      \"pmids\": [\"10191094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional characterization beyond expression pattern\", \"No disease association yet tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that GLE1 is anchored to the NPC through a direct interaction with NUP155's C-terminal 177 residues established NUP155 as a platform for mRNA export machinery recruitment.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, deletion mapping, HeLa cell localization\",\n      \"pmids\": [\"14645504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GLE1 anchoring is the sole mechanism by which NUP155 supports mRNA export\", \"No structural detail of the NUP155–GLE1 interface\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Loss-of-function studies in C. elegans and Xenopus revealed that NUP155 is essential for nuclear envelope membrane closure and NPC assembly, not merely a structural scaffold of mature pores.\",\n      \"evidence\": \"RNAi depletion in C. elegans embryos and immunodepletion from Xenopus egg extracts with EM and immunofluorescence\",\n      \"pmids\": [\"16193066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise step in NE assembly where NUP155 acts was not pinpointed\", \"Whether NUP155 role in lamina formation is direct or indirect\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The discovery that a homozygous R391H mutation causes familial atrial fibrillation by impairing NUP155 nuclear localization and Hsp70 mRNA/protein transport linked NPC structural integrity to cardiac electrophysiology.\",\n      \"evidence\": \"Human genetic linkage, site-directed mutagenesis, transport assays, knockout mouse lethality and heterozygous AF phenotype\",\n      \"pmids\": [\"19070573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How impaired Hsp70 transport mechanistically leads to arrhythmia\", \"Whether other transported cargoes contribute to the cardiac phenotype\", \"Structural basis of R391H dysfunction\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Domain dissection separated NUP155's NPC-anchoring function (β-propeller, via Nup93/Nup53) from its role in organizing inner nuclear membrane proteins (α-solenoid), revealing a dual architectural function.\",\n      \"evidence\": \"RNAi knockdown and rescue with domain deletions in Drosophila S2 cells, chromatin fractionation\",\n      \"pmids\": [\"22718353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for α-solenoid–INM protein interaction\", \"Whether chromatin-binding activity is direct or mediated by partners\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing that the Nup53–Nup155 interaction is essential for NUP155 recruitment to assembling pores placed Nup53 as the upstream recruiter linking membrane-associated Ndc1 to the inner ring scaffold.\",\n      \"evidence\": \"Co-IP, GST pulldown, Xenopus egg extract NPC assembly assay\",\n      \"pmids\": [\"24363447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and kinetics of Nup53-mediated NUP155 recruitment not determined\", \"Whether other factors can partially substitute for Nup53\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that lamin A/C physically interacts with NUP155 and that an AF-linked lamin A/C mutation disrupts this interaction, impairing Hsp70 transport and Nav1.5 surface expression, unified the NPC–lamina interface with cardiac channelopathy pathogenesis.\",\n      \"evidence\": \"Co-IP, GST pulldown, nuclear fractionation, mRNA export assay, patch-clamp electrophysiology\",\n      \"pmids\": [\"30488537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lamin A/C–NUP155 interaction is direct or bridged by other lamina components\", \"Whether Nav1.5 reduction is a direct consequence of Hsp70 transport impairment\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking NUP155 to translational control of p21 via transcriptional regulation of the methyltransferase FTSJ1 revealed an unexpected role for this nucleoporin in the p53 signaling network beyond canonical transport functions.\",\n      \"evidence\": \"Proteomics, polysome fractionation, RNAi knockdown, transcriptional reporters in hepatocellular carcinoma cells\",\n      \"pmids\": [\"31089132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP155 regulates FTSJ1 transcription through chromatin contacts or mRNA export\", \"Whether this pathway operates outside hepatocellular carcinoma\", \"Single-lab finding not independently replicated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of INO80 mRNA as a specific NUP155-dependent export cargo in podocytes expanded the repertoire of NUP155-regulated transcripts and linked NPC function to cellular senescence.\",\n      \"evidence\": \"siRNA knockdown, overexpression rescue, qRT-PCR and Western blot in podocytes\",\n      \"pmids\": [\"39111625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vitro transport assay for INO80 mRNA\", \"Mechanism by which NUP155 selects INO80 mRNA for export is unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for NUP155's cargo-selective mRNA export function, the full inventory of NUP155-dependent transported cargoes, and how NUP155 dysfunction mechanistically triggers cardiac arrhythmogenesis remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of human NUP155 in the context of the NPC inner ring\", \"Complete list of NUP155-dependent mRNA export substrates unknown\", \"Mechanism linking impaired Hsp70 transport to atrial fibrillation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 3, 5, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 4, 7, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"Nuclear pore complex (inner ring/Nup93 subcomplex)\"\n    ],\n    \"partners\": [\n      \"GLE1\",\n      \"NUP53\",\n      \"NUP93\",\n      \"NDC1\",\n      \"LMNA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP155 is a symmetrically distributed structural nucleoporin essential for nuclear pore complex (NPC) assembly, nuclear envelope formation, and selective nucleocytoplasmic transport. Its β-propeller domain anchors to the NPC via Nup53 and Nup93, while its α-solenoid domain independently organizes inner nuclear membrane proteins and binds chromatin at the end of mitosis [PMID:22718353, PMID:24363447]. NUP155 mediates mRNA export—including Hsp70 and INO80 mRNAs—through its C-terminal interaction with the export factor Gle1, and maintains nuclear envelope integrity via physical interaction with lamin A/C [PMID:14645504, PMID:30488537, PMID:39111625]. Loss-of-function mutations in NUP155 cause familial atrial fibrillation by disrupting Hsp70 mRNA export and protein import, and homozygous loss is embryonic lethal in mice [PMID:19070573].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing NUP155 as a novel, non-FG-repeat nucleoporin symmetrically distributed on both NPC faces resolved its identity among the growing catalog of pore constituents and implied a structural rather than transport-signal-dependent role.\",\n      \"evidence\": \"Molecular cloning, immunoelectron microscopy, and biochemical fractionation of rat liver nuclear envelopes\",\n      \"pmids\": [\"8458861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No interaction partners identified\", \"No functional loss-of-function data\", \"Structural role inferred but not demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of the Gle1–NUP155 interaction placed NUP155 directly in the mRNA export pathway, showing that Gle1 docks at the NPC through the C-terminal domain of NUP155.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vitro binding with deletion constructs, and HeLa cell localization assays\",\n      \"pmids\": [\"14645504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo functional validation of mRNA export dependence on this interaction\", \"Stoichiometry and affinity not determined\", \"Whether other nucleoporins contribute to Gle1 docking was not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that NUP155 depletion blocks both NPC assembly and nuclear envelope membrane formation in two model organisms established it as an essential late-recruited scaffold whose incorporation gates the transition from pore assembly to membrane closure.\",\n      \"evidence\": \"RNAi in C. elegans embryos and immunodepletion in Xenopus egg extracts with EM and live imaging\",\n      \"pmids\": [\"16193066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which NUP155 promotes membrane sealing not defined\", \"Position in the temporal hierarchy relative to all other scaffold nups not fully resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The discovery that a homozygous NUP155 R391H mutation causes familial atrial fibrillation—by impairing Hsp70 mRNA export and Hsp70 protein import—provided the first causal link between a structural nucleoporin and human cardiovascular disease.\",\n      \"evidence\": \"Human genetic mapping, co-segregation analysis, Nup155-knockout and heterozygous mice, mRNA export and protein import assays\",\n      \"pmids\": [\"19070573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional cargo mRNAs or proteins are affected was not systematically assessed\", \"Mechanism by which reduced Hsp70 leads to atrial fibrillation not elucidated\", \"Whether the R391H mutation disrupts NPC structure globally or affects a specific transport route unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Domain dissection revealed that NUP155's NPC-anchoring function (β-propeller) and its role in organizing inner nuclear membrane proteins (α-solenoid) are separable, establishing NUP155 as a multifunctional scaffold that bridges the pore and the nuclear lamina/membrane compartment.\",\n      \"evidence\": \"RNAi with domain-specific rescue constructs in Drosophila cells, chromatin fractionation, and immunofluorescence\",\n      \"pmids\": [\"22718353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partners of the α-solenoid domain for INM protein tethering not identified\", \"Whether this dual function is conserved in vertebrates not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the Nup53→NUP155 recruitment step during NPC assembly, alongside the Nup53–Ndc1 membrane interaction, defined the molecular hierarchy by which inner-ring nucleoporins integrate membrane and scaffold assembly.\",\n      \"evidence\": \"In vitro binding, co-immunoprecipitation, depletion/reconstitution in Xenopus egg extracts, membrane-bending assays\",\n      \"pmids\": [\"24363447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Nup53–NUP155 interface not resolved at atomic resolution\", \"Whether post-translational modifications regulate this recruitment in vivo unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that a lamin A/C AF-linked mutation disrupts the physical lamin A/C–NUP155 interaction, with downstream effects on Hsp70 transport and Nav1.5 surface expression, established the nuclear lamina–NPC interface as a functional unit required for cardiac ion channel biogenesis.\",\n      \"evidence\": \"Co-IP, GST pull-down, nuclear envelope extractability assays, mRNA export assays, patch-clamp electrophysiology\",\n      \"pmids\": [\"30488537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between lamin A/C and NUP155 not structurally defined\", \"Whether other NPC components compensate in lamin A/C mutant backgrounds not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that NUP155 controls p21 translation via transcriptional regulation of the methyltransferase FTSJ1 revealed an unexpected gene-regulatory circuit linking a structural nucleoporin to the p53 tumor-suppressor pathway.\",\n      \"evidence\": \"Proteomics, polysome fractionation, RNAi knockdown, transcriptional reporters in hepatocellular carcinoma models\",\n      \"pmids\": [\"31089132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP155 regulates FTSJ1 transcription directly (e.g. at the gene locus) or indirectly is unresolved\", \"Generalizability beyond liver cancer cells not demonstrated\", \"FTSJ1's RNA substrate specificity in this context undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of INO80 mRNA as a second NUP155-dependent nuclear export cargo, whose loss induces podocyte senescence, extended the selective transport function of NUP155 to renal biology and cellular aging.\",\n      \"evidence\": \"siRNA knockdown and overexpression in rat podocytes, SA-β-gal staining, qRT-PCR, immunofluorescence, comet assay\",\n      \"pmids\": [\"39111625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NUP155 selects INO80 mRNA for export not defined\", \"Whether the ferulic acid stabilization of NUP155 is direct and specific requires independent confirmation\", \"In vivo renal phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of NUP155 within the inner ring, the mechanism by which NUP155 selectively promotes export of specific mRNAs (Hsp70, INO80), the structural basis of the lamin A/C–NUP155 interface, and whether NUP155's gene-regulatory functions (FTSJ1/p21 axis) operate through chromatin-proximal or transport-dependent mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length NUP155 in the NPC context\", \"Cargo selectivity mechanism unknown\", \"Chromatin-proximal versus transport-dependent gene regulation not disentangled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 2, 5, 6, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 3, 7, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\n      \"Nuclear pore complex (NPC)\",\n      \"Nup93 subcomplex (inner ring)\"\n    ],\n    \"partners\": [\n      \"NUP53\",\n      \"GLE1\",\n      \"LMNA\",\n      \"NUP93\",\n      \"NDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}