{"gene":"NUP160","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"Nup160 and Nup133 are novel vertebrate nucleoporins that exist as a complex (Nup160 complex) together with Nup107, Nup96, and Sec13 in Xenopus egg extracts and in assembled nuclear pores. Nup98 and Nup153 each bind this complex, and specific fragments of Nup160 and Nup133 block poly[A]+ RNA (mRNA) export but not protein import or export, establishing a direct role in mRNA export.","method":"Pulldown from Xenopus egg extracts, co-immunoprecipitation, immunofluorescence, protein purification and sequencing, transfection with in vivo transport assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldowns, complex reconstitution from egg extracts, functional transport assays with dominant-negative fragments, multiple orthogonal methods in a single focused study","pmids":["11684705"],"is_preprint":false},{"year":2001,"finding":"The binding site on Nup98 for the Nup160 subcomplex is used to tether Nup98 to the nucleus; the binding site on Nup153 for the Nup160 subcomplex targets Nup153 to the nuclear pore.","method":"Domain mapping via pulldown experiments with fragments of Nup98 and Nup153 from Xenopus egg extracts, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with pulldowns and localization assays, single study","pmids":["11684705"],"is_preprint":false},{"year":2018,"finding":"Knockdown of NUP160 in mouse podocytes inhibits cell proliferation by decreasing cyclin D1 and CDK4 expression, increasing p27, and inducing S-phase arrest; it also promotes apoptosis and autophagy, enhances cell migration, decreases expression of nephrin, podocin, and CD2AP, increases α-actinin-4, and alters subcellular localization of nephrin, podocin, and CD2AP.","method":"shRNA-mediated knockdown in conditionally immortalized mouse podocytes; Western blot, flow cytometry, immunofluorescence","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotypes and multiple molecular readouts, single lab, single organism model","pmids":["29704630"],"is_preprint":false},{"year":2019,"finding":"Silencing of Drosophila NUP160 specifically in nephrocytes leads to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure; these defects are completely rescued by wild-type human NUP160, but not by the NUP160 disease-associated mutant allele, establishing loss-of-function phenotypes for two compound-heterozygous mutations identified in a patient with steroid-resistant nephrotic syndrome.","method":"Drosophila nephrocyte-specific RNAi knockdown; rescue by wild-type and mutant human NUP160 expression; functional assays for nephrocyte function, cell size, nuclear volume, nuclear membrane structure","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model organism loss-of-function with allele-specific rescue, single lab","pmids":["30910934"],"is_preprint":false},{"year":2024,"finding":"Podocyte-specific knockout of Nup160 in mice causes progressive proteinuria, reduced serum albumin, and glomerulosclerosis, directly demonstrating that loss of Nup160 in podocytes is sufficient to produce nephrotic syndrome phenotypes.","method":"Podocyte-specific Nup160 knockout mice generated by CRISPR/Cas9 and Cre/loxP; protein and DNA level verification; urinary albumin/creatinine ratio, serum albumin, histology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with rigorous phenotypic characterization and littermate controls, multiple independent phenotypic readouts","pmids":["38224683"],"is_preprint":false},{"year":2025,"finding":"Loss of Nup160 in podocytes of podocyte-specific knockout mice decreases Cdc42 protein levels and reduces Cdc42 activity (despite elevated Cdc42 mRNA), linking NUP160 to post-transcriptional regulation of Cdc42 and suggesting that CDC42 dysregulation contributes to NUP160-associated steroid-resistant nephrotic syndrome pathogenesis.","method":"Podocyte-specific Nup160 KO mouse with double-fluorescent Cre reporter; single-cell transcriptomics and proteomics of glomerular cells; primary podocyte culture; Cdc42 activity assay; Western blot; RT-qPCR","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with multi-omic analysis and functional activity assay, single lab","pmids":["40298220"],"is_preprint":false},{"year":2021,"finding":"Knockdown of NUP160 in high glucose-treated kidney tubular cells and STZ-induced diabetic nephropathy mice restores autophagic flux (increased LC3II/LC3I ratio, decreased p62) and reduces NF-κB-dependent inflammation and fibrosis, identifying NUP160 as a regulator of autophagy in diabetic nephropathy.","method":"shRNA knockdown in NRK-52E cells; STZ mouse model; Western blot for autophagy markers, NF-κB pathway components, and inflammatory cytokines; histological staining in vivo","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with multiple molecular readouts, single lab","pmids":["34533106"],"is_preprint":false},{"year":2023,"finding":"NUP160 knockdown in high glucose-treated podocytes activates the JAK2/STAT3 signaling pathway (increased p-JAK2/JAK2 and p-STAT3/STAT3 ratios) and reduces autophagic flux (decreased LC3B-II/LC3B-I), indicating that NUP160 regulates cellular autophagy through the JAK2/STAT3 pathway.","method":"siRNA knockdown in podocytes; Western blot for JAK2/STAT3 phosphorylation and LC3B; flow cytometry for apoptosis","journal":"Iranian journal of kidney diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown method, signaling pathway inferred from phospho-Western blots only","pmids":["38043110"],"is_preprint":false},{"year":2019,"finding":"microRNA-577 directly targets NUP160 mRNA (validated by dual-luciferase reporter assay), and upregulation of miR-577 reduces NUP160 expression in CML cells, linking NUP160 to imatinib sensitivity in chronic myeloid leukemia.","method":"Dual-luciferase reporter assay; qRT-PCR; cell proliferation and cycle assays; cell reverse test for drug sensitivity","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter for direct targeting, single lab, limited mechanistic depth for NUP160 specifically","pmids":["31486501"],"is_preprint":false},{"year":2025,"finding":"circRAPGEF5 interacts with the KH3-4 domain of IGF2BP2, which then stabilizes NUP160 mRNA; elevated NUP160 suppresses autophagic flux in lung adenocarcinoma cells, and RNAi-mediated knockdown of NUP160 restores autophagy and attenuates malignant behaviors in vitro and in vivo.","method":"RNA pulldown, mass spectrometry, RNA immunoprecipitation; m6A-RIP-PCR; immunofluorescence; FISH; mRFP-GFP-LC3 lentiviral labeling for autophagy flux; xenograft mouse model; siRNA knockdown","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pulldown, MS, RIP, functional autophagy assay, xenograft), single lab","pmids":["40629330"],"is_preprint":false}],"current_model":"NUP160 encodes a component of the outer ring of the nuclear pore complex (NPC), where it forms the Nup160 complex with Nup133, Nup107, Nup96, and Sec13; this complex is anchored at the basket side of the pore through interactions with Nup98 and Nup153, and is required for mRNA export but not protein import/export. In podocytes, NUP160 is essential for normal podocyte function—its loss causes dysregulation of CDC42 (at the post-transcriptional level), disrupts expression and localization of slit diaphragm proteins (nephrin, podocin, CD2AP), perturbs cell cycle (via cyclin D1/CDK4/p27), and in vivo knockout produces proteinuria, glomerulosclerosis, and nephrotic syndrome. NUP160 also modulates autophagic flux (partly via NF-κB and JAK2/STAT3 pathways) and its mRNA is stabilized by the IGF2BP2/circRAPGEF5 axis in lung adenocarcinoma cells."},"narrative":{"mechanistic_narrative":"NUP160 is a structural nucleoporin of the nuclear pore complex (NPC) that assembles into the Nup160 outer-ring complex together with Nup133, Nup107, Nup96, and Sec13 [PMID:11684705]. This complex is tethered to the pore through interactions with Nup98 and Nup153, and these contacts are required to target Nup98 and Nup153 to the nucleus and the pore respectively [PMID:11684705]. Functionally, dominant-negative fragments of Nup160 selectively block poly[A]+ mRNA export without affecting protein import or export, establishing a dedicated role in mRNA export [PMID:11684705]. Beyond its core NPC function, NUP160 is essential for podocyte biology: loss of NUP160 in podocytes disrupts expression and subcellular localization of slit diaphragm proteins nephrin, podocin, and CD2AP, perturbs cell-cycle progression through cyclin D1/CDK4/p27, and post-transcriptionally lowers CDC42 protein and activity despite elevated mRNA [PMID:29704630, PMID:40298220]. Allele-specific rescue in Drosophila nephrocytes and a podocyte-specific knockout mouse that develops proteinuria, hypoalbuminemia, and glomerulosclerosis demonstrate that NUP160 loss-of-function causes steroid-resistant nephrotic syndrome [PMID:30910934, PMID:38224683]. NUP160 additionally modulates autophagic flux in disease contexts, and its mRNA is stabilized by the circRAPGEF5/IGF2BP2 axis in lung adenocarcinoma [PMID:40629330].","teleology":[{"year":2001,"claim":"Whether vertebrate Nup160 was a discrete nucleoporin with a defined complex and transport function was unknown; this work defined the Nup160 outer-ring complex and assigned it a direct role in mRNA export.","evidence":"Pulldown, co-IP, and reconstitution from Xenopus egg extracts with dominant-negative fragment transport assays","pmids":["11684705"],"confidence":"High","gaps":["Atomic structure of the complex not resolved","Mechanism by which the complex selects mRNA versus protein cargo not defined"]},{"year":2001,"claim":"How peripheral nucleoporins are anchored to the pore was unclear; mapping showed the Nup160 complex provides the binding sites that tether Nup98 to the nucleus and target Nup153 to the pore.","evidence":"Domain-mapping pulldowns with Nup98/Nup153 fragments and immunofluorescence in Xenopus extracts","pmids":["11684705"],"confidence":"Medium","gaps":["Single-study domain mapping","Stoichiometry and structural interface not determined"]},{"year":2018,"claim":"The cellular consequence of NUP160 loss in podocytes was unknown; knockdown linked NUP160 to slit-diaphragm protein expression/localization, cell-cycle control, and survival.","evidence":"shRNA knockdown in immortalized mouse podocytes with Western blot, flow cytometry, immunofluorescence","pmids":["29704630"],"confidence":"Medium","gaps":["Whether effects are direct or secondary to NPC dysfunction unknown","Single cell-line model"]},{"year":2019,"claim":"Whether patient NUP160 mutations are pathogenic was untested; nephrocyte-specific rescue showed wild-type but not the mutant allele restores function, establishing loss-of-function disease causation.","evidence":"Drosophila nephrocyte RNAi with allele-specific human NUP160 rescue and functional/structural assays","pmids":["30910934"],"confidence":"Medium","gaps":["Molecular defect of the mutant protein not defined","Single lab"]},{"year":2024,"claim":"Whether podocyte NUP160 loss alone is sufficient for disease was open; conditional knockout mice developed proteinuria, hypoalbuminemia, and glomerulosclerosis, proving sufficiency.","evidence":"Podocyte-specific Nup160 knockout mouse (CRISPR/Cre-loxP) with albumin/creatinine, serum albumin, and histology","pmids":["38224683"],"confidence":"High","gaps":["Downstream effector cascade not fully mapped in this study"]},{"year":2025,"claim":"The molecular driver of NUP160-associated nephrotic syndrome was unresolved; KO mice revealed post-transcriptional CDC42 downregulation as a candidate effector.","evidence":"Podocyte-specific KO mouse with single-cell omics, primary podocyte culture, and Cdc42 activity assay","pmids":["40298220"],"confidence":"Medium","gaps":["Mechanism coupling NPC function to CDC42 protein stability unknown","Causality of CDC42 loss for the full phenotype not formally tested"]},{"year":2021,"claim":"A role for NUP160 in autophagy and inflammation was untested; knockdown in diabetic-nephropathy models restored autophagic flux and reduced NF-kB-driven inflammation/fibrosis.","evidence":"shRNA knockdown in NRK-52E cells and STZ diabetic mice with autophagy/NF-kB markers and histology","pmids":["34533106"],"confidence":"Medium","gaps":["Direct vs indirect link to autophagy machinery unresolved","Whether NPC transport role mediates the effect unknown"]},{"year":2023,"claim":"The signaling route for NUP160's autophagy effect was unknown; knockdown in high-glucose podocytes implicated the JAK2/STAT3 pathway.","evidence":"siRNA knockdown in podocytes with phospho-JAK2/STAT3 and LC3B Westerns, apoptosis flow cytometry","pmids":["38043110"],"confidence":"Low","gaps":["Pathway inferred from phospho-Westerns only","No epistasis or rescue to confirm JAK2/STAT3 dependence"]},{"year":2019,"claim":"Whether NUP160 is regulated by non-coding RNA was unaddressed; miR-577 was shown to directly target NUP160 mRNA, linking it to imatinib sensitivity in CML.","evidence":"Dual-luciferase reporter, qRT-PCR, proliferation and drug-sensitivity assays in CML cells","pmids":["31486501"],"confidence":"Low","gaps":["Limited mechanistic depth for NUP160 itself","Single lab, single reporter validation"]},{"year":2025,"claim":"Post-transcriptional control of NUP160 in cancer was uncharacterized; circRAPGEF5/IGF2BP2 was found to stabilize NUP160 mRNA, with elevated NUP160 suppressing autophagy and promoting lung adenocarcinoma malignancy.","evidence":"RNA pulldown/MS/RIP, m6A-RIP, autophagy flux reporter, siRNA knockdown, and xenografts","pmids":["40629330"],"confidence":"Medium","gaps":["Mechanism by which NUP160 suppresses autophagy not defined","Single lab"]},{"year":null,"claim":"How NUP160's core NPC/mRNA-export function mechanistically connects to its tissue-specific roles in podocyte CDC42 regulation, autophagy, and cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No molecular link established between mRNA-export function and CDC42 protein stability","Mechanism of autophagy regulation undefined","Structural basis of disease mutations not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,9]}],"complexes":["Nup160 complex (Nup107-160 outer ring)","nuclear pore complex"],"partners":["NUP133","NUP107","NUP96","SEC13","NUP98","NUP153"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12769","full_name":"Nuclear pore complex protein Nup160","aliases":["160 kDa nucleoporin","Nucleoporin Nup160"],"length_aa":1436,"mass_kda":162.1,"function":"Functions as a component of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Involved in poly(A)+ RNA transport","subcellular_location":"Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q12769/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP160","classification":"Common Essential","n_dependent_lines":1133,"n_total_lines":1208,"dependency_fraction":0.9379139072847682},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP160","total_profiled":1310},"omim":[{"mim_id":"618348","title":"GALLOWAY-MOWAT SYNDROME 7; GAMOS7","url":"https://www.omim.org/entry/618348"},{"mim_id":"618178","title":"NEPHROTIC SYNDROME, TYPE 19; NPHS19","url":"https://www.omim.org/entry/618178"},{"mim_id":"618176","title":"NEPHROTIC SYNDROME, TYPE 17; NPHS17","url":"https://www.omim.org/entry/618176"},{"mim_id":"615753","title":"POM121 TRANSMEMBRANE NUCLEOPORIN; POM121","url":"https://www.omim.org/entry/615753"},{"mim_id":"610853","title":"AT-HOOK-CONTAINING TRANSCRIPTION FACTOR 1; AHCTF1","url":"https://www.omim.org/entry/610853"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP160"},"hgnc":{"alias_symbol":["KIAA0197","FLJ22583"],"prev_symbol":[]},"alphafold":{"accession":"Q12769","domains":[{"cath_id":"-","chopping":"1212-1333","consensus_level":"medium","plddt":82.9312,"start":1212,"end":1333},{"cath_id":"1.20.58","chopping":"1335-1436","consensus_level":"medium","plddt":79.3018,"start":1335,"end":1436}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12769","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12769-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12769-F1-predicted_aligned_error_v6.png","plddt_mean":80.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP160","jax_strain_url":"https://www.jax.org/strain/search?query=NUP160"},"sequence":{"accession":"Q12769","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12769.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12769/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12769"}},"corpus_meta":[{"pmid":"11684705","id":"PMC_11684705","title":"Novel vertebrate nucleoporins Nup133 and Nup160 play a role in mRNA export.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11684705","citation_count":154,"is_preprint":false},{"pmid":"26527604","id":"PMC_26527604","title":"NUP160-SLC43A3 is a novel recurrent fusion oncogene in angiosarcoma.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26527604","citation_count":44,"is_preprint":false},{"pmid":"30910934","id":"PMC_30910934","title":"Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome.","date":"2019","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/30910934","citation_count":34,"is_preprint":false},{"pmid":"29704630","id":"PMC_29704630","title":"Knockdown of NUP160 inhibits cell proliferation, induces apoptosis, autophagy and cell migration, and alters the expression and localization of podocyte associated molecules in mouse podocytes.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29704630","citation_count":15,"is_preprint":false},{"pmid":"34533106","id":"PMC_34533106","title":"Nucleoporin 160 (NUP160) inhibition alleviates diabetic nephropathy by activating autophagy.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34533106","citation_count":13,"is_preprint":false},{"pmid":"31486501","id":"PMC_31486501","title":"MicroRNA-577 promotes the sensitivity of chronic myeloid leukemia cells to imatinib by targeting NUP160.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31486501","citation_count":13,"is_preprint":false},{"pmid":"26022241","id":"PMC_26022241","title":"Lineage-Specific Evolution of the Complex Nup160 Hybrid Incompatibility Between Drosophila melanogaster and Its Sister Species.","date":"2015","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26022241","citation_count":12,"is_preprint":false},{"pmid":"38224683","id":"PMC_38224683","title":"Podocyte-specific Nup160 knockout mice develop nephrotic syndrome and glomerulosclerosis.","date":"2024","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38224683","citation_count":8,"is_preprint":false},{"pmid":"38650033","id":"PMC_38650033","title":"Mutations in the NUP93, NUP107 and NUP160 genes cause steroid-resistant nephrotic syndrome in Chinese children.","date":"2024","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38650033","citation_count":7,"is_preprint":false},{"pmid":"40629330","id":"PMC_40629330","title":"M6A-Methylated circRAPGEF5 drives lung adenocarcinoma progression and metastasis via IGF2BP2/NUP160-mediated autophagy suppression.","date":"2025","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40629330","citation_count":6,"is_preprint":false},{"pmid":"22820383","id":"PMC_22820383","title":"Genetic dissection of Nucleoporin 160 (Nup160), a gene involved in multiple phenotypes of reproductive isolation in Drosophila.","date":"2012","source":"Genes & genetic systems","url":"https://pubmed.ncbi.nlm.nih.gov/22820383","citation_count":6,"is_preprint":false},{"pmid":"35785044","id":"PMC_35785044","title":"NUP160 knockdown inhibits the progression of diabetic nephropathy in vitro and in vivo.","date":"2022","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35785044","citation_count":4,"is_preprint":false},{"pmid":"40298220","id":"PMC_40298220","title":"Loss of Nup160 dysregulates Cdc42 in the podocytes of podocyte-specific Nup160 knockout mice.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40298220","citation_count":3,"is_preprint":false},{"pmid":"38043110","id":"PMC_38043110","title":"Role and Mechanism of NUP160-regulated Autophagy in Pathogenesis of Diabetic Nephropathy.","date":"2023","source":"Iranian journal of kidney diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38043110","citation_count":2,"is_preprint":false},{"pmid":"37900929","id":"PMC_37900929","title":"Novel LAGE3 Pathogenic Variants Combined with TRPC6 and NUP160 Variants in Galloway-Mowat Syndrome: A Case Report.","date":"2023","source":"Case reports in nephrology and dialysis","url":"https://pubmed.ncbi.nlm.nih.gov/37900929","citation_count":2,"is_preprint":false},{"pmid":"41394771","id":"PMC_41394771","title":"Identification of Aging-Related Hub Genes (ATP11B, RBBP7, DOCK10, and NUP160) as Potential Biomarkers and Therapeutic Targets in Sepsis.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41394771","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10672,"output_tokens":2761,"usd":0.036715,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10003,"output_tokens":3256,"usd":0.065708,"stage2_stop_reason":"end_turn"},"total_usd":0.102423,"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\": 2001,\n      \"finding\": \"Nup160 and Nup133 are novel vertebrate nucleoporins that exist as a complex (Nup160 complex) together with Nup107, Nup96, and Sec13 in Xenopus egg extracts and in assembled nuclear pores. Nup98 and Nup153 each bind this complex, and specific fragments of Nup160 and Nup133 block poly[A]+ RNA (mRNA) export but not protein import or export, establishing a direct role in mRNA export.\",\n      \"method\": \"Pulldown from Xenopus egg extracts, co-immunoprecipitation, immunofluorescence, protein purification and sequencing, transfection with in vivo transport assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldowns, complex reconstitution from egg extracts, functional transport assays with dominant-negative fragments, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"11684705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The binding site on Nup98 for the Nup160 subcomplex is used to tether Nup98 to the nucleus; the binding site on Nup153 for the Nup160 subcomplex targets Nup153 to the nuclear pore.\",\n      \"method\": \"Domain mapping via pulldown experiments with fragments of Nup98 and Nup153 from Xenopus egg extracts, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with pulldowns and localization assays, single study\",\n      \"pmids\": [\"11684705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of NUP160 in mouse podocytes inhibits cell proliferation by decreasing cyclin D1 and CDK4 expression, increasing p27, and inducing S-phase arrest; it also promotes apoptosis and autophagy, enhances cell migration, decreases expression of nephrin, podocin, and CD2AP, increases α-actinin-4, and alters subcellular localization of nephrin, podocin, and CD2AP.\",\n      \"method\": \"shRNA-mediated knockdown in conditionally immortalized mouse podocytes; Western blot, flow cytometry, immunofluorescence\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotypes and multiple molecular readouts, single lab, single organism model\",\n      \"pmids\": [\"29704630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Silencing of Drosophila NUP160 specifically in nephrocytes leads to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure; these defects are completely rescued by wild-type human NUP160, but not by the NUP160 disease-associated mutant allele, establishing loss-of-function phenotypes for two compound-heterozygous mutations identified in a patient with steroid-resistant nephrotic syndrome.\",\n      \"method\": \"Drosophila nephrocyte-specific RNAi knockdown; rescue by wild-type and mutant human NUP160 expression; functional assays for nephrocyte function, cell size, nuclear volume, nuclear membrane structure\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model organism loss-of-function with allele-specific rescue, single lab\",\n      \"pmids\": [\"30910934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Podocyte-specific knockout of Nup160 in mice causes progressive proteinuria, reduced serum albumin, and glomerulosclerosis, directly demonstrating that loss of Nup160 in podocytes is sufficient to produce nephrotic syndrome phenotypes.\",\n      \"method\": \"Podocyte-specific Nup160 knockout mice generated by CRISPR/Cas9 and Cre/loxP; protein and DNA level verification; urinary albumin/creatinine ratio, serum albumin, histology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with rigorous phenotypic characterization and littermate controls, multiple independent phenotypic readouts\",\n      \"pmids\": [\"38224683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Nup160 in podocytes of podocyte-specific knockout mice decreases Cdc42 protein levels and reduces Cdc42 activity (despite elevated Cdc42 mRNA), linking NUP160 to post-transcriptional regulation of Cdc42 and suggesting that CDC42 dysregulation contributes to NUP160-associated steroid-resistant nephrotic syndrome pathogenesis.\",\n      \"method\": \"Podocyte-specific Nup160 KO mouse with double-fluorescent Cre reporter; single-cell transcriptomics and proteomics of glomerular cells; primary podocyte culture; Cdc42 activity assay; Western blot; RT-qPCR\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with multi-omic analysis and functional activity assay, single lab\",\n      \"pmids\": [\"40298220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of NUP160 in high glucose-treated kidney tubular cells and STZ-induced diabetic nephropathy mice restores autophagic flux (increased LC3II/LC3I ratio, decreased p62) and reduces NF-κB-dependent inflammation and fibrosis, identifying NUP160 as a regulator of autophagy in diabetic nephropathy.\",\n      \"method\": \"shRNA knockdown in NRK-52E cells; STZ mouse model; Western blot for autophagy markers, NF-κB pathway components, and inflammatory cytokines; histological staining in vivo\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with multiple molecular readouts, single lab\",\n      \"pmids\": [\"34533106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUP160 knockdown in high glucose-treated podocytes activates the JAK2/STAT3 signaling pathway (increased p-JAK2/JAK2 and p-STAT3/STAT3 ratios) and reduces autophagic flux (decreased LC3B-II/LC3B-I), indicating that NUP160 regulates cellular autophagy through the JAK2/STAT3 pathway.\",\n      \"method\": \"siRNA knockdown in podocytes; Western blot for JAK2/STAT3 phosphorylation and LC3B; flow cytometry for apoptosis\",\n      \"journal\": \"Iranian journal of kidney diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown method, signaling pathway inferred from phospho-Western blots only\",\n      \"pmids\": [\"38043110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"microRNA-577 directly targets NUP160 mRNA (validated by dual-luciferase reporter assay), and upregulation of miR-577 reduces NUP160 expression in CML cells, linking NUP160 to imatinib sensitivity in chronic myeloid leukemia.\",\n      \"method\": \"Dual-luciferase reporter assay; qRT-PCR; cell proliferation and cycle assays; cell reverse test for drug sensitivity\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter for direct targeting, single lab, limited mechanistic depth for NUP160 specifically\",\n      \"pmids\": [\"31486501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"circRAPGEF5 interacts with the KH3-4 domain of IGF2BP2, which then stabilizes NUP160 mRNA; elevated NUP160 suppresses autophagic flux in lung adenocarcinoma cells, and RNAi-mediated knockdown of NUP160 restores autophagy and attenuates malignant behaviors in vitro and in vivo.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RNA immunoprecipitation; m6A-RIP-PCR; immunofluorescence; FISH; mRFP-GFP-LC3 lentiviral labeling for autophagy flux; xenograft mouse model; siRNA knockdown\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pulldown, MS, RIP, functional autophagy assay, xenograft), single lab\",\n      \"pmids\": [\"40629330\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP160 encodes a component of the outer ring of the nuclear pore complex (NPC), where it forms the Nup160 complex with Nup133, Nup107, Nup96, and Sec13; this complex is anchored at the basket side of the pore through interactions with Nup98 and Nup153, and is required for mRNA export but not protein import/export. In podocytes, NUP160 is essential for normal podocyte function—its loss causes dysregulation of CDC42 (at the post-transcriptional level), disrupts expression and localization of slit diaphragm proteins (nephrin, podocin, CD2AP), perturbs cell cycle (via cyclin D1/CDK4/p27), and in vivo knockout produces proteinuria, glomerulosclerosis, and nephrotic syndrome. NUP160 also modulates autophagic flux (partly via NF-κB and JAK2/STAT3 pathways) and its mRNA is stabilized by the IGF2BP2/circRAPGEF5 axis in lung adenocarcinoma cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP160 is a structural nucleoporin of the nuclear pore complex (NPC) that assembles into the Nup160 outer-ring complex together with Nup133, Nup107, Nup96, and Sec13 [#0]. This complex is tethered to the pore through interactions with Nup98 and Nup153, and these contacts are required to target Nup98 and Nup153 to the nucleus and the pore respectively [#0, #1]. Functionally, dominant-negative fragments of Nup160 selectively block poly[A]+ mRNA export without affecting protein import or export, establishing a dedicated role in mRNA export [#0]. Beyond its core NPC function, NUP160 is essential for podocyte biology: loss of NUP160 in podocytes disrupts expression and subcellular localization of slit diaphragm proteins nephrin, podocin, and CD2AP, perturbs cell-cycle progression through cyclin D1/CDK4/p27, and post-transcriptionally lowers CDC42 protein and activity despite elevated mRNA [#2, #5]. Allele-specific rescue in Drosophila nephrocytes and a podocyte-specific knockout mouse that develops proteinuria, hypoalbuminemia, and glomerulosclerosis demonstrate that NUP160 loss-of-function causes steroid-resistant nephrotic syndrome [#3, #4]. NUP160 additionally modulates autophagic flux in disease contexts, and its mRNA is stabilized by the circRAPGEF5/IGF2BP2 axis in lung adenocarcinoma [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Whether vertebrate Nup160 was a discrete nucleoporin with a defined complex and transport function was unknown; this work defined the Nup160 outer-ring complex and assigned it a direct role in mRNA export.\",\n      \"evidence\": \"Pulldown, co-IP, and reconstitution from Xenopus egg extracts with dominant-negative fragment transport assays\",\n      \"pmids\": [\"11684705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the complex not resolved\", \"Mechanism by which the complex selects mRNA versus protein cargo not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"How peripheral nucleoporins are anchored to the pore was unclear; mapping showed the Nup160 complex provides the binding sites that tether Nup98 to the nucleus and target Nup153 to the pore.\",\n      \"evidence\": \"Domain-mapping pulldowns with Nup98/Nup153 fragments and immunofluorescence in Xenopus extracts\",\n      \"pmids\": [\"11684705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-study domain mapping\", \"Stoichiometry and structural interface not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The cellular consequence of NUP160 loss in podocytes was unknown; knockdown linked NUP160 to slit-diaphragm protein expression/localization, cell-cycle control, and survival.\",\n      \"evidence\": \"shRNA knockdown in immortalized mouse podocytes with Western blot, flow cytometry, immunofluorescence\",\n      \"pmids\": [\"29704630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effects are direct or secondary to NPC dysfunction unknown\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether patient NUP160 mutations are pathogenic was untested; nephrocyte-specific rescue showed wild-type but not the mutant allele restores function, establishing loss-of-function disease causation.\",\n      \"evidence\": \"Drosophila nephrocyte RNAi with allele-specific human NUP160 rescue and functional/structural assays\",\n      \"pmids\": [\"30910934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular defect of the mutant protein not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether podocyte NUP160 loss alone is sufficient for disease was open; conditional knockout mice developed proteinuria, hypoalbuminemia, and glomerulosclerosis, proving sufficiency.\",\n      \"evidence\": \"Podocyte-specific Nup160 knockout mouse (CRISPR/Cre-loxP) with albumin/creatinine, serum albumin, and histology\",\n      \"pmids\": [\"38224683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector cascade not fully mapped in this study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The molecular driver of NUP160-associated nephrotic syndrome was unresolved; KO mice revealed post-transcriptional CDC42 downregulation as a candidate effector.\",\n      \"evidence\": \"Podocyte-specific KO mouse with single-cell omics, primary podocyte culture, and Cdc42 activity assay\",\n      \"pmids\": [\"40298220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling NPC function to CDC42 protein stability unknown\", \"Causality of CDC42 loss for the full phenotype not formally tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A role for NUP160 in autophagy and inflammation was untested; knockdown in diabetic-nephropathy models restored autophagic flux and reduced NF-kB-driven inflammation/fibrosis.\",\n      \"evidence\": \"shRNA knockdown in NRK-52E cells and STZ diabetic mice with autophagy/NF-kB markers and histology\",\n      \"pmids\": [\"34533106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect link to autophagy machinery unresolved\", \"Whether NPC transport role mediates the effect unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The signaling route for NUP160's autophagy effect was unknown; knockdown in high-glucose podocytes implicated the JAK2/STAT3 pathway.\",\n      \"evidence\": \"siRNA knockdown in podocytes with phospho-JAK2/STAT3 and LC3B Westerns, apoptosis flow cytometry\",\n      \"pmids\": [\"38043110\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway inferred from phospho-Westerns only\", \"No epistasis or rescue to confirm JAK2/STAT3 dependence\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether NUP160 is regulated by non-coding RNA was unaddressed; miR-577 was shown to directly target NUP160 mRNA, linking it to imatinib sensitivity in CML.\",\n      \"evidence\": \"Dual-luciferase reporter, qRT-PCR, proliferation and drug-sensitivity assays in CML cells\",\n      \"pmids\": [\"31486501\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic depth for NUP160 itself\", \"Single lab, single reporter validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Post-transcriptional control of NUP160 in cancer was uncharacterized; circRAPGEF5/IGF2BP2 was found to stabilize NUP160 mRNA, with elevated NUP160 suppressing autophagy and promoting lung adenocarcinoma malignancy.\",\n      \"evidence\": \"RNA pulldown/MS/RIP, m6A-RIP, autophagy flux reporter, siRNA knockdown, and xenografts\",\n      \"pmids\": [\"40629330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NUP160 suppresses autophagy not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUP160's core NPC/mRNA-export function mechanistically connects to its tissue-specific roles in podocyte CDC42 regulation, autophagy, and cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular link established between mRNA-export function and CDC42 protein stability\", \"Mechanism of autophagy regulation undefined\", \"Structural basis of disease mutations not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [\"Nup160 complex (Nup107-160 outer ring)\", \"nuclear pore complex\"],\n    \"partners\": [\"NUP133\", \"NUP107\", \"NUP96\", \"SEC13\", \"NUP98\", \"NUP153\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}