{"gene":"NUP85","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2024,"finding":"NUP85 protein interacts with C-C motif chemokine receptor 2 (CCR2), and knockdown of NUP85 reduces CCR2 protein levels and inhibits phosphorylation of the PI3K/AKT signaling pathway, thereby reducing lipid accumulation and inflammation in NAFLD models.","method":"Co-immunoprecipitation (protein interaction), siRNA knockdown in AML-12 cells and MCD-diet mouse model with downstream signaling readouts","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal protein interaction shown and knockdown phenotype with pathway readout, single lab, mechanistic follow-up present but limited orthogonal validation","pmids":["38617542"],"is_preprint":false},{"year":2021,"finding":"Biallelic loss-of-function variants in NUP85 result in a reduced number of nuclear pore complexes (NPCs) without altering nucleocytoplasmic compartmentalization, but cause abnormal mitotic spindle morphology and decreased cell viability and proliferation in patient-derived cells, placing NUP85 in control of NPC number and mitotic spindle integrity.","method":"Patient-derived fibroblast analysis: immunofluorescence for NPC number, nucleocytoplasmic transport assay, mitotic spindle imaging, cell viability/proliferation assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cellular assays in patient-derived cells, single lab, no reconstitution or in vitro biochemistry","pmids":["34170319"],"is_preprint":false},{"year":2023,"finding":"Compound heterozygous missense variants in NUP85 reduce cell viability of patient-derived fibroblasts, and structural simulation predicts altered NUP85 structure and disrupted interactions with neighboring nucleoporins.","method":"Patient-derived fibroblast viability assay; structural simulation/modeling of variant effects","journal":"Frontiers in neurology","confidence":"Low","confidence_rationale":"Tier 3-4 / Weak — cell viability is a single assay with no pathway placement; structural data is computational only; single case report","pmids":["36846113"],"is_preprint":false},{"year":2025,"finding":"NUP85 promotes lipid accumulation in lipotoxic hepatocytes by modulating the SLC27A1/PPAR-γ signaling pathway, enhancing expression of lipid synthesis-related genes and inflammatory factors; siRNA-mediated knockdown of NUP85 in vivo alleviates hepatic steatosis and inflammation.","method":"siRNA knockdown in hepatocytes (in vitro) and HFD/MCD-diet mouse models (in vivo); mechanistic pathway analysis via SLC27A1/PPAR-γ gene expression","journal":"Journal of nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro and in vivo knockdown with defined pathway readout, single lab, no reconstitution or direct binding evidence for the SLC27A1 link","pmids":["41413582"],"is_preprint":false},{"year":2026,"finding":"NUP85 competitively binds ubiquitin-specific peptidase 47 (USP47) to apoptosis signal-regulating kinase 1 (ASK1), thereby preventing USP47-mediated deubiquitination at lysine residue 805 of ASK1 and activating ASK1, which drives endoplasmic reticulum stress and collagen deposition in liver fibrosis.","method":"Co-immunoprecipitation for NUP85-USP47 and NUP85-ASK1 interactions; site-specific mutagenesis identifying K805 on ASK1; NUP85 knockdown/overexpression with ERS and fibrosis readouts in cells and mice","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding and specific ubiquitination site identified by Co-IP and mutagenesis, with in vivo validation; single lab","pmids":["41903125"],"is_preprint":false},{"year":2023,"finding":"In Drosophila testes, Nup75 (the ortholog of human NUP85) controls proliferation of early germ cells but not differentiating spermatogonia, and is involved in keeping hub cells quiescent; lineage-specific depletion results in loss of the germline lineage.","method":"Lineage-specific RNAi knockdown in Drosophila testis; immunofluorescence and cell fate marker analysis","journal":"Cells & development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean lineage-specific knockdown with defined proliferation and cell fate phenotype, but single Drosophila study with no mammalian validation","pmids":["37286104"],"is_preprint":false}],"current_model":"NUP85 is a nuclear pore complex (NPC) Y-complex component required for NPC biogenesis and mitotic spindle integrity; in liver, NUP85 drives lipid accumulation and fibrosis by interacting with CCR2/PI3K-AKT and USP47-ASK1 signaling axes and by modulating the SLC27A1/PPAR-γ pathway, while loss-of-function variants in NUP85 reduce NPC number, impair mitotic spindle morphology, and decrease cell viability, causing steroid-resistant nephrotic syndrome, microcephaly, and Seckel syndrome spectrum disorders in humans."},"narrative":{"mechanistic_narrative":"NUP85 is a nuclear pore complex (NPC) component required for normal NPC abundance and mitotic fidelity, and it additionally functions in hepatic lipid and fibrotic signaling [PMID:34170319, PMID:41903125]. Biallelic loss-of-function variants reduce the number of assembled NPCs without disrupting nucleocytoplasmic compartmentalization, while producing abnormal mitotic spindle morphology and decreased cell viability and proliferation in patient-derived fibroblasts, establishing a role in NPC number control and mitotic spindle integrity [PMID:34170319]. In the liver, NUP85 acts as a driver of lipid accumulation and inflammation: it interacts with the chemokine receptor CCR2 to sustain PI3K/AKT phosphorylation, and modulates the SLC27A1/PPAR-γ axis to upregulate lipid-synthesis and inflammatory genes, such that NUP85 knockdown alleviates hepatic steatosis [PMID:38617542, PMID:41413582]. NUP85 also promotes liver fibrosis by competitively binding USP47 away from ASK1, blocking deubiquitination of ASK1 at K805 and thereby activating ASK1-driven endoplasmic reticulum stress and collagen deposition [PMID:41903125]. In Drosophila testes, the ortholog Nup75 controls early germ-cell proliferation and maintains hub-cell quiescence, with lineage-specific depletion causing germline loss [PMID:37286104].","teleology":[{"year":2021,"claim":"Established that NUP85 controls NPC abundance and mitotic spindle integrity rather than acting primarily through bulk nucleocytoplasmic transport, reframing how its loss causes disease.","evidence":"Patient-derived fibroblast immunofluorescence for NPC number, transport assays, spindle imaging, and viability/proliferation assays","pmids":["34170319"],"confidence":"Medium","gaps":["No reconstitution or in vitro biochemistry defining NUP85's structural role in the Y-complex","Mechanism linking reduced NPC number to spindle defects unresolved"]},{"year":2023,"claim":"Tested whether additional NUP85 missense variants impair function, linking patient genotypes to reduced viability and predicted disruption of neighboring nucleoporin contacts.","evidence":"Patient-derived fibroblast viability assay with computational structural modeling of variants","pmids":["36846113"],"confidence":"Low","gaps":["Cell viability is a single assay with no pathway placement","Structural prediction is computational only without experimental validation","Single case report"]},{"year":2023,"claim":"Extended NUP85 function to tissue-specific stem cell regulation by showing the Drosophila ortholog governs early germ-cell proliferation and hub-cell quiescence.","evidence":"Lineage-specific RNAi knockdown in Drosophila testis with cell-fate marker immunofluorescence","pmids":["37286104"],"confidence":"Medium","gaps":["No mammalian validation of the germline role","Molecular pathway connecting Nup75 to proliferation control not defined"]},{"year":2024,"claim":"Identified a non-NPC signaling role: NUP85 interacts with CCR2 and sustains PI3K/AKT signaling to promote hepatic lipid accumulation and inflammation.","evidence":"Co-immunoprecipitation, siRNA knockdown in AML-12 cells and MCD-diet mouse model with signaling readouts","pmids":["38617542"],"confidence":"Medium","gaps":["Single lab with limited orthogonal validation","Direct vs indirect nature of CCR2 interaction not fully resolved","How a nucleoporin engages a chemokine receptor mechanistically unclear"]},{"year":2025,"claim":"Defined a second hepatic lipid mechanism through the SLC27A1/PPAR-γ axis, showing in vivo knockdown relieves steatosis and inflammation.","evidence":"siRNA knockdown in hepatocytes and HFD/MCD mouse models with SLC27A1/PPAR-γ expression analysis","pmids":["41413582"],"confidence":"Medium","gaps":["No direct binding evidence for the SLC27A1 link","Relationship between this axis and the CCR2/PI3K-AKT axis unresolved"]},{"year":2026,"claim":"Mechanistically connected NUP85 to liver fibrosis via competitive binding to USP47, blocking ASK1 deubiquitination at K805 to activate ER stress and collagen deposition.","evidence":"Co-IP for NUP85-USP47 and NUP85-ASK1, site-specific mutagenesis of ASK1 K805, knockdown/overexpression with ERS and fibrosis readouts in cells and mice","pmids":["41903125"],"confidence":"Medium","gaps":["Single lab without orthogonal structural validation of the competitive binding model","How NUP85's nuclear pore role relates to cytoplasmic USP47/ASK1 regulation unclear"]},{"year":null,"claim":"It remains unresolved how NUP85's structural role at the nuclear pore mechanistically connects to its diverse cytoplasmic signaling functions in liver lipid metabolism and fibrosis.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical reconstitution of NUP85 within the Y-complex in the corpus","No unifying model linking NPC function to CCR2, SLC27A1/PPAR-γ, and USP47/ASK1 signaling"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]}],"complexes":["nuclear pore complex"],"partners":["CCR2","USP47","ASK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BW27","full_name":"Nuclear pore complex protein Nup85","aliases":["85 kDa nucleoporin","FROUNT","Nucleoporin Nup75","Nucleoporin Nup85","Pericentrin-1"],"length_aa":656,"mass_kda":75.0,"function":"Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance (PubMed:12718872). As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus (PubMed:12718872). The Nup107-160 complex seems to be required for spindle assembly during mitosis (PubMed:16807356). NUP85 is required for membrane clustering of CCL2-activated CCR2 (PubMed:15995708). Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade (PubMed:15995708). Involved in nephrogenesis (PubMed:30179222)","subcellular_location":"Nucleus, nuclear pore complex; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle; Cytoplasm; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q9BW27/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP85","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUP107","stoichiometry":10.0},{"gene":"NUP98","stoichiometry":10.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"PKN1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP85","total_profiled":1310},"omim":[{"mim_id":"618176","title":"NEPHROTIC SYNDROME, TYPE 17; NPHS17","url":"https://www.omim.org/entry/618176"},{"mim_id":"609264","title":"NUCLEOPORIN, 37-KD; NUP37","url":"https://www.omim.org/entry/609264"},{"mim_id":"609263","title":"SEH1-LIKE PROTEIN; SEH1L","url":"https://www.omim.org/entry/609263"},{"mim_id":"608141","title":"NUCLEOPORIN, 43-KD; NUP43","url":"https://www.omim.org/entry/608141"},{"mim_id":"607617","title":"NUCLEOPORIN, 107-KD; NUP107","url":"https://www.omim.org/entry/607617"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP85"},"hgnc":{"alias_symbol":["NUP75","FLJ12549"],"prev_symbol":[]},"alphafold":{"accession":"Q9BW27","domains":[{"cath_id":"-","chopping":"170-306","consensus_level":"high","plddt":91.1826,"start":170,"end":306},{"cath_id":"1.20.930","chopping":"552-611_622-656","consensus_level":"medium","plddt":84.6347,"start":552,"end":656}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BW27","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BW27-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BW27-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP85","jax_strain_url":"https://www.jax.org/strain/search?query=NUP85"},"sequence":{"accession":"Q9BW27","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BW27.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BW27/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BW27"}},"corpus_meta":[{"pmid":"38617542","id":"PMC_38617542","title":"NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38617542","citation_count":33,"is_preprint":false},{"pmid":"34170319","id":"PMC_34170319","title":"Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.","date":"2021","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34170319","citation_count":14,"is_preprint":false},{"pmid":"36846113","id":"PMC_36846113","title":"Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36846113","citation_count":9,"is_preprint":false},{"pmid":"38136965","id":"PMC_38136965","title":"NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38136965","citation_count":4,"is_preprint":false},{"pmid":"38952090","id":"PMC_38952090","title":"[Analysis of correlation between high expression of nucleoporin 85 (NUP85) and immune cell infiltration in hepatocellular carcinoma].","date":"2024","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38952090","citation_count":2,"is_preprint":false},{"pmid":"41413582","id":"PMC_41413582","title":"NUP85 siRNA loaded red blood cell-derived extracellular vesicles alleviate hepatic steatosis in MASLD.","date":"2025","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41413582","citation_count":1,"is_preprint":false},{"pmid":"39949197","id":"PMC_39949197","title":"A Novel NUP85 Variant Expanding the Phenotypic Spectrum of NUP85-Associated Steroid-Resistant Nephrotic Syndrome.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39949197","citation_count":1,"is_preprint":false},{"pmid":"37286104","id":"PMC_37286104","title":"Analysis of Bub3 and Nup75 in the Drosophila male germline lineage.","date":"2023","source":"Cells & development","url":"https://pubmed.ncbi.nlm.nih.gov/37286104","citation_count":0,"is_preprint":false},{"pmid":"41903125","id":"PMC_41903125","title":"NUP85 Mediates Endoplasmic Reticulum Stress through the USP47/ASK1 Signaling Pathway to Regulate the Progression of Liver Fibrosis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41903125","citation_count":0,"is_preprint":false},{"pmid":"40712764","id":"PMC_40712764","title":"WITHDRAWN: Red blood cell-derived extracellular vesicles deliver NUP85 siRNA to alleviate MASLD through downregulating SLC27A1/PPAR-γ in hepatocyte.","date":"2025","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/40712764","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6981,"output_tokens":1600,"usd":0.022471,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8390,"output_tokens":2385,"usd":0.050787,"stage2_stop_reason":"end_turn"},"total_usd":0.073258,"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\": 2024,\n      \"finding\": \"NUP85 protein interacts with C-C motif chemokine receptor 2 (CCR2), and knockdown of NUP85 reduces CCR2 protein levels and inhibits phosphorylation of the PI3K/AKT signaling pathway, thereby reducing lipid accumulation and inflammation in NAFLD models.\",\n      \"method\": \"Co-immunoprecipitation (protein interaction), siRNA knockdown in AML-12 cells and MCD-diet mouse model with downstream signaling readouts\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal protein interaction shown and knockdown phenotype with pathway readout, single lab, mechanistic follow-up present but limited orthogonal validation\",\n      \"pmids\": [\"38617542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic loss-of-function variants in NUP85 result in a reduced number of nuclear pore complexes (NPCs) without altering nucleocytoplasmic compartmentalization, but cause abnormal mitotic spindle morphology and decreased cell viability and proliferation in patient-derived cells, placing NUP85 in control of NPC number and mitotic spindle integrity.\",\n      \"method\": \"Patient-derived fibroblast analysis: immunofluorescence for NPC number, nucleocytoplasmic transport assay, mitotic spindle imaging, cell viability/proliferation assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cellular assays in patient-derived cells, single lab, no reconstitution or in vitro biochemistry\",\n      \"pmids\": [\"34170319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Compound heterozygous missense variants in NUP85 reduce cell viability of patient-derived fibroblasts, and structural simulation predicts altered NUP85 structure and disrupted interactions with neighboring nucleoporins.\",\n      \"method\": \"Patient-derived fibroblast viability assay; structural simulation/modeling of variant effects\",\n      \"journal\": \"Frontiers in neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 / Weak — cell viability is a single assay with no pathway placement; structural data is computational only; single case report\",\n      \"pmids\": [\"36846113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP85 promotes lipid accumulation in lipotoxic hepatocytes by modulating the SLC27A1/PPAR-γ signaling pathway, enhancing expression of lipid synthesis-related genes and inflammatory factors; siRNA-mediated knockdown of NUP85 in vivo alleviates hepatic steatosis and inflammation.\",\n      \"method\": \"siRNA knockdown in hepatocytes (in vitro) and HFD/MCD-diet mouse models (in vivo); mechanistic pathway analysis via SLC27A1/PPAR-γ gene expression\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro and in vivo knockdown with defined pathway readout, single lab, no reconstitution or direct binding evidence for the SLC27A1 link\",\n      \"pmids\": [\"41413582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NUP85 competitively binds ubiquitin-specific peptidase 47 (USP47) to apoptosis signal-regulating kinase 1 (ASK1), thereby preventing USP47-mediated deubiquitination at lysine residue 805 of ASK1 and activating ASK1, which drives endoplasmic reticulum stress and collagen deposition in liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation for NUP85-USP47 and NUP85-ASK1 interactions; site-specific mutagenesis identifying K805 on ASK1; NUP85 knockdown/overexpression with ERS and fibrosis readouts in cells and mice\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding and specific ubiquitination site identified by Co-IP and mutagenesis, with in vivo validation; single lab\",\n      \"pmids\": [\"41903125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila testes, Nup75 (the ortholog of human NUP85) controls proliferation of early germ cells but not differentiating spermatogonia, and is involved in keeping hub cells quiescent; lineage-specific depletion results in loss of the germline lineage.\",\n      \"method\": \"Lineage-specific RNAi knockdown in Drosophila testis; immunofluorescence and cell fate marker analysis\",\n      \"journal\": \"Cells & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean lineage-specific knockdown with defined proliferation and cell fate phenotype, but single Drosophila study with no mammalian validation\",\n      \"pmids\": [\"37286104\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP85 is a nuclear pore complex (NPC) Y-complex component required for NPC biogenesis and mitotic spindle integrity; in liver, NUP85 drives lipid accumulation and fibrosis by interacting with CCR2/PI3K-AKT and USP47-ASK1 signaling axes and by modulating the SLC27A1/PPAR-γ pathway, while loss-of-function variants in NUP85 reduce NPC number, impair mitotic spindle morphology, and decrease cell viability, causing steroid-resistant nephrotic syndrome, microcephaly, and Seckel syndrome spectrum disorders in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP85 is a nuclear pore complex (NPC) component required for normal NPC abundance and mitotic fidelity, and it additionally functions in hepatic lipid and fibrotic signaling [#1, #4]. Biallelic loss-of-function variants reduce the number of assembled NPCs without disrupting nucleocytoplasmic compartmentalization, while producing abnormal mitotic spindle morphology and decreased cell viability and proliferation in patient-derived fibroblasts, establishing a role in NPC number control and mitotic spindle integrity [#1]. In the liver, NUP85 acts as a driver of lipid accumulation and inflammation: it interacts with the chemokine receptor CCR2 to sustain PI3K/AKT phosphorylation, and modulates the SLC27A1/PPAR-\\u03b3 axis to upregulate lipid-synthesis and inflammatory genes, such that NUP85 knockdown alleviates hepatic steatosis [#0, #3]. NUP85 also promotes liver fibrosis by competitively binding USP47 away from ASK1, blocking deubiquitination of ASK1 at K805 and thereby activating ASK1-driven endoplasmic reticulum stress and collagen deposition [#4]. In Drosophila testes, the ortholog Nup75 controls early germ-cell proliferation and maintains hub-cell quiescence, with lineage-specific depletion causing germline loss [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that NUP85 controls NPC abundance and mitotic spindle integrity rather than acting primarily through bulk nucleocytoplasmic transport, reframing how its loss causes disease.\",\n      \"evidence\": \"Patient-derived fibroblast immunofluorescence for NPC number, transport assays, spindle imaging, and viability/proliferation assays\",\n      \"pmids\": [\"34170319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution or in vitro biochemistry defining NUP85's structural role in the Y-complex\", \"Mechanism linking reduced NPC number to spindle defects unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tested whether additional NUP85 missense variants impair function, linking patient genotypes to reduced viability and predicted disruption of neighboring nucleoporin contacts.\",\n      \"evidence\": \"Patient-derived fibroblast viability assay with computational structural modeling of variants\",\n      \"pmids\": [\"36846113\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cell viability is a single assay with no pathway placement\", \"Structural prediction is computational only without experimental validation\", \"Single case report\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended NUP85 function to tissue-specific stem cell regulation by showing the Drosophila ortholog governs early germ-cell proliferation and hub-cell quiescence.\",\n      \"evidence\": \"Lineage-specific RNAi knockdown in Drosophila testis with cell-fate marker immunofluorescence\",\n      \"pmids\": [\"37286104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mammalian validation of the germline role\", \"Molecular pathway connecting Nup75 to proliferation control not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-NPC signaling role: NUP85 interacts with CCR2 and sustains PI3K/AKT signaling to promote hepatic lipid accumulation and inflammation.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown in AML-12 cells and MCD-diet mouse model with signaling readouts\",\n      \"pmids\": [\"38617542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with limited orthogonal validation\", \"Direct vs indirect nature of CCR2 interaction not fully resolved\", \"How a nucleoporin engages a chemokine receptor mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a second hepatic lipid mechanism through the SLC27A1/PPAR-\\u03b3 axis, showing in vivo knockdown relieves steatosis and inflammation.\",\n      \"evidence\": \"siRNA knockdown in hepatocytes and HFD/MCD mouse models with SLC27A1/PPAR-\\u03b3 expression analysis\",\n      \"pmids\": [\"41413582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding evidence for the SLC27A1 link\", \"Relationship between this axis and the CCR2/PI3K-AKT axis unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mechanistically connected NUP85 to liver fibrosis via competitive binding to USP47, blocking ASK1 deubiquitination at K805 to activate ER stress and collagen deposition.\",\n      \"evidence\": \"Co-IP for NUP85-USP47 and NUP85-ASK1, site-specific mutagenesis of ASK1 K805, knockdown/overexpression with ERS and fibrosis readouts in cells and mice\",\n      \"pmids\": [\"41903125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without orthogonal structural validation of the competitive binding model\", \"How NUP85's nuclear pore role relates to cytoplasmic USP47/ASK1 regulation unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how NUP85's structural role at the nuclear pore mechanistically connects to its diverse cytoplasmic signaling functions in liver lipid metabolism and fibrosis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical reconstitution of NUP85 within the Y-complex in the corpus\", \"No unifying model linking NPC function to CCR2, SLC27A1/PPAR-\\u03b3, and USP47/ASK1 signaling\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"nuclear pore complex\"],\n    \"partners\": [\"CCR2\", \"USP47\", \"ASK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}