{"gene":"NUP85","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2002,"finding":"NUP85 (also called Nup75 in some nomenclatures) was identified as a component of the mammalian nuclear pore complex (NPC) through mass spectrometry-based proteomic analysis of biochemically purified NPCs, classifying it as one of ~29 nucleoporins based on sequence homology and subcellular localization.","method":"Biochemical purification of NPCs followed by mass spectrometry and subcellular localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — proteomic identification in purified NPC fraction with localization confirmation, foundational study with >785 citations","pmids":["12196509"],"is_preprint":false},{"year":2004,"finding":"NUP85 was established as a core component of the Nup107-160 complex (a major NPC subcomplex), and the entire Nup107-160 complex — including NUP85 — was shown to relocalize to kinetochores from prophase to anaphase during mitosis, implicating NUP85 in mitotic chromosome segregation.","method":"GFP-tagged nucleoporin imaging, immunofluorescence with specific antibodies, RNA interference knockdown","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-complex membership established by biochemical isolation, live imaging, and RNAi phenotyping; >220 citations","pmids":["15146057"],"is_preprint":false},{"year":2013,"finding":"Integrated cryo-electron tomography and crosslinking mass spectrometry revealed that 32 copies of the Nup107 subcomplex (which includes NUP85) assemble into two reticulated rings at the cytoplasmic and nuclear faces of the human NPC, defining NUP85's structural position within the NPC scaffold.","method":"Electron tomography, single-particle EM, crosslinking mass spectrometry","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — integrated structural analysis with crosslinking MS and EM, >280 citations","pmids":["24315095"],"is_preprint":false},{"year":2014,"finding":"BioID proximity labeling applied to the Nup107-160 complex demonstrated a direct in vivo interaction between Nup43 and NUP85 within the NPC, and defined NUP85's spatial neighborhood within the NPC scaffold.","method":"BioID proximity-dependent biotinylation, mass spectrometry, expressed in living cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — proximity labeling in living cells with the NPC as molecular ruler; direct Nup43-NUP85 interaction demonstrated","pmids":["24927568"],"is_preprint":false},{"year":2021,"finding":"Biallelic loss-of-function variants in NUP85 in patient-derived cells caused a reduced number of nuclear pore complexes, abnormal mitotic spindle morphology, and decreased cell viability and proliferation, without altering bulk nucleocytoplasmic compartmentalization, expanding NUP85's disease spectrum to primary microcephaly and Seckel syndrome and linking NUP85 to nervous system development.","method":"Patient-derived fibroblast analysis, immunofluorescence for NPC number and mitotic spindle morphology, nucleocytoplasmic compartmentalization assay, cell viability assays, structural modeling","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in patient cells, single lab","pmids":["34170319"],"is_preprint":false},{"year":2024,"finding":"NUP85 was found to physically interact with C-C motif chemokine receptor 2 (CCR2) in hepatocytes; knockdown of NUP85 reduced CCR2 protein levels and inhibited PI3K/AKT signaling pathway phosphorylation, thereby alleviating lipid accumulation and inflammation in nonalcoholic fatty liver disease models.","method":"Co-immunoprecipitation, siRNA knockdown in AML-12 cells and MCD-diet mouse model, Western blotting for PI3K/AKT phosphorylation, lipid accumulation assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP interaction plus pathway readout in both in vitro and in vivo models, single lab","pmids":["38617542"],"is_preprint":false},{"year":2025,"finding":"NUP85 promotes hepatic lipid accumulation in lipotoxic hepatocytes by modulating the SLC27A1/PPAR-γ signaling pathway, enhancing expression of lipid synthesis genes and inflammatory factors; siRNA-mediated NUP85 silencing via RBC-derived extracellular vesicles alleviated hepatic steatosis in HFD and MCD mouse models.","method":"siRNA knockdown in vitro and in vivo (HFD/MCD mouse models), RBC-EV delivery system, gene expression analysis, lipid accumulation assays","journal":"Journal of nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vivo and in vitro KD with defined pathway readout, single lab","pmids":["41413582"],"is_preprint":false},{"year":2026,"finding":"NUP85 promotes liver fibrosis by competitively binding USP47 (ubiquitin-specific peptidase 47), thereby displacing it from ASK1 (apoptosis signal-regulating kinase 1) and preventing deubiquitination of ASK1 at lysine residue 805, which leads to ASK1 activation, enhanced collagen deposition, and exacerbated endoplasmic reticulum stress.","method":"Co-immunoprecipitation, competitive binding assays, site-specific ubiquitination analysis (K805 of ASK1), NUP85 knockdown and overexpression in liver fibrosis mouse models and cell lines","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, site-specific ubiquitination, KD/OE with phenotype) in single lab","pmids":["41903125"],"is_preprint":false}],"current_model":"NUP85 is a structural component of the Nup107-160 subcomplex of the nuclear pore complex, where it occupies defined positions in two reticulated rings, directly interacts with Nup43, and relocalizes to kinetochores during mitosis to support chromosome segregation; loss-of-function mutations reduce NPC number and cause abnormal mitotic spindle morphology linked to microcephaly and nephrotic syndrome, while in hepatocytes NUP85 additionally modulates lipid metabolism via SLC27A1/PPAR-γ and promotes liver fibrosis by competitively inhibiting USP47-mediated deubiquitination of ASK1 at K805."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing NUP85 as a bona fide nucleoporin resolved its identity as one of the ~29 proteins constituting the mammalian nuclear pore complex, providing the foundation for all subsequent functional studies.","evidence":"Biochemical purification of NPCs followed by mass spectrometry and subcellular localization in HeLa cells","pmids":["12196509"],"confidence":"High","gaps":["Subcomplex membership and direct binding partners were not defined","No functional data on NUP85 depletion phenotype"]},{"year":2004,"claim":"Demonstrating that NUP85 is a core member of the Nup107-160 subcomplex and that this entire complex relocalizes to kinetochores during mitosis established a dual role for NUP85 in both interphase nuclear transport and mitotic chromosome segregation.","evidence":"GFP-tagged nucleoporin live imaging, immunofluorescence, and RNAi knockdown in mammalian cells","pmids":["15146057"],"confidence":"High","gaps":["Precise position of NUP85 within the Nup107-160 complex was unknown","Mechanism by which NUP85 contributes to kinetochore function was not defined"]},{"year":2013,"claim":"Defining the stoichiometry and spatial arrangement of the Nup107-160 subcomplex within the intact NPC—32 copies forming two reticulated rings—positioned NUP85 within the three-dimensional NPC scaffold and explained how multiple copies contribute to NPC integrity.","evidence":"Cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry of human NPCs","pmids":["24315095"],"confidence":"High","gaps":["Atomic-resolution contacts between NUP85 and its immediate neighbors were not resolved","Functional consequence of disrupting NUP85's specific ring position was untested"]},{"year":2014,"claim":"BioID proximity labeling identified Nup43 as a direct in vivo neighbor of NUP85 within the NPC, establishing a specific molecular contact within the Nup107-160 subcomplex.","evidence":"BioID proximity-dependent biotinylation and mass spectrometry in living cells","pmids":["24927568"],"confidence":"High","gaps":["Whether Nup43 binding is required for NUP85 incorporation into the NPC was not tested","Full interaction surface and stoichiometry of the NUP85–Nup43 contact remain unresolved"]},{"year":2021,"claim":"Linking biallelic NUP85 loss-of-function variants to reduced NPC number, abnormal mitotic spindles, and primary microcephaly/Seckel syndrome established NUP85 as essential for nervous system development and demonstrated that its structural role has direct clinical consequences.","evidence":"Patient-derived fibroblast analysis with immunofluorescence for NPC number, mitotic spindle morphology, and cell viability assays","pmids":["34170319"],"confidence":"Medium","gaps":["Mechanism by which reduced NPC number leads to microcephaly is not defined","No rescue experiment restoring NUP85 expression in patient cells was reported","Bulk nucleocytoplasmic transport was unaffected, leaving the critical cargo or signaling deficit unknown"]},{"year":2024,"claim":"Identifying a physical interaction between NUP85 and CCR2 in hepatocytes, with NUP85 knockdown reducing CCR2 levels and PI3K/AKT signaling, revealed an NPC-independent role for NUP85 in hepatic lipid metabolism and inflammation.","evidence":"Co-immunoprecipitation and siRNA knockdown in AML-12 cells and MCD-diet mouse model with Western blot and lipid accumulation assays","pmids":["38617542"],"confidence":"Medium","gaps":["NUP85–CCR2 interaction lacks reciprocal validation or structural evidence","Whether this function requires NUP85 at the NPC or involves a soluble pool is unknown","Single-lab finding not independently replicated"]},{"year":2025,"claim":"Demonstrating that NUP85 promotes hepatic lipid accumulation through the SLC27A1/PPAR-γ axis defined a specific transcriptional and metabolic pathway downstream of NUP85 in lipotoxic hepatocytes.","evidence":"siRNA knockdown in vitro and in vivo (HFD/MCD mouse models) delivered via RBC-derived extracellular vesicles, with gene expression and lipid accumulation readouts","pmids":["41413582"],"confidence":"Medium","gaps":["Whether NUP85 directly regulates SLC27A1 transcription or acts indirectly is not resolved","Relationship between NPC structural role and metabolic function is unclear","Single-lab finding not independently replicated"]},{"year":2026,"claim":"Showing that NUP85 competitively displaces USP47 from ASK1 to prevent deubiquitination at K805, thereby promoting ASK1 activation and liver fibrosis, established a precise non-NPC mechanism through which NUP85 modulates ubiquitin signaling.","evidence":"Co-immunoprecipitation, competitive binding assays, site-specific ubiquitination analysis at ASK1 K805, knockdown and overexpression in liver fibrosis mouse models and cell lines","pmids":["41903125"],"confidence":"Medium","gaps":["Whether the NUP85–USP47 interaction occurs at the NPC or in the soluble pool is unknown","Structural basis for competitive displacement has not been determined","Single-lab finding; independent replication needed"]},{"year":null,"claim":"It remains unknown how NUP85's canonical NPC scaffold role and its emerging non-NPC functions in hepatic lipid metabolism and fibrosis are coordinated, and whether a soluble or NPC-associated pool of NUP85 mediates these distinct activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study has determined whether NUP85 exists in functionally distinct pools","Atomic-resolution structure of NUP85 in complex with its NPC neighbors is lacking","Mechanism linking reduced NPC number to microcephaly is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6]}],"complexes":["Nup107-160 complex","Nuclear pore complex"],"partners":["NUP43","CCR2","USP47","ASK1","SLC27A1"],"other_free_text":[]},"mechanistic_narrative":"NUP85 is a structural nucleoporin that functions as a core subunit of the Nup107-160 subcomplex, contributing to the scaffold architecture of the nuclear pore complex and relocalizing to kinetochores during mitosis to support chromosome segregation. Proteomic analysis of purified NPCs identified NUP85 as one of ~29 nucleoporins [PMID:12196509], and integrated cryo-electron tomography established that 32 copies of the Nup107-160 subcomplex—including NUP85—assemble into two reticulated rings at the cytoplasmic and nuclear faces of the NPC, with NUP85 directly contacting Nup43 [PMID:24315095, PMID:24927568]. Biallelic loss-of-function NUP85 variants reduce NPC number and cause abnormal mitotic spindle morphology, linking NUP85 to primary microcephaly and Seckel syndrome [PMID:34170319]. Beyond its canonical NPC role, NUP85 modulates hepatic lipid metabolism through the SLC27A1/PPAR-γ axis and promotes liver fibrosis by competitively displacing USP47 from ASK1, preventing deubiquitination at K805 and thereby activating ASK1-dependent collagen deposition [PMID:41413582, PMID:41903125]."},"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":"29232718","id":"PMC_29232718","title":"An 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heterochromatin.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26949251","citation_count":265,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23752268","id":"PMC_23752268","title":"The functional interactome landscape of the human histone deacetylase family.","date":"2013","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/23752268","citation_count":235,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30033366","id":"PMC_30033366","title":"Mapping the Genetic Landscape of Human Cells.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30033366","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15146057","id":"PMC_15146057","title":"The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15146057","citation_count":223,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6686,"output_tokens":1516,"usd":0.021399},"stage2":{"model":"claude-opus-4-6","input_tokens":4775,"output_tokens":2019,"usd":0.111525},"total_usd":0.318137,"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":18350,"output_tokens":3101,"usd":0.050783},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5524,"output_tokens":2480,"usd":0.13443}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant NUP85 in patient-derived cells is associated with a reduced number of nuclear pore complexes, abnormal mitotic spindle morphology, and decreased cell viability and proliferation, without altering nucleocytoplasmic compartmentalization, establishing NUP85's role in NPC architecture and mitosis in human cells.\",\n      \"method\": \"Patient-derived fibroblast analysis (NPC counting, mitotic spindle imaging, cell viability assay, nucleocytoplasmic transport assay)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cellular phenotyping in patient-derived cells with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34170319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Arabidopsis, NUP85 (plant ortholog) physically interacts with the mediator subunit MED18 and is associated with HOS1 and other nucleoporins within the nup107-160 complex, as revealed by immunoprecipitation and mass spectrometry; this interaction is required for ABA- and salt stress-responsive gene expression.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, direct protein-protein interaction assay (MED18–NUP85), forward genetics screen with luciferase reporter\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — plant ortholog with potential symbol collision context; mechanistic findings in Arabidopsis NUP85 are not directly transferable to human NUP85\",\n      \"pmids\": [\"29232718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human 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 (NUP85–CCR2 interaction), siRNA knockdown in AML-12 cells and MCD-diet mouse model, Western blot for PI3K/AKT phosphorylation\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP plus KD with defined signaling readout, two orthogonal model systems (in vitro and in vivo)\",\n      \"pmids\": [\"38617542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NUP85 competitively binds ubiquitin-specific peptidase USP47 to apoptosis signal-regulating kinase 1 (ASK1), prevents USP47-mediated deubiquitination at ASK1 lysine 805, thereby activating ASK1 and promoting endoplasmic reticulum stress and collagen deposition in liver fibrosis.\",\n      \"method\": \"Competitive binding/Co-IP assay (NUP85–USP47–ASK1 interaction), site-specific ubiquitination assay (K805), NUP85 KD and OE in liver fibrosis mouse model and cell lines\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with mechanistic detail (specific ubiquitination site, competitive binding), multiple models (in vitro/in vivo), but not independently replicated\",\n      \"pmids\": [\"41903125\"],\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, as demonstrated by siRNA-mediated NUP85 silencing in hepatocytes and HFD/MCD-diet mouse models.\",\n      \"method\": \"siRNA knockdown (RBC-EV delivered siNUP85), in vitro and in vivo (HFD/MCD mouse models), Western blot and gene expression for SLC27A1/PPAR-γ pathway\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, two orthogonal model systems (in vitro + in vivo), defined pathway placement via KD\",\n      \"pmids\": [\"41413582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel NUP85 missense variant (p.Arg460Gln) destabilizes the protein's helix bundle as predicted by molecular dynamics simulations, suggesting this structural perturbation underlies pathogenic effects in steroid-resistant nephrotic syndrome.\",\n      \"method\": \"Molecular dynamics simulation of NUP85 variant\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation\",\n      \"pmids\": [\"39949197\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP85 is a structural component of the nuclear pore complex Y-complex (nup107-160 complex) required for normal NPC number and mitotic spindle integrity; in disease contexts it interacts with CCR2 to activate PI3K/AKT signaling in lipid metabolism, competes with USP47 for ASK1 binding to regulate ASK1 ubiquitination and endoplasmic reticulum stress in liver fibrosis, and modulates the SLC27A1/PPAR-γ pathway to promote hepatic lipid accumulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers only.\n\n**Classification:**\n\n- Paper [1] (PMID:29232718): Arabidopsis NUP85 — plant gene, fundamentally different context (ABA/salt stress in plants). EXCLUDE — symbol collision with plant gene.\n- Paper [2] (PMID:38617542): Human NUP85 in NAFLD — KEEP\n- Paper [3] (PMID:34170319): Human NUP85 in microcephaly/Seckel — KEEP\n- Paper [4] (PMID:36846113): Human NUP85 in MCPH — KEEP\n- Paper [5] (PMID:38136965): Human NUP85 in SRNS/neurodevelopment — KEEP\n- Paper [6] (PMID:38952090): Human NUP85 in HCC — expression/biomarker study, no direct mechanism. EXCLUDE\n- Paper [7] (PMID:41413582): Human NUP85 in MASLD — KEEP (mechanistic: SLC27A1/PPAR-γ pathway)\n- Paper [8] (PMID:39949197): Human NUP85 variant in SRNS — KEEP\n- Paper [9] (PMID:37286104): Drosophila Nup75 (not NUP85 ortholog — Nup75 is a different nucleoporin). EXCLUDE\n- Paper [10] (PMID:40712764): WITHDRAWN. EXCLUDE\n- Paper [11] (PMID:41903125): Human NUP85 in liver fibrosis — KEEP\n\n**Gene2pubmed curated papers:**\n- PMID:16169070: Large Y2H screen, NUP85 may be incidentally included. No specific NUP85 mechanism described. EXCLUDE (no specific NUP85 finding extractable)\n- PMID:12477932: cDNA sequencing project. EXCLUDE\n- PMID:19615732: DUB interaction landscape — no specific NUP85 mechanism. EXCLUDE\n- PMID:18187620: HIV screen — no specific NUP85 mechanism. EXCLUDE\n- PMID:26186194: BioPlex network — NUP85 may appear but no specific mechanism. EXCLUDE\n- PMID:28514442: BioPlex 2.0 — same. EXCLUDE\n- PMID:26496610: Human interactome — same. EXCLUDE\n- PMID:32296183: HuRI — same. EXCLUDE\n- PMID:29507755: VIRMA/m6A — not about NUP85. EXCLUDE\n- PMID:12196509: Mammalian NPC proteomics — identifies NUP85 as NPC component. KEEP\n- PMID:14702039: FLJ cDNA sequencing. EXCLUDE\n- PMID:21873635: GO annotation. EXCLUDE\n- PMID:24927568: BioID of NPC — demonstrates direct Nup43-Nup85 interaction. KEEP\n- PMID:26638075: Centrosome-cilium BioID — NUP85 not central focus. EXCLUDE\n- PMID:35271311: OpenCell — localization resource. EXCLUDE (no specific NUP85 mechanism)\n- PMID:20360068: MitoCheck — NUP85 in chromosome segregation. KEEP\n- PMID:16344560: Alternative promoters. EXCLUDE\n- PMID:26344197: Metazoan complexes — NUP85 in conserved NPC complex. EXCLUDE (no specific mechanism)\n- PMID:8889548: cDNA normalization. EXCLUDE\n- PMID:34079125: BioID human cell map — localization resource. EXCLUDE\n- PMID:32838362: SARS-CoV-2 interactome — no specific NUP85 mechanism. EXCLUDE\n- PMID:24315095: Integrated structural analysis of human NPC. KEEP\n- PMID:22863882: Interactome temporal changes. EXCLUDE\n- PMID:26949251: Ki-67 heterochromatin. EXCLUDE\n- PMID:23752268: HDAC interactome. EXCLUDE\n- PMID:30033366: Genetic landscape mapping. EXCLUDE\n- PMID:15146057: Nup107-160 complex members and kinetochore targeting. KEEP\n- PMID:29568061: MAC-tag approach. EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"NUP85 (also called Nup75 in some nomenclatures) was identified as a component of the mammalian nuclear pore complex (NPC) through mass spectrometry-based proteomic analysis of biochemically purified NPCs, classifying it as one of ~29 nucleoporins based on sequence homology and subcellular localization.\",\n      \"method\": \"Biochemical purification of NPCs followed by mass spectrometry and subcellular localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — proteomic identification in purified NPC fraction with localization confirmation, foundational study with >785 citations\",\n      \"pmids\": [\"12196509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NUP85 was established as a core component of the Nup107-160 complex (a major NPC subcomplex), and the entire Nup107-160 complex — including NUP85 — was shown to relocalize to kinetochores from prophase to anaphase during mitosis, implicating NUP85 in mitotic chromosome segregation.\",\n      \"method\": \"GFP-tagged nucleoporin imaging, immunofluorescence with specific antibodies, RNA interference knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-complex membership established by biochemical isolation, live imaging, and RNAi phenotyping; >220 citations\",\n      \"pmids\": [\"15146057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Integrated cryo-electron tomography and crosslinking mass spectrometry revealed that 32 copies of the Nup107 subcomplex (which includes NUP85) assemble into two reticulated rings at the cytoplasmic and nuclear faces of the human NPC, defining NUP85's structural position within the NPC scaffold.\",\n      \"method\": \"Electron tomography, single-particle EM, crosslinking mass spectrometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — integrated structural analysis with crosslinking MS and EM, >280 citations\",\n      \"pmids\": [\"24315095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BioID proximity labeling applied to the Nup107-160 complex demonstrated a direct in vivo interaction between Nup43 and NUP85 within the NPC, and defined NUP85's spatial neighborhood within the NPC scaffold.\",\n      \"method\": \"BioID proximity-dependent biotinylation, mass spectrometry, expressed in living cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proximity labeling in living cells with the NPC as molecular ruler; direct Nup43-NUP85 interaction demonstrated\",\n      \"pmids\": [\"24927568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic loss-of-function variants in NUP85 in patient-derived cells caused a reduced number of nuclear pore complexes, abnormal mitotic spindle morphology, and decreased cell viability and proliferation, without altering bulk nucleocytoplasmic compartmentalization, expanding NUP85's disease spectrum to primary microcephaly and Seckel syndrome and linking NUP85 to nervous system development.\",\n      \"method\": \"Patient-derived fibroblast analysis, immunofluorescence for NPC number and mitotic spindle morphology, nucleocytoplasmic compartmentalization assay, cell viability assays, structural modeling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient cells, single lab\",\n      \"pmids\": [\"34170319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP85 was found to physically interact with C-C motif chemokine receptor 2 (CCR2) in hepatocytes; knockdown of NUP85 reduced CCR2 protein levels and inhibited PI3K/AKT signaling pathway phosphorylation, thereby alleviating lipid accumulation and inflammation in nonalcoholic fatty liver disease models.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown in AML-12 cells and MCD-diet mouse model, Western blotting for PI3K/AKT phosphorylation, lipid accumulation assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP interaction plus pathway readout in both in vitro and in vivo models, single lab\",\n      \"pmids\": [\"38617542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NUP85 promotes hepatic lipid accumulation in lipotoxic hepatocytes by modulating the SLC27A1/PPAR-γ signaling pathway, enhancing expression of lipid synthesis genes and inflammatory factors; siRNA-mediated NUP85 silencing via RBC-derived extracellular vesicles alleviated hepatic steatosis in HFD and MCD mouse models.\",\n      \"method\": \"siRNA knockdown in vitro and in vivo (HFD/MCD mouse models), RBC-EV delivery system, gene expression analysis, lipid accumulation assays\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vivo and in vitro KD with defined pathway readout, single lab\",\n      \"pmids\": [\"41413582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NUP85 promotes liver fibrosis by competitively binding USP47 (ubiquitin-specific peptidase 47), thereby displacing it from ASK1 (apoptosis signal-regulating kinase 1) and preventing deubiquitination of ASK1 at lysine residue 805, which leads to ASK1 activation, enhanced collagen deposition, and exacerbated endoplasmic reticulum stress.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, site-specific ubiquitination analysis (K805 of ASK1), NUP85 knockdown and overexpression in liver fibrosis mouse models and cell lines\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, site-specific ubiquitination, KD/OE with phenotype) in single lab\",\n      \"pmids\": [\"41903125\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP85 is a structural component of the Nup107-160 subcomplex of the nuclear pore complex, where it occupies defined positions in two reticulated rings, directly interacts with Nup43, and relocalizes to kinetochores during mitosis to support chromosome segregation; loss-of-function mutations reduce NPC number and cause abnormal mitotic spindle morphology linked to microcephaly and nephrotic syndrome, while in hepatocytes NUP85 additionally modulates lipid metabolism via SLC27A1/PPAR-γ and promotes liver fibrosis by competitively inhibiting USP47-mediated deubiquitination of ASK1 at K805.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP85 is a structural subunit of the Nup107-160 (Y-complex) sub-complex of the nuclear pore complex, required for normal NPC number and proper mitotic spindle morphology; mutant NUP85 in patient-derived cells reduces NPC density and impairs cell viability without disrupting nucleocytoplasmic compartmentalization [PMID:34170319]. Beyond its canonical nuclear pore role, NUP85 physically interacts with CCR2 to sustain PI3K/AKT signaling and promote hepatic lipid accumulation and inflammation [PMID:38617542], and modulates the SLC27A1/PPAR-γ pathway to enhance lipid synthesis gene expression in lipotoxic hepatocytes [PMID:41413582]. NUP85 also competitively binds USP47 at ASK1, blocking USP47-mediated deubiquitination of ASK1 at lysine 805 and thereby activating ASK1-dependent endoplasmic reticulum stress and collagen deposition in liver fibrosis [PMID:41903125]. Biallelic NUP85 mutations cause steroid-resistant nephrotic syndrome [PMID:34170319].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that the NUP85 ortholog in Arabidopsis physically associates with mediator subunit MED18 and other Nup107-160 complex members established that NUP85 bridges nuclear pore and transcriptional regulation machineries, though transferability to humans is uncertain.\",\n      \"evidence\": \"Immunoprecipitation and mass spectrometry of plant NUP85 complex in Arabidopsis\",\n      \"pmids\": [\"29232718\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Plant ortholog findings have not been validated for human NUP85\",\n        \"Whether human NUP85 similarly connects to Mediator is untested\",\n        \"Functional conservation of NUP85-Mediator coupling across kingdoms is uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Analysis of patient-derived cells carrying pathogenic NUP85 mutations resolved whether NUP85 is needed for NPC assembly versus transport: NPC number and mitotic spindle integrity depend on NUP85, but nucleocytoplasmic compartmentalization does not, establishing NUP85 as a structural scaffold rather than a transport-gating factor.\",\n      \"evidence\": \"NPC counting, mitotic spindle imaging, nucleocytoplasmic transport assays, and cell viability assays in patient fibroblasts\",\n      \"pmids\": [\"34170319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which reduced NUP85 leads to spindle defects is not delineated\",\n        \"Whether NPC density reduction is a direct structural consequence or secondary effect is unclear\",\n        \"Findings from a single patient genotype; allelic series not examined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CCR2 as a NUP85 physical interactor and demonstration that NUP85 knockdown suppresses PI3K/AKT phosphorylation revealed an unexpected non-canonical role for NUP85 in sustaining inflammatory and lipogenic signaling in NAFLD.\",\n      \"evidence\": \"Co-immunoprecipitation of NUP85–CCR2, siRNA knockdown in AML-12 hepatocytes and MCD-diet mouse model with PI3K/AKT Western blot readout\",\n      \"pmids\": [\"38617542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal IP and domain mapping of NUP85–CCR2 interaction not reported\",\n        \"Whether NUP85 stabilizes CCR2 at the pore or elsewhere is unresolved\",\n        \"Independence of CCR2 effect from NPC structural role not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that NUP85 silencing reduces SLC27A1/PPAR-γ pathway activity and lipid synthesis gene expression extended the hepatic lipid-regulatory role of NUP85 to a second, distinct signaling axis beyond CCR2/PI3K/AKT.\",\n      \"evidence\": \"siRNA-mediated NUP85 knockdown delivered via RBC-extracellular vesicles in hepatocytes and HFD/MCD-diet mouse models with pathway-specific readouts\",\n      \"pmids\": [\"41413582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP85 directly binds SLC27A1 or PPAR-γ versus indirect regulation is unknown\",\n        \"Relationship between CCR2/PI3K and SLC27A1/PPAR-γ axes downstream of NUP85 is not clarified\",\n        \"Specificity of NUP85 versus other Y-complex nucleoporins in lipid regulation is untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Elucidation of a competitive binding mechanism whereby NUP85 displaces USP47 from ASK1, preventing deubiquitination at K805, resolved how NUP85 activates ASK1 and drives ER stress and fibrosis — the first substrate-level mechanistic detail for NUP85 outside the NPC.\",\n      \"evidence\": \"Competitive binding/co-IP of NUP85–USP47–ASK1, site-specific ubiquitination assay at K805, NUP85 knockdown and overexpression in liver fibrosis mouse model and cell lines\",\n      \"pmids\": [\"41903125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for NUP85–USP47 competition at ASK1 is unknown\",\n        \"Whether this mechanism operates in contexts beyond liver fibrosis is untested\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how NUP85's canonical NPC/Y-complex scaffold role relates mechanistically to its non-canonical cytoplasmic signaling functions (CCR2/PI3K, SLC27A1/PPAR-γ, USP47/ASK1), and whether these reflect NPC-associated or NPC-independent pools of NUP85.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data for human NUP85 in the context of full NPC or its non-canonical partners\",\n        \"Subcellular pool-specific functions of NUP85 have not been dissected\",\n        \"Genotype–phenotype correlation across nephrotic syndrome alleles is incomplete\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\n      \"Nup107-160 complex (Y-complex)\"\n    ],\n    \"partners\": [\n      \"CCR2\",\n      \"USP47\",\n      \"ASK1\",\n      \"SLC27A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP85 is a structural nucleoporin that functions as a core subunit of the Nup107-160 subcomplex, contributing to the scaffold architecture of the nuclear pore complex and relocalizing to kinetochores during mitosis to support chromosome segregation. Proteomic analysis of purified NPCs identified NUP85 as one of ~29 nucleoporins [PMID:12196509], and integrated cryo-electron tomography established that 32 copies of the Nup107-160 subcomplex—including NUP85—assemble into two reticulated rings at the cytoplasmic and nuclear faces of the NPC, with NUP85 directly contacting Nup43 [PMID:24315095, PMID:24927568]. Biallelic loss-of-function NUP85 variants reduce NPC number and cause abnormal mitotic spindle morphology, linking NUP85 to primary microcephaly and Seckel syndrome [PMID:34170319]. Beyond its canonical NPC role, NUP85 modulates hepatic lipid metabolism through the SLC27A1/PPAR-γ axis and promotes liver fibrosis by competitively displacing USP47 from ASK1, preventing deubiquitination at K805 and thereby activating ASK1-dependent collagen deposition [PMID:41413582, PMID:41903125].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing NUP85 as a bona fide nucleoporin resolved its identity as one of the ~29 proteins constituting the mammalian nuclear pore complex, providing the foundation for all subsequent functional studies.\",\n      \"evidence\": \"Biochemical purification of NPCs followed by mass spectrometry and subcellular localization in HeLa cells\",\n      \"pmids\": [\"12196509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Subcomplex membership and direct binding partners were not defined\",\n        \"No functional data on NUP85 depletion phenotype\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that NUP85 is a core member of the Nup107-160 subcomplex and that this entire complex relocalizes to kinetochores during mitosis established a dual role for NUP85 in both interphase nuclear transport and mitotic chromosome segregation.\",\n      \"evidence\": \"GFP-tagged nucleoporin live imaging, immunofluorescence, and RNAi knockdown in mammalian cells\",\n      \"pmids\": [\"15146057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise position of NUP85 within the Nup107-160 complex was unknown\",\n        \"Mechanism by which NUP85 contributes to kinetochore function was not defined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the stoichiometry and spatial arrangement of the Nup107-160 subcomplex within the intact NPC—32 copies forming two reticulated rings—positioned NUP85 within the three-dimensional NPC scaffold and explained how multiple copies contribute to NPC integrity.\",\n      \"evidence\": \"Cryo-electron tomography, single-particle EM, and crosslinking mass spectrometry of human NPCs\",\n      \"pmids\": [\"24315095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution contacts between NUP85 and its immediate neighbors were not resolved\",\n        \"Functional consequence of disrupting NUP85's specific ring position was untested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"BioID proximity labeling identified Nup43 as a direct in vivo neighbor of NUP85 within the NPC, establishing a specific molecular contact within the Nup107-160 subcomplex.\",\n      \"evidence\": \"BioID proximity-dependent biotinylation and mass spectrometry in living cells\",\n      \"pmids\": [\"24927568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Nup43 binding is required for NUP85 incorporation into the NPC was not tested\",\n        \"Full interaction surface and stoichiometry of the NUP85–Nup43 contact remain unresolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking biallelic NUP85 loss-of-function variants to reduced NPC number, abnormal mitotic spindles, and primary microcephaly/Seckel syndrome established NUP85 as essential for nervous system development and demonstrated that its structural role has direct clinical consequences.\",\n      \"evidence\": \"Patient-derived fibroblast analysis with immunofluorescence for NPC number, mitotic spindle morphology, and cell viability assays\",\n      \"pmids\": [\"34170319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which reduced NPC number leads to microcephaly is not defined\",\n        \"No rescue experiment restoring NUP85 expression in patient cells was reported\",\n        \"Bulk nucleocytoplasmic transport was unaffected, leaving the critical cargo or signaling deficit unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying a physical interaction between NUP85 and CCR2 in hepatocytes, with NUP85 knockdown reducing CCR2 levels and PI3K/AKT signaling, revealed an NPC-independent role for NUP85 in hepatic lipid metabolism and inflammation.\",\n      \"evidence\": \"Co-immunoprecipitation and siRNA knockdown in AML-12 cells and MCD-diet mouse model with Western blot and lipid accumulation assays\",\n      \"pmids\": [\"38617542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NUP85–CCR2 interaction lacks reciprocal validation or structural evidence\",\n        \"Whether this function requires NUP85 at the NPC or involves a soluble pool is unknown\",\n        \"Single-lab finding not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that NUP85 promotes hepatic lipid accumulation through the SLC27A1/PPAR-γ axis defined a specific transcriptional and metabolic pathway downstream of NUP85 in lipotoxic hepatocytes.\",\n      \"evidence\": \"siRNA knockdown in vitro and in vivo (HFD/MCD mouse models) delivered via RBC-derived extracellular vesicles, with gene expression and lipid accumulation readouts\",\n      \"pmids\": [\"41413582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP85 directly regulates SLC27A1 transcription or acts indirectly is not resolved\",\n        \"Relationship between NPC structural role and metabolic function is unclear\",\n        \"Single-lab finding not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that NUP85 competitively displaces USP47 from ASK1 to prevent deubiquitination at K805, thereby promoting ASK1 activation and liver fibrosis, established a precise non-NPC mechanism through which NUP85 modulates ubiquitin signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, competitive binding assays, site-specific ubiquitination analysis at ASK1 K805, knockdown and overexpression in liver fibrosis mouse models and cell lines\",\n      \"pmids\": [\"41903125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the NUP85–USP47 interaction occurs at the NPC or in the soluble pool is unknown\",\n        \"Structural basis for competitive displacement has not been determined\",\n        \"Single-lab finding; independent replication needed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how NUP85's canonical NPC scaffold role and its emerging non-NPC functions in hepatic lipid metabolism and fibrosis are coordinated, and whether a soluble or NPC-associated pool of NUP85 mediates these distinct activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study has determined whether NUP85 exists in functionally distinct pools\",\n        \"Atomic-resolution structure of NUP85 in complex with its NPC neighbors is lacking\",\n        \"Mechanism linking reduced NPC number to microcephaly is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\n      \"Nup107-160 complex\",\n      \"Nuclear pore complex\"\n    ],\n    \"partners\": [\n      \"NUP43\",\n      \"CCR2\",\n      \"USP47\",\n      \"ASK1\",\n      \"SLC27A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}