{"gene":"OSBPL7","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2007,"finding":"ORP7 (OSBPL7) binds 25-hydroxycholesterol via an evolutionarily conserved sterol-binding pocket in its OSBP-related ligand-binding domain (ORD), demonstrated by live-cell photo-cross-linking with [3H]photo-25OH in COS7 cells.","method":"In vitro [3H]25-hydroxycholesterol binding assay with purified recombinant proteins; live-cell photo-cross-linking with [3H]photo-25OH","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro ligand-binding assay with recombinant protein plus live-cell photo-cross-linking, two orthogonal methods in one study","pmids":["17428193"],"is_preprint":false},{"year":2003,"finding":"OSBPL7 (ORP7) protein distributes between the cytosol and ER membranes, with a minor fraction at the plasma membrane; the N-terminal PH-domain-containing region confers strong plasma membrane targeting, while the C-terminal ORD half remains largely cytosolic.","method":"Subcellular fractionation and expression of truncated constructs in cultured cells; immunolocalization","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation plus domain-mapping with truncation constructs, single lab","pmids":["14593528"],"is_preprint":false},{"year":2011,"finding":"ORP7 (OSBPL7) interacts with GATE-16 (GABARAPL2) through residues aa 1–142 of ORP7 and aa 30–117 of GATE-16, and this interaction mediates ORP7-dependent destabilization of the Golgi SNARE GS28 via proteasomal degradation. ORP7 knockdown increases GS28 protein ~40%, while ORP7 overexpression decreases it ~25%; a truncated ORP7 lacking the GATE-16-binding region fails to affect GS28 stability. 25-hydroxycholesterol treatment also destabilizes GS28, and this effect is potentiated by excess ORP7 and inhibited by ORP7 silencing. ORP7 overexpression causes formation of RFP-LC3-positive vacuolar structures containing GATE-16, indicating autophagosome association.","method":"Yeast two-hybrid screening; bimolecular fluorescence complementation (BiFC); siRNA knockdown and cDNA overexpression in 293A cells; truncation mutant analysis; immunoblotting; RFP-LC3 live-cell imaging","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by BiFC, knockdown/overexpression with domain-mapping controls, multiple orthogonal methods in one study","pmids":["21669198"],"is_preprint":false},{"year":2021,"finding":"OSBPL7 is the direct molecular target of 5-arylnicotinamide compounds that upregulate ABCA1-dependent cholesterol efflux; target engagement was established by photoactivatable compound cross-linking/immunoprecipitation in cells. Pharmacological targeting of OSBPL7 with these compounds induced ABCA1 expression and cholesterol efflux from podocytes in vitro and normalized proteinuria in mouse models of kidney disease.","method":"Photoactivatable compound cellular cross-linking/immunoprecipitation (chemical biology target-ID); in vitro cholesterol efflux assay; mouse models (Adriamycin nephropathy, Alport Syndrome)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — chemical biology target-ID (photo-crosslink/IP) combined with cellular and in vivo functional validation, replicated across two disease models","pmids":["34341345"],"is_preprint":false},{"year":2024,"finding":"OSBPL7 deficiency in podocytes causes ER stress-mediated apoptosis (not via reduced autophagic flux or lipid dysmetabolism) as the primary injury mechanism; osbpl7 knockdown in zebrafish induces proteinuria and glomerular damage. OSBPL7 deficiency also increases cellular triglyceride but not cholesterol content.","method":"siRNA knockdown in cultured podocytes; mouse CKD models with OSBPL7 reduction; zebrafish osbpl7 morpholino knockdown; ER stress markers; apoptosis assays; lipid droplet/triglyceride quantification; autophagic flux assays","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays with genetic knockdown plus in vivo zebrafish model, single lab, mechanistic pathway placement by exclusion of alternative pathways","pmids":["38961844"],"is_preprint":false},{"year":2024,"finding":"ORP7 (OSBPL7) interacts with AKT1 as identified by proximity biotinylation interactomics in primary HUVECs. Pharmacological ORP7 inhibition in HUVECs decreased ABCG1-mediated cholesterol efflux, reduced angiogenic tube formation, increased ceramides and lysophosphatidylcholines, decreased all cholesteryl ester species, and downregulated cell-cycle/division genes while upregulating lipid metabolism and proinflammatory genes.","method":"Proximity biotinylation interactomics (BioID); transcriptomics; lipidomics; cholesterol efflux assay; angiogenesis tube-formation assay; lipid droplet quantification","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics approach with functional assays in primary cells, single lab, interactomics identification of AKT1 partner not yet validated by orthogonal method","pmids":["39695567"],"is_preprint":false}],"current_model":"OSBPL7/ORP7 is an ER/plasma membrane-localized sterol-binding protein (binding 25-hydroxycholesterol via a conserved ORD pocket) whose N-terminal PH domain confers plasma membrane targeting; it interacts with GATE-16 (GABARAPL2) to promote proteasomal degradation of the Golgi SNARE GS28 and associates with autophagosomes, and also interacts with AKT1; it positively regulates ABCA1- and ABCG1-dependent cholesterol efflux, and its deficiency triggers ER stress-mediated podocyte apoptosis, proteinuria, and lipid dysregulation (elevated triglycerides)."},"narrative":{"mechanistic_narrative":"OSBPL7/ORP7 is a sterol-binding protein of the oxysterol-binding protein family that links sterol sensing to membrane traffic, autophagy-related machinery, and cholesterol efflux [PMID:17428193, PMID:21669198, PMID:34341345]. It binds 25-hydroxycholesterol through a conserved pocket in its C-terminal OSBP-related ligand-binding domain (ORD), while its N-terminal PH-domain region confers plasma membrane targeting; the protein partitions between cytosol, ER membranes, and a minor plasma membrane pool [PMID:17428193, PMID:14593528]. ORP7 interacts with the autophagy-related SNARE-modifier GATE-16 (GABARAPL2) via its N-terminal region, and this interaction drives proteasomal destabilization of the Golgi SNARE GS28; 25-hydroxycholesterol potentiates this effect, and ORP7 overexpression promotes association with LC3-positive autophagosomal structures, coupling sterol ligand status to SNARE turnover [PMID:21669198]. OSBPL7 is the direct molecular target of 5-arylnicotinamide compounds that upregulate ABCA1- and ABCG1-dependent cholesterol efflux, and it interacts with AKT1; pharmacological engagement induces cholesterol efflux from podocytes and endothelial cells, while its inhibition perturbs cellular lipid composition and angiogenesis [PMID:34341345, PMID:39695567]. Functionally, OSBPL7 deficiency triggers ER stress-mediated podocyte apoptosis, proteinuria, and elevated cellular triglyceride, establishing a role in podocyte and glomerular integrity [PMID:34341345, PMID:38961844].","teleology":[{"year":2003,"claim":"Established where ORP7 acts in the cell and which domain directs its localization, framing it as a membrane-associated protein with PH-domain-driven plasma membrane targeting.","evidence":"Subcellular fractionation and truncation-construct expression/immunolocalization in cultured cells","pmids":["14593528"],"confidence":"Medium","gaps":["The phosphoinositide or lipid recognized by the PH domain is not defined","Functional consequence of the ER versus plasma membrane pools is unresolved"]},{"year":2007,"claim":"Defined the molecular ligand of ORP7, showing its ORD binds 25-hydroxycholesterol through a conserved pocket and establishing it as a bona fide sterol-binding protein.","evidence":"In vitro [3H]25-hydroxycholesterol binding with recombinant protein plus live-cell photo-cross-linking in COS7 cells","pmids":["17428193"],"confidence":"High","gaps":["Whether sterol binding gates a transport or signaling activity was not addressed","No structural model of the bound pocket"]},{"year":2011,"claim":"Connected ORP7's sterol-sensing to membrane-traffic machinery by identifying GATE-16 as a partner and GS28 as a destabilized SNARE, with 25-hydroxycholesterol potentiating the effect.","evidence":"Yeast two-hybrid, BiFC, siRNA/overexpression with domain-mapping, immunoblotting, and RFP-LC3 imaging in 293A cells","pmids":["21669198"],"confidence":"High","gaps":["Direct ubiquitin-ligase or proteasome-targeting mechanism for GS28 not identified","Physiological consequence of GS28 turnover not established in vivo"]},{"year":2021,"claim":"Identified OSBPL7 as the direct druggable target of cholesterol-efflux-inducing compounds, linking it causally to ABCA1-dependent efflux and therapeutic correction of proteinuria.","evidence":"Photoactivatable compound cross-linking/IP target-ID, cholesterol efflux assays, and Adriamycin/Alport mouse models","pmids":["34341345"],"confidence":"High","gaps":["Molecular mechanism by which OSBPL7 represses ABCA1 expression is undefined","Whether sterol binding mediates the efflux regulation is not shown"]},{"year":2024,"claim":"Placed ER stress-mediated apoptosis as the primary injury pathway in OSBPL7-deficient podocytes, distinguishing it from autophagic or lipid-dysmetabolism mechanisms.","evidence":"siRNA knockdown in podocytes, mouse CKD models, zebrafish morpholino knockdown, ER stress/apoptosis markers and lipid quantification","pmids":["38961844"],"confidence":"Medium","gaps":["How OSBPL7 loss triggers ER stress mechanistically is unknown","Morpholino-based zebrafish phenotype awaits genetic confirmation"]},{"year":2024,"claim":"Extended OSBPL7 function to endothelial cholesterol efflux and angiogenesis and identified AKT1 as an interaction partner, broadening its lipid-handling and signaling roles.","evidence":"BioID proximity interactomics, lipidomics, transcriptomics, cholesterol efflux and tube-formation assays in primary HUVECs","pmids":["39695567"],"confidence":"Medium","gaps":["AKT1 interaction not validated by an orthogonal method","Functional significance of the OSBPL7-AKT1 association is not defined"]},{"year":null,"claim":"It remains unresolved how sterol binding mechanistically couples to OSBPL7's regulation of SNARE turnover, ABCA1/ABCG1-dependent efflux, and ER stress signaling within a unified model.","evidence":"No single study integrates the ligand-binding, traffic, and efflux functions mechanistically","pmids":[],"confidence":"Low","gaps":["No structure of the full-length protein or its complexes","Whether sterol transfer activity exists is undemonstrated","Direct molecular link between OSBPL7 and ABCA1/ABCG1 transcription not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[],"complexes":[],"partners":["GABARAPL2","AKT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZF2","full_name":"Oxysterol-binding protein-related protein 7","aliases":[],"length_aa":842,"mass_kda":95.4,"function":"","subcellular_location":"Cytoplasm, cytosol; Endoplasmic reticulum membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BZF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OSBPL7","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OSBPL7","total_profiled":1310},"omim":[{"mim_id":"606735","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 7; OSBPL7","url":"https://www.omim.org/entry/606735"},{"mim_id":"606734","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 6; OSBPL6","url":"https://www.omim.org/entry/606734"},{"mim_id":"606732","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 3; OSBPL3","url":"https://www.omim.org/entry/606732"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OSBPL7"},"hgnc":{"alias_symbol":["ORP7","MGC71150"],"prev_symbol":[]},"alphafold":{"accession":"Q9BZF2","domains":[{"cath_id":"2.30.29.30","chopping":"48-143","consensus_level":"high","plddt":88.8154,"start":48,"end":143},{"cath_id":"2.40.160.120","chopping":"501-836","consensus_level":"high","plddt":92.6778,"start":501,"end":836}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZF2-F1-predicted_aligned_error_v6.png","plddt_mean":70.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OSBPL7","jax_strain_url":"https://www.jax.org/strain/search?query=OSBPL7"},"sequence":{"accession":"Q9BZF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZF2"}},"corpus_meta":[{"pmid":"17428193","id":"PMC_17428193","title":"The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket.","date":"2007","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17428193","citation_count":127,"is_preprint":false},{"pmid":"34341345","id":"PMC_34341345","title":"Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34341345","citation_count":52,"is_preprint":false},{"pmid":"14593528","id":"PMC_14593528","title":"Subfamily III of mammalian oxysterol-binding protein (OSBP) homologues: the expression and intracellular localization of ORP3, ORP6, and ORP7.","date":"2003","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/14593528","citation_count":51,"is_preprint":false},{"pmid":"34785669","id":"PMC_34785669","title":"Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34785669","citation_count":30,"is_preprint":false},{"pmid":"21763455","id":"PMC_21763455","title":"Expression of oxysterol binding protein isoforms in opisthorchiasis-associated cholangiocarcinoma: a potential molecular marker for tumor metastasis.","date":"2011","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/21763455","citation_count":29,"is_preprint":false},{"pmid":"23028956","id":"PMC_23028956","title":"OSBP-related proteins (ORPs) in human adipose depots and cultured adipocytes: evidence for impacts on the adipocyte phenotype.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23028956","citation_count":21,"is_preprint":false},{"pmid":"21669198","id":"PMC_21669198","title":"OSBP-related protein 7 interacts with GATE-16 and negatively regulates GS28 protein stability.","date":"2011","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21669198","citation_count":18,"is_preprint":false},{"pmid":"34524948","id":"PMC_34524948","title":"Global Proximity Interactome of the Human Macroautophagy Pathway.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34524948","citation_count":10,"is_preprint":false},{"pmid":"38961844","id":"PMC_38961844","title":"Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria.","date":"2024","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38961844","citation_count":5,"is_preprint":false},{"pmid":"37901794","id":"PMC_37901794","title":"Clinical effects of novel susceptibility genes for beta-amyloid: a gene-based association study in the Korean population.","date":"2023","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37901794","citation_count":5,"is_preprint":false},{"pmid":"39695567","id":"PMC_39695567","title":"Functional omics of ORP7 in primary endothelial cells.","date":"2024","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/39695567","citation_count":4,"is_preprint":false},{"pmid":"36980993","id":"PMC_36980993","title":"Hypercholesterolemia in the Malaysian Cohort Participants: Genetic and Non-Genetic Risk Factors.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36980993","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8551,"output_tokens":1866,"usd":0.026822,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8736,"output_tokens":2477,"usd":0.052803,"stage2_stop_reason":"end_turn"},"total_usd":0.079625,"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\": 2007,\n      \"finding\": \"ORP7 (OSBPL7) binds 25-hydroxycholesterol via an evolutionarily conserved sterol-binding pocket in its OSBP-related ligand-binding domain (ORD), demonstrated by live-cell photo-cross-linking with [3H]photo-25OH in COS7 cells.\",\n      \"method\": \"In vitro [3H]25-hydroxycholesterol binding assay with purified recombinant proteins; live-cell photo-cross-linking with [3H]photo-25OH\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro ligand-binding assay with recombinant protein plus live-cell photo-cross-linking, two orthogonal methods in one study\",\n      \"pmids\": [\"17428193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OSBPL7 (ORP7) protein distributes between the cytosol and ER membranes, with a minor fraction at the plasma membrane; the N-terminal PH-domain-containing region confers strong plasma membrane targeting, while the C-terminal ORD half remains largely cytosolic.\",\n      \"method\": \"Subcellular fractionation and expression of truncated constructs in cultured cells; immunolocalization\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation plus domain-mapping with truncation constructs, single lab\",\n      \"pmids\": [\"14593528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ORP7 (OSBPL7) interacts with GATE-16 (GABARAPL2) through residues aa 1–142 of ORP7 and aa 30–117 of GATE-16, and this interaction mediates ORP7-dependent destabilization of the Golgi SNARE GS28 via proteasomal degradation. ORP7 knockdown increases GS28 protein ~40%, while ORP7 overexpression decreases it ~25%; a truncated ORP7 lacking the GATE-16-binding region fails to affect GS28 stability. 25-hydroxycholesterol treatment also destabilizes GS28, and this effect is potentiated by excess ORP7 and inhibited by ORP7 silencing. ORP7 overexpression causes formation of RFP-LC3-positive vacuolar structures containing GATE-16, indicating autophagosome association.\",\n      \"method\": \"Yeast two-hybrid screening; bimolecular fluorescence complementation (BiFC); siRNA knockdown and cDNA overexpression in 293A cells; truncation mutant analysis; immunoblotting; RFP-LC3 live-cell imaging\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by BiFC, knockdown/overexpression with domain-mapping controls, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21669198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OSBPL7 is the direct molecular target of 5-arylnicotinamide compounds that upregulate ABCA1-dependent cholesterol efflux; target engagement was established by photoactivatable compound cross-linking/immunoprecipitation in cells. Pharmacological targeting of OSBPL7 with these compounds induced ABCA1 expression and cholesterol efflux from podocytes in vitro and normalized proteinuria in mouse models of kidney disease.\",\n      \"method\": \"Photoactivatable compound cellular cross-linking/immunoprecipitation (chemical biology target-ID); in vitro cholesterol efflux assay; mouse models (Adriamycin nephropathy, Alport Syndrome)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chemical biology target-ID (photo-crosslink/IP) combined with cellular and in vivo functional validation, replicated across two disease models\",\n      \"pmids\": [\"34341345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBPL7 deficiency in podocytes causes ER stress-mediated apoptosis (not via reduced autophagic flux or lipid dysmetabolism) as the primary injury mechanism; osbpl7 knockdown in zebrafish induces proteinuria and glomerular damage. OSBPL7 deficiency also increases cellular triglyceride but not cholesterol content.\",\n      \"method\": \"siRNA knockdown in cultured podocytes; mouse CKD models with OSBPL7 reduction; zebrafish osbpl7 morpholino knockdown; ER stress markers; apoptosis assays; lipid droplet/triglyceride quantification; autophagic flux assays\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays with genetic knockdown plus in vivo zebrafish model, single lab, mechanistic pathway placement by exclusion of alternative pathways\",\n      \"pmids\": [\"38961844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ORP7 (OSBPL7) interacts with AKT1 as identified by proximity biotinylation interactomics in primary HUVECs. Pharmacological ORP7 inhibition in HUVECs decreased ABCG1-mediated cholesterol efflux, reduced angiogenic tube formation, increased ceramides and lysophosphatidylcholines, decreased all cholesteryl ester species, and downregulated cell-cycle/division genes while upregulating lipid metabolism and proinflammatory genes.\",\n      \"method\": \"Proximity biotinylation interactomics (BioID); transcriptomics; lipidomics; cholesterol efflux assay; angiogenesis tube-formation assay; lipid droplet quantification\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics approach with functional assays in primary cells, single lab, interactomics identification of AKT1 partner not yet validated by orthogonal method\",\n      \"pmids\": [\"39695567\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OSBPL7/ORP7 is an ER/plasma membrane-localized sterol-binding protein (binding 25-hydroxycholesterol via a conserved ORD pocket) whose N-terminal PH domain confers plasma membrane targeting; it interacts with GATE-16 (GABARAPL2) to promote proteasomal degradation of the Golgi SNARE GS28 and associates with autophagosomes, and also interacts with AKT1; it positively regulates ABCA1- and ABCG1-dependent cholesterol efflux, and its deficiency triggers ER stress-mediated podocyte apoptosis, proteinuria, and lipid dysregulation (elevated triglycerides).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OSBPL7/ORP7 is a sterol-binding protein of the oxysterol-binding protein family that links sterol sensing to membrane traffic, autophagy-related machinery, and cholesterol efflux [#0, #2, #3]. It binds 25-hydroxycholesterol through a conserved pocket in its C-terminal OSBP-related ligand-binding domain (ORD), while its N-terminal PH-domain region confers plasma membrane targeting; the protein partitions between cytosol, ER membranes, and a minor plasma membrane pool [#0, #1]. ORP7 interacts with the autophagy-related SNARE-modifier GATE-16 (GABARAPL2) via its N-terminal region, and this interaction drives proteasomal destabilization of the Golgi SNARE GS28; 25-hydroxycholesterol potentiates this effect, and ORP7 overexpression promotes association with LC3-positive autophagosomal structures, coupling sterol ligand status to SNARE turnover [#2]. OSBPL7 is the direct molecular target of 5-arylnicotinamide compounds that upregulate ABCA1- and ABCG1-dependent cholesterol efflux, and it interacts with AKT1; pharmacological engagement induces cholesterol efflux from podocytes and endothelial cells, while its inhibition perturbs cellular lipid composition and angiogenesis [#3, #5]. Functionally, OSBPL7 deficiency triggers ER stress-mediated podocyte apoptosis, proteinuria, and elevated cellular triglyceride, establishing a role in podocyte and glomerular integrity [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established where ORP7 acts in the cell and which domain directs its localization, framing it as a membrane-associated protein with PH-domain-driven plasma membrane targeting.\",\n      \"evidence\": \"Subcellular fractionation and truncation-construct expression/immunolocalization in cultured cells\",\n      \"pmids\": [\"14593528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The phosphoinositide or lipid recognized by the PH domain is not defined\", \"Functional consequence of the ER versus plasma membrane pools is unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the molecular ligand of ORP7, showing its ORD binds 25-hydroxycholesterol through a conserved pocket and establishing it as a bona fide sterol-binding protein.\",\n      \"evidence\": \"In vitro [3H]25-hydroxycholesterol binding with recombinant protein plus live-cell photo-cross-linking in COS7 cells\",\n      \"pmids\": [\"17428193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sterol binding gates a transport or signaling activity was not addressed\", \"No structural model of the bound pocket\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected ORP7's sterol-sensing to membrane-traffic machinery by identifying GATE-16 as a partner and GS28 as a destabilized SNARE, with 25-hydroxycholesterol potentiating the effect.\",\n      \"evidence\": \"Yeast two-hybrid, BiFC, siRNA/overexpression with domain-mapping, immunoblotting, and RFP-LC3 imaging in 293A cells\",\n      \"pmids\": [\"21669198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitin-ligase or proteasome-targeting mechanism for GS28 not identified\", \"Physiological consequence of GS28 turnover not established in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified OSBPL7 as the direct druggable target of cholesterol-efflux-inducing compounds, linking it causally to ABCA1-dependent efflux and therapeutic correction of proteinuria.\",\n      \"evidence\": \"Photoactivatable compound cross-linking/IP target-ID, cholesterol efflux assays, and Adriamycin/Alport mouse models\",\n      \"pmids\": [\"34341345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which OSBPL7 represses ABCA1 expression is undefined\", \"Whether sterol binding mediates the efflux regulation is not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed ER stress-mediated apoptosis as the primary injury pathway in OSBPL7-deficient podocytes, distinguishing it from autophagic or lipid-dysmetabolism mechanisms.\",\n      \"evidence\": \"siRNA knockdown in podocytes, mouse CKD models, zebrafish morpholino knockdown, ER stress/apoptosis markers and lipid quantification\",\n      \"pmids\": [\"38961844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How OSBPL7 loss triggers ER stress mechanistically is unknown\", \"Morpholino-based zebrafish phenotype awaits genetic confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended OSBPL7 function to endothelial cholesterol efflux and angiogenesis and identified AKT1 as an interaction partner, broadening its lipid-handling and signaling roles.\",\n      \"evidence\": \"BioID proximity interactomics, lipidomics, transcriptomics, cholesterol efflux and tube-formation assays in primary HUVECs\",\n      \"pmids\": [\"39695567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AKT1 interaction not validated by an orthogonal method\", \"Functional significance of the OSBPL7-AKT1 association is not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how sterol binding mechanistically couples to OSBPL7's regulation of SNARE turnover, ABCA1/ABCG1-dependent efflux, and ER stress signaling within a unified model.\",\n      \"evidence\": \"No single study integrates the ligand-binding, traffic, and efflux functions mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the full-length protein or its complexes\", \"Whether sterol transfer activity exists is undemonstrated\", \"Direct molecular link between OSBPL7 and ABCA1/ABCG1 transcription not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GABARAPL2\", \"AKT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}