{"gene":"OSBPL11","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2010,"finding":"ORP11 localizes to the Golgi complex and late endosomes (co-localizing with GFP-Rab9, TGN46, GFP-Rab7, and a medial-trans-Golgi marker), and the N-terminal fragment (aa 1-292) contains the membrane-targeting determinants. The C-terminal ligand-binding domain (aa 273-747) is cytosolic.","method":"Fluorescence microscopy with GFP-tagged organelle markers, subcellular fractionation, overexpression of truncation mutants in HEK293 cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fluorescence microscopy with multiple organelle markers, functional consequence (lipid body formation upon overexpression), single lab","pmids":["20599956"],"is_preprint":false},{"year":2010,"finding":"ORP11 forms a heterodimer with ORP9 via interaction between aa 98-372 of ORP9 and aa 154-292 of ORP11. Overexpressed ORP9 recruits EGFP-ORP11 to membranes, and ORP9 silencing inhibits ORP11 Golgi association, establishing the ORP9-ORP11 dimer as a functional unit.","method":"Yeast two-hybrid screen, overexpression and co-localization in HEK293 cells, ORP9 siRNA silencing","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional validation by silencing, single lab, two orthogonal methods","pmids":["20599956"],"is_preprint":false},{"year":2007,"finding":"ORP11 (via its ORD domain) binds 25-hydroxycholesterol in live cells, as shown by photo-cross-linking with [3H]photo-25OH, indicating it is a sterol-binding protein with a conserved ligand-binding pocket.","method":"In vitro [3H]25OH-binding assay with recombinant proteins; live cell photo-cross-linking with [3H]photo-25OH in COS7 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay plus live-cell photo-cross-linking, single lab, two orthogonal methods","pmids":["17428193"],"is_preprint":false},{"year":2022,"finding":"Upon lysosomal membrane permeabilization (LMP), ORP11 (along with ORP9, ORP10, and OSBP) is recruited to damaged lysosomes via lysosomal phosphatidylinositol-4-phosphate generated by PI4K2A, forming new ER-lysosome membrane contact sites that mediate ER-to-lysosome transfer of phosphatidylserine and cholesterol to support lysosomal repair.","method":"Unbiased proteomics of damaged lysosomes, live imaging, functional lipid transport assays, LMP induction in cell culture","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteomic approach plus functional validation with lipid transfer assays, replicated across multiple ORP family members, high-impact journal","pmids":["36071159"],"is_preprint":false},{"year":2023,"finding":"ORP11 (with ORP9) localizes at ER-trans-Golgi network contact sites via interaction between ORP9's tandem α-helices and ORP10/ORP11. The ORP9-ORP11 complex extracts PI4P from the TGN to prevent its overaccumulation, thereby suppressing OSBP-mediated cholesterol transport to the Golgi.","method":"Genetic knockout, live fluorescence imaging, lipid mass spectrometry, epistasis experiments in cells depleted of ORP9 and/or GRAMD1s","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout studies with lipidomics and functional epistasis, multiple orthogonal methods, independent replication of ORP9-ORP11 interaction","pmids":["37735529"],"is_preprint":false},{"year":2024,"finding":"The ORP9-ORP11 heterodimer localizes at ER-trans-Golgi membrane contact sites and exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Loss of either ORP9 or ORP11 causes phospholipid imbalances in the Golgi that result in lowered sphingomyelin synthesis.","method":"Gene knockout library targeting 90 LTPs, whole-cell lipidomics, co-localization imaging, lipid transfer assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — gene knockout with whole-cell lipidomics plus mechanistic lipid transfer assays, multiple orthogonal methods in single rigorous study","pmids":["39106189"],"is_preprint":false},{"year":2019,"finding":"ORP11 knockdown in RAW264.7 macrophages abrogates the protective action of bis(monoacylglycero)phosphate (BMP) against oxidized LDL-induced apoptosis, causes accumulation of free cholesterol, decreases cholesterol efflux, and reduces ABCG1 expression, demonstrating that ORP11 cooperates with BMP in intracellular cholesterol trafficking at the late endosome.","method":"Stable shRNA knockdown in RAW264.7 macrophages, lipidomics (oxysterol measurement), cholesterol efflux assays, western blotting for ABCG1","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable knockdown with multiple functional readouts (lipidomics, efflux, apoptosis), single lab","pmids":["31136841"],"is_preprint":false},{"year":2012,"finding":"ORP11 silencing in differentiating SGBS adipocytes reduces adiponectin and aP2 mRNA expression and markedly decreases cellular triglyceride storage, demonstrating a functional role for ORP11 in adipocyte differentiation and lipid accumulation.","method":"siRNA knockdown during SGBS adipocyte differentiation, qRT-PCR, triglyceride content measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and gene expression readouts, single lab","pmids":["23028956"],"is_preprint":false},{"year":2025,"finding":"OSBPL11 knockdown accelerates mitotic slippage and represses cell death during mitotic arrest (induced by the Eg5 inhibitor STLC or paclitaxel), with decreased cyclin B1 levels in knockdown mitotic cells. Rescue with wild-type OSBPL11 but not lipid transport/binding mutants restores normal cell fate, and the APC/C inhibitor proTAME reverses the knockdown phenotype, placing OSBPL11's lipid transport activity upstream of APC/C-mediated cyclin B1 degradation.","method":"siRNA knockdown, rescue with wild-type and mutant OSBPL11, cyclin B1 immunoblotting, APC/C inhibition with proTAME, cell fate tracking","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus structure-function rescue with mutants plus epistasis with APC/C inhibitor, single lab","pmids":["41313943"],"is_preprint":false},{"year":2025,"finding":"In vitro binding assays and molecular docking showed that OSBPL11 is a vitamin D binding protein capable of binding vitamin D metabolites (25-hydroxyvitamin D). OSBPL11 knockdown in mice results in increased fat mass, reduced triglycerides, and improved glucose tolerance.","method":"In vitro binding assays, molecular docking, OSBPL11 knockdown mouse model with metabolic phenotyping","journal":"medRxiv (preprint) / Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro binding and docking (no mutagenesis validation), mouse KD phenotype without mechanistic pathway placement, single study","pmids":["40492082"],"is_preprint":false},{"year":2017,"finding":"Homozygous Arg171Trp variant in OSBPL11 causes intracellular cholesterol accumulation in skin fibroblasts and skin biopsy cells, demonstrating that functional OSBPL11 is required for normal intracellular cholesterol distribution. This effect was also seen in a clinically unaffected sibling homozygous for the variant, suggesting OSBPL11 loss-of-function causes a cholesterol trafficking defect without overt neurological disease.","method":"Filipin staining for free cholesterol in skin fibroblasts and biopsies from patients and carrier sibling with homozygous OSBPL11 variant","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional verification in patient-derived cells with filipin cholesterol staining, human genetics context, single study","pmids":["28051070"],"is_preprint":false}],"current_model":"OSBPL11 (ORP11) is a sterol- and phosphoinositide-binding lipid transfer protein that forms a heterodimer with ORP9 at ER–trans-Golgi network and ER–late endosome membrane contact sites, where it exchanges phosphatidylserine for PI(4)P to support sphingomyelin synthesis at the Golgi and maintain cellular cholesterol distribution; upon lysosomal damage, it is additionally recruited to damaged lysosomes via PI4K2A-generated PI4P to mediate ER-to-lysosome lipid transfer for membrane repair, and its lipid transport activity also influences mitotic cell fate by modulating APC/C-dependent cyclin B1 degradation."},"narrative":{"mechanistic_narrative":"OSBPL11 (ORP11) is a sterol- and phosphoinositide-binding lipid transfer protein that operates at endoplasmic reticulum membrane contact sites to control cellular lipid distribution [PMID:36071159, PMID:39106189]. It localizes to the Golgi complex and late endosomes through N-terminal targeting determinants, while its C-terminal ORD domain binds sterol ligands such as 25-hydroxycholesterol [PMID:20599956, PMID:17428193]. ORP11 functions obligately as a heterodimer with ORP9, which recruits it to membranes; loss of ORP9 abolishes ORP11 Golgi association [PMID:20599956]. At ER–trans-Golgi network contacts the ORP9–ORP11 complex exchanges phosphatidylserine for PI(4)P, extracting Golgi PI4P to support sphingomyelin synthesis and to restrain OSBP-mediated cholesterol transport [PMID:37735529, PMID:39106189]. Upon lysosomal membrane permeabilization, ORP11 is additionally recruited to damaged lysosomes via PI4K2A-generated PI4P, forming ER–lysosome contacts that deliver phosphatidylserine and cholesterol for membrane repair [PMID:36071159]. Consistent with these transport roles, ORP11 maintains intracellular cholesterol distribution: a homozygous Arg171Trp variant causes free cholesterol accumulation in patient fibroblasts, and ORP11 cooperates with BMP in late-endosomal cholesterol efflux in macrophages [PMID:28051070, PMID:31136841]. Its lipid transport activity also acts upstream of APC/C-dependent cyclin B1 degradation to influence mitotic cell fate [PMID:41313943].","teleology":[{"year":2007,"claim":"Established that ORP11 is a genuine sterol-binding protein, defining its ORD domain as a functional ligand-binding pocket rather than a structural vestige.","evidence":"In vitro [3H]25OH binding with recombinant protein plus live-cell photo-cross-linking with [3H]photo-25OH in COS7 cells","pmids":["17428193"],"confidence":"Medium","gaps":["Did not establish a transport function for the bound sterol","Cellular site of sterol binding not resolved"]},{"year":2010,"claim":"Defined ORP11's subcellular addresses (Golgi and late endosomes) and its domain architecture, and showed it acts as an obligate heterodimer with ORP9 that is required for membrane targeting.","evidence":"Fluorescence microscopy with organelle markers, truncation mutants, yeast two-hybrid, and ORP9 siRNA silencing in HEK293 cells","pmids":["20599956"],"confidence":"Medium","gaps":["The lipid species transported was not identified","Functional consequence of dimerization beyond localization unknown"]},{"year":2012,"claim":"Linked ORP11 to physiological lipid storage by showing it is required for adipocyte differentiation and triglyceride accumulation.","evidence":"siRNA knockdown during SGBS adipocyte differentiation with qRT-PCR and triglyceride measurement","pmids":["23028956"],"confidence":"Medium","gaps":["Molecular mechanism connecting ORP11 to adipogenic gene expression not defined","Direct lipid transport activity not measured"]},{"year":2017,"claim":"Provided human-genetic evidence that ORP11 function is required for normal intracellular cholesterol distribution.","evidence":"Filipin cholesterol staining of fibroblasts and biopsies from patients homozygous for the Arg171Trp variant","pmids":["28051070"],"confidence":"Medium","gaps":["Cellular pathway by which the variant disrupts cholesterol handling not defined","Variant present in clinically unaffected sibling, leaving genotype-phenotype relationship unclear"]},{"year":2019,"claim":"Placed ORP11 in late-endosomal cholesterol egress, showing it cooperates with BMP to support cholesterol efflux and protect against oxLDL-induced apoptosis.","evidence":"Stable shRNA knockdown in RAW264.7 macrophages with oxysterol lipidomics, cholesterol efflux assays, and ABCG1 immunoblotting","pmids":["31136841"],"confidence":"Medium","gaps":["Direct physical interaction with BMP not demonstrated","Mechanism of ABCG1 regulation not established"]},{"year":2022,"claim":"Revealed a stress-response role: ORP11 is recruited to damaged lysosomes via PI4K2A-generated PI4P to form ER-lysosome contacts that transfer lipids for membrane repair.","evidence":"Unbiased proteomics of damaged lysosomes, live imaging, and lipid transport assays after LMP induction","pmids":["36071159"],"confidence":"High","gaps":["Relative contributions of ORP9/ORP10/ORP11/OSBP not dissected","Quantitative repair kinetics attributable to ORP11 alone unknown"]},{"year":2023,"claim":"Defined the directional lipid logic at the TGN, showing ORP9-ORP11 extracts PI4P to suppress OSBP-mediated cholesterol delivery.","evidence":"Genetic knockout, live imaging, lipid mass spectrometry, and epistasis with ORP9/GRAMD1 depletion","pmids":["37735529"],"confidence":"High","gaps":["Regulation of contact-site assembly not defined","Counter-cargo for PI4P extraction not specified in this study"]},{"year":2024,"claim":"Identified the transported lipid pair, establishing ORP9-ORP11 as a PS/PI(4)P exchanger whose activity sustains Golgi sphingomyelin synthesis.","evidence":"Genome-scale LTP knockout screen, whole-cell lipidomics, co-localization, and lipid transfer assays","pmids":["39106189"],"confidence":"High","gaps":["Structural basis of PS/PI4P selectivity not resolved","Regulation linking exchange to sphingomyelin synthase activity unclear"]},{"year":2025,"claim":"Connected ORP11 lipid transport to mitotic cell-fate decisions, placing its activity upstream of APC/C-mediated cyclin B1 degradation.","evidence":"siRNA knockdown, structure-function rescue with lipid-transport mutants, cyclin B1 immunoblotting, and proTAME APC/C inhibition with cell-fate tracking","pmids":["41313943"],"confidence":"Medium","gaps":["Molecular link between membrane lipid transport and APC/C activity not defined","Site of action during mitosis not localized"]},{"year":2025,"claim":"Proposed ORP11 as a vitamin D binding protein with whole-animal metabolic consequences.","evidence":"In vitro binding assays, molecular docking, and OSBPL11 knockdown mouse metabolic phenotyping","pmids":["40492082"],"confidence":"Low","gaps":["Binding lacks mutagenesis validation and relies partly on docking","Mouse phenotype not connected to a defined molecular pathway","Physiological relevance of vitamin D binding not established"]},{"year":null,"claim":"How ORP11/ORP9 lipid exchange is mechanistically coupled to downstream effects on sphingomyelin synthase, ABCG1-dependent efflux, and APC/C remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the ORP9-ORP11 complex on membranes","Causal chain from lipid imbalance to cyclin B1 degradation undefined","Regulation of contact-site recruitment across organelles not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]}],"complexes":["ORP9-ORP11 heterodimer"],"partners":["OSBPL9","PI4K2A","OSBP","OSBPL10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXB4","full_name":"Oxysterol-binding protein-related protein 11","aliases":[],"length_aa":747,"mass_kda":83.6,"function":"Plays a role in regulating ADIPOQ and FABP4 levels in differentiating adipocytes and is also involved in regulation of adipocyte triglyceride storage (PubMed:23028956). Weakly binds 25-hydroxycholesterol (PubMed:17428193). Interacts with OSBPL9 to function as lipid transfer proteins (PubMed:39106189). Together they form a heterodimer that localizes at the ER-trans-Golgi membrane contact sites, and exchanges phosphatidylserine (1,2-diacyl-sn-glycero-3-phospho-L-serine, PS) for phosphatidylinositol-4-phosphate (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate), PI(4)P) between the two organelles, a step that is critical for sphingomyelin synthesis in the Golgi complex (PubMed:39106189)","subcellular_location":"Late endosome membrane; Golgi apparatus, trans-Golgi network membrane","url":"https://www.uniprot.org/uniprotkb/Q9BXB4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OSBPL11","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000144909","cell_line_id":"CID000413","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"OSBPL9","stoichiometry":10.0},{"gene":"VAPB","stoichiometry":4.0},{"gene":"VAPA","stoichiometry":0.2},{"gene":"OSBPL10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000413","total_profiled":1310},"omim":[{"mim_id":"620675","title":"LEUKODYSTROPHY, HYPOMYELINATING, 27; HLD27","url":"https://www.omim.org/entry/620675"},{"mim_id":"616404","title":"POLYMERASE I, RNA, SUBUNIT A; POLR1A","url":"https://www.omim.org/entry/616404"},{"mim_id":"606739","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 11; OSBPL11","url":"https://www.omim.org/entry/606739"},{"mim_id":"606738","title":"OXYSTEROL-BINDING PROTEIN-LIKE PROTEIN 10; OSBPL10","url":"https://www.omim.org/entry/606738"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":51.5},{"tissue":"tongue","ntpm":74.8}],"url":"https://www.proteinatlas.org/search/OSBPL11"},"hgnc":{"alias_symbol":["ORP-11","ORP11","FLJ13012","FLJ13164"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXB4","domains":[{"cath_id":"2.30.29.30","chopping":"60-163","consensus_level":"high","plddt":88.7901,"start":60,"end":163},{"cath_id":"2.40.160.120","chopping":"355-471_498-663","consensus_level":"high","plddt":89.6952,"start":355,"end":663}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXB4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXB4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXB4-F1-predicted_aligned_error_v6.png","plddt_mean":74.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OSBPL11","jax_strain_url":"https://www.jax.org/strain/search?query=OSBPL11"},"sequence":{"accession":"Q9BXB4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXB4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXB4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXB4"}},"corpus_meta":[{"pmid":"36071159","id":"PMC_36071159","title":"A 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The C-terminal ligand-binding domain (aa 273-747) is cytosolic.\",\n      \"method\": \"Fluorescence microscopy with GFP-tagged organelle markers, subcellular fractionation, overexpression of truncation mutants in HEK293 cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fluorescence microscopy with multiple organelle markers, functional consequence (lipid body formation upon overexpression), single lab\",\n      \"pmids\": [\"20599956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ORP11 forms a heterodimer with ORP9 via interaction between aa 98-372 of ORP9 and aa 154-292 of ORP11. Overexpressed ORP9 recruits EGFP-ORP11 to membranes, and ORP9 silencing inhibits ORP11 Golgi association, establishing the ORP9-ORP11 dimer as a functional unit.\",\n      \"method\": \"Yeast two-hybrid screen, overexpression and co-localization in HEK293 cells, ORP9 siRNA silencing\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional validation by silencing, single lab, two orthogonal methods\",\n      \"pmids\": [\"20599956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ORP11 (via its ORD domain) binds 25-hydroxycholesterol in live cells, as shown by photo-cross-linking with [3H]photo-25OH, indicating it is a sterol-binding protein with a conserved ligand-binding pocket.\",\n      \"method\": \"In vitro [3H]25OH-binding assay with recombinant proteins; live cell photo-cross-linking with [3H]photo-25OH in COS7 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay plus live-cell photo-cross-linking, single lab, two orthogonal methods\",\n      \"pmids\": [\"17428193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Upon lysosomal membrane permeabilization (LMP), ORP11 (along with ORP9, ORP10, and OSBP) is recruited to damaged lysosomes via lysosomal phosphatidylinositol-4-phosphate generated by PI4K2A, forming new ER-lysosome membrane contact sites that mediate ER-to-lysosome transfer of phosphatidylserine and cholesterol to support lysosomal repair.\",\n      \"method\": \"Unbiased proteomics of damaged lysosomes, live imaging, functional lipid transport assays, LMP induction in cell culture\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteomic approach plus functional validation with lipid transfer assays, replicated across multiple ORP family members, high-impact journal\",\n      \"pmids\": [\"36071159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ORP11 (with ORP9) localizes at ER-trans-Golgi network contact sites via interaction between ORP9's tandem α-helices and ORP10/ORP11. The ORP9-ORP11 complex extracts PI4P from the TGN to prevent its overaccumulation, thereby suppressing OSBP-mediated cholesterol transport to the Golgi.\",\n      \"method\": \"Genetic knockout, live fluorescence imaging, lipid mass spectrometry, epistasis experiments in cells depleted of ORP9 and/or GRAMD1s\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout studies with lipidomics and functional epistasis, multiple orthogonal methods, independent replication of ORP9-ORP11 interaction\",\n      \"pmids\": [\"37735529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The ORP9-ORP11 heterodimer localizes at ER-trans-Golgi membrane contact sites and exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Loss of either ORP9 or ORP11 causes phospholipid imbalances in the Golgi that result in lowered sphingomyelin synthesis.\",\n      \"method\": \"Gene knockout library targeting 90 LTPs, whole-cell lipidomics, co-localization imaging, lipid transfer assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — gene knockout with whole-cell lipidomics plus mechanistic lipid transfer assays, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39106189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ORP11 knockdown in RAW264.7 macrophages abrogates the protective action of bis(monoacylglycero)phosphate (BMP) against oxidized LDL-induced apoptosis, causes accumulation of free cholesterol, decreases cholesterol efflux, and reduces ABCG1 expression, demonstrating that ORP11 cooperates with BMP in intracellular cholesterol trafficking at the late endosome.\",\n      \"method\": \"Stable shRNA knockdown in RAW264.7 macrophages, lipidomics (oxysterol measurement), cholesterol efflux assays, western blotting for ABCG1\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable knockdown with multiple functional readouts (lipidomics, efflux, apoptosis), single lab\",\n      \"pmids\": [\"31136841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ORP11 silencing in differentiating SGBS adipocytes reduces adiponectin and aP2 mRNA expression and markedly decreases cellular triglyceride storage, demonstrating a functional role for ORP11 in adipocyte differentiation and lipid accumulation.\",\n      \"method\": \"siRNA knockdown during SGBS adipocyte differentiation, qRT-PCR, triglyceride content measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and gene expression readouts, single lab\",\n      \"pmids\": [\"23028956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OSBPL11 knockdown accelerates mitotic slippage and represses cell death during mitotic arrest (induced by the Eg5 inhibitor STLC or paclitaxel), with decreased cyclin B1 levels in knockdown mitotic cells. Rescue with wild-type OSBPL11 but not lipid transport/binding mutants restores normal cell fate, and the APC/C inhibitor proTAME reverses the knockdown phenotype, placing OSBPL11's lipid transport activity upstream of APC/C-mediated cyclin B1 degradation.\",\n      \"method\": \"siRNA knockdown, rescue with wild-type and mutant OSBPL11, cyclin B1 immunoblotting, APC/C inhibition with proTAME, cell fate tracking\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus structure-function rescue with mutants plus epistasis with APC/C inhibitor, single lab\",\n      \"pmids\": [\"41313943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vitro binding assays and molecular docking showed that OSBPL11 is a vitamin D binding protein capable of binding vitamin D metabolites (25-hydroxyvitamin D). OSBPL11 knockdown in mice results in increased fat mass, reduced triglycerides, and improved glucose tolerance.\",\n      \"method\": \"In vitro binding assays, molecular docking, OSBPL11 knockdown mouse model with metabolic phenotyping\",\n      \"journal\": \"medRxiv (preprint) / Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro binding and docking (no mutagenesis validation), mouse KD phenotype without mechanistic pathway placement, single study\",\n      \"pmids\": [\"40492082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Homozygous Arg171Trp variant in OSBPL11 causes intracellular cholesterol accumulation in skin fibroblasts and skin biopsy cells, demonstrating that functional OSBPL11 is required for normal intracellular cholesterol distribution. This effect was also seen in a clinically unaffected sibling homozygous for the variant, suggesting OSBPL11 loss-of-function causes a cholesterol trafficking defect without overt neurological disease.\",\n      \"method\": \"Filipin staining for free cholesterol in skin fibroblasts and biopsies from patients and carrier sibling with homozygous OSBPL11 variant\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional verification in patient-derived cells with filipin cholesterol staining, human genetics context, single study\",\n      \"pmids\": [\"28051070\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OSBPL11 (ORP11) is a sterol- and phosphoinositide-binding lipid transfer protein that forms a heterodimer with ORP9 at ER–trans-Golgi network and ER–late endosome membrane contact sites, where it exchanges phosphatidylserine for PI(4)P to support sphingomyelin synthesis at the Golgi and maintain cellular cholesterol distribution; upon lysosomal damage, it is additionally recruited to damaged lysosomes via PI4K2A-generated PI4P to mediate ER-to-lysosome lipid transfer for membrane repair, and its lipid transport activity also influences mitotic cell fate by modulating APC/C-dependent cyclin B1 degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OSBPL11 (ORP11) is a sterol- and phosphoinositide-binding lipid transfer protein that operates at endoplasmic reticulum membrane contact sites to control cellular lipid distribution [#3, #5]. It localizes to the Golgi complex and late endosomes through N-terminal targeting determinants, while its C-terminal ORD domain binds sterol ligands such as 25-hydroxycholesterol [#0, #2]. ORP11 functions obligately as a heterodimer with ORP9, which recruits it to membranes; loss of ORP9 abolishes ORP11 Golgi association [#1]. At ER\\u2013trans-Golgi network contacts the ORP9\\u2013ORP11 complex exchanges phosphatidylserine for PI(4)P, extracting Golgi PI4P to support sphingomyelin synthesis and to restrain OSBP-mediated cholesterol transport [#4, #5]. Upon lysosomal membrane permeabilization, ORP11 is additionally recruited to damaged lysosomes via PI4K2A-generated PI4P, forming ER\\u2013lysosome contacts that deliver phosphatidylserine and cholesterol for membrane repair [#3]. Consistent with these transport roles, ORP11 maintains intracellular cholesterol distribution: a homozygous Arg171Trp variant causes free cholesterol accumulation in patient fibroblasts, and ORP11 cooperates with BMP in late-endosomal cholesterol efflux in macrophages [#10, #6]. Its lipid transport activity also acts upstream of APC/C-dependent cyclin B1 degradation to influence mitotic cell fate [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that ORP11 is a genuine sterol-binding protein, defining its ORD domain as a functional ligand-binding pocket rather than a structural vestige.\",\n      \"evidence\": \"In vitro [3H]25OH binding with recombinant protein plus live-cell photo-cross-linking with [3H]photo-25OH in COS7 cells\",\n      \"pmids\": [\"17428193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish a transport function for the bound sterol\", \"Cellular site of sterol binding not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined ORP11's subcellular addresses (Golgi and late endosomes) and its domain architecture, and showed it acts as an obligate heterodimer with ORP9 that is required for membrane targeting.\",\n      \"evidence\": \"Fluorescence microscopy with organelle markers, truncation mutants, yeast two-hybrid, and ORP9 siRNA silencing in HEK293 cells\",\n      \"pmids\": [\"20599956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The lipid species transported was not identified\", \"Functional consequence of dimerization beyond localization unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ORP11 to physiological lipid storage by showing it is required for adipocyte differentiation and triglyceride accumulation.\",\n      \"evidence\": \"siRNA knockdown during SGBS adipocyte differentiation with qRT-PCR and triglyceride measurement\",\n      \"pmids\": [\"23028956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting ORP11 to adipogenic gene expression not defined\", \"Direct lipid transport activity not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided human-genetic evidence that ORP11 function is required for normal intracellular cholesterol distribution.\",\n      \"evidence\": \"Filipin cholesterol staining of fibroblasts and biopsies from patients homozygous for the Arg171Trp variant\",\n      \"pmids\": [\"28051070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular pathway by which the variant disrupts cholesterol handling not defined\", \"Variant present in clinically unaffected sibling, leaving genotype-phenotype relationship unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed ORP11 in late-endosomal cholesterol egress, showing it cooperates with BMP to support cholesterol efflux and protect against oxLDL-induced apoptosis.\",\n      \"evidence\": \"Stable shRNA knockdown in RAW264.7 macrophages with oxysterol lipidomics, cholesterol efflux assays, and ABCG1 immunoblotting\",\n      \"pmids\": [\"31136841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with BMP not demonstrated\", \"Mechanism of ABCG1 regulation not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a stress-response role: ORP11 is recruited to damaged lysosomes via PI4K2A-generated PI4P to form ER-lysosome contacts that transfer lipids for membrane repair.\",\n      \"evidence\": \"Unbiased proteomics of damaged lysosomes, live imaging, and lipid transport assays after LMP induction\",\n      \"pmids\": [\"36071159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of ORP9/ORP10/ORP11/OSBP not dissected\", \"Quantitative repair kinetics attributable to ORP11 alone unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the directional lipid logic at the TGN, showing ORP9-ORP11 extracts PI4P to suppress OSBP-mediated cholesterol delivery.\",\n      \"evidence\": \"Genetic knockout, live imaging, lipid mass spectrometry, and epistasis with ORP9/GRAMD1 depletion\",\n      \"pmids\": [\"37735529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of contact-site assembly not defined\", \"Counter-cargo for PI4P extraction not specified in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the transported lipid pair, establishing ORP9-ORP11 as a PS/PI(4)P exchanger whose activity sustains Golgi sphingomyelin synthesis.\",\n      \"evidence\": \"Genome-scale LTP knockout screen, whole-cell lipidomics, co-localization, and lipid transfer assays\",\n      \"pmids\": [\"39106189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PS/PI4P selectivity not resolved\", \"Regulation linking exchange to sphingomyelin synthase activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ORP11 lipid transport to mitotic cell-fate decisions, placing its activity upstream of APC/C-mediated cyclin B1 degradation.\",\n      \"evidence\": \"siRNA knockdown, structure-function rescue with lipid-transport mutants, cyclin B1 immunoblotting, and proTAME APC/C inhibition with cell-fate tracking\",\n      \"pmids\": [\"41313943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between membrane lipid transport and APC/C activity not defined\", \"Site of action during mitosis not localized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed ORP11 as a vitamin D binding protein with whole-animal metabolic consequences.\",\n      \"evidence\": \"In vitro binding assays, molecular docking, and OSBPL11 knockdown mouse metabolic phenotyping\",\n      \"pmids\": [\"40492082\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding lacks mutagenesis validation and relies partly on docking\", \"Mouse phenotype not connected to a defined molecular pathway\", \"Physiological relevance of vitamin D binding not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ORP11/ORP9 lipid exchange is mechanistically coupled to downstream effects on sphingomyelin synthase, ABCG1-dependent efflux, and APC/C remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the ORP9-ORP11 complex on membranes\", \"Causal chain from lipid imbalance to cyclin B1 degradation undefined\", \"Regulation of contact-site recruitment across organelles not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"ORP9-ORP11 heterodimer\"],\n    \"partners\": [\"OSBPL9\", \"PI4K2A\", \"OSBP\", \"OSBPL10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}