{"gene":"OSBPL6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2001,"finding":"ORP6 (OSBPL6) protein contains two major structural features: a highly conserved OSBP-type sterol-binding domain in the C-terminal half and a pleckstrin homology (PH) domain in the N-terminal region. ORP6 mRNA was upregulated ~2-fold in acetylated LDL-loaded human macrophages, suggesting sterol-regulated expression.","method":"cDNA sequencing, genomic structure analysis, Northern blot analysis of macrophage transcriptomes","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — structural characterization from cDNA sequence and a single expression experiment; no in vitro functional assay for ORP6 specifically","pmids":["11483621"],"is_preprint":false},{"year":2003,"finding":"ORP6 protein localizes primarily to the nuclear envelope in endogenous F9 embryonic carcinoma cells. When expressed from cDNA in cultured cells, ORP6 distributes between cytosol and ER membranes, with a minor portion at the plasma membrane. The N-terminal portion containing the PH domain has strong plasma membrane targeting specificity, while the C-terminal half remains largely cytosolic. ORP6 gene expression is induced upon differentiation of F9 cells into parietal endoderm.","method":"Monospecific peptide antibody immunostaining, truncated construct expression in cultured cells, subcellular fractionation, cDNA hybridization","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by antibody and truncation constructs, two orthogonal methods (immunostaining + fractionation), single lab","pmids":["14593528"],"is_preprint":false},{"year":2007,"finding":"ORP6 binds 25-hydroxycholesterol in live cells. Photo-cross-linking experiments with [3H]photo-25-hydroxycholesterol in live COS7 cells demonstrated that the ORD (OSBP-related ligand-binding domain) of ORP6 binds sterol. Both truncated ORD-only constructs and full-length ORP6 were cross-linked with photo-25OH.","method":"In vitro [3H]25-hydroxycholesterol binding assay with purified recombinant proteins; live cell photo-cross-linking with [3H]photo-25-hydroxycholesterol","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with recombinant protein plus live-cell photo-cross-linking, two orthogonal methods, demonstrated for ORP6 directly","pmids":["17428193"],"is_preprint":false},{"year":2016,"finding":"ORP6 localizes to the endolysosomal network and endoplasmic reticulum. OSBPL6 contains dual membrane- and ER-targeting motifs. Knockdown of OSBPL6 causes aberrant clustering of endosomes, accumulation of free cholesterol in endosomal structures, and reduced cholesterol esterification at the ER. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. ORP6 expression is transcriptionally regulated by liver X receptor and in response to cholesterol loading.","method":"Subcellular localization studies, siRNA knockdown with filipin staining and cholesterol esterification assays, ORP6 overexpression with cholesterol efflux assays, LXR agonist treatment","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined biochemical readouts (cholesterol esterification, efflux), multiple orthogonal methods, supported by localization data","pmids":["26941018"],"is_preprint":false},{"year":2018,"finding":"ORP6 localizes to the ER and ER-plasma membrane (ER-PM) contact sites in cerebellar granule neurons, co-localizing with the ER-PM contact site marker extended synaptotagmin 2 (E-Syt2). ORP6 physically interacts with ORP3 (via the intermediate region of ORP6) and forms a homodimer (ORP6-ORP6 interaction) as demonstrated by co-immunoprecipitation. Co-expression with ORP3 (but not ORP5) altered ORP6 distribution into neuronal processes. Knockdown of ORP6 shifted the PI4P marker from the Golgi to the plasma membrane, indicating ORP6 is involved in PI4P turnover at ER-PM contact sites.","method":"Deconvolution microscopy, co-immunoprecipitation, siRNA knockdown, PI4P marker (GFP-FAPP-PH) live imaging, dominant-negative construct expression","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for binding partners, direct localization with functional readout (PI4P redistribution upon knockdown), multiple orthogonal methods in single lab","pmids":["30028970"],"is_preprint":false},{"year":2018,"finding":"ORP6 mediates cholesterol transfer from endosomes to the ER at endosomal-organelle membrane contact sites, contributing to regulation of cholesterol homeostasis.","method":"Review summarizing experimental findings from referenced studies (ORP6 mentioned alongside ORP1L and ORP5 as mediating endosome-to-ER cholesterol transfer)","journal":"Current opinion in lipidology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper summarizing others' findings, no primary experiment described for ORP6 specifically in this paper","pmids":["29629999"],"is_preprint":false},{"year":2022,"finding":"ORP6 is involved in the counter-transport of phosphatidylinositol-4-phosphate (PI4P) and phosphatidylserine (PS) at ER-PM contact sites in neurons. Knockdown of ORP6 shifted PS marker localization but not filipin (cholesterol) in cerebellar neurons. A PI4KIIIα inhibitor that reduces PM PI4P suppressed ORP6 localization and PS marker at the PM. Overexpression of dominant-negative ORP6 (lacking ORD) shifted the PS marker away from PM. Introduction of full-length ORP6 (but not dominant-negative) rescued PS marker redistribution to PM caused by mutant PSS1 overexpression.","method":"Deconvolution microscopy of primary cultured cerebellar neurons, PI4KIIIα inhibitor treatment, mutant PSS1 overexpression, dominant-negative ORP6 constructs, PS marker (GFP-LactC2) and PI4P marker imaging","journal":"Biochemistry and biophysics reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological inhibition, dominant-negative, rescue experiment), direct lipid marker readouts, single lab","pmids":["35518199"],"is_preprint":false},{"year":2025,"finding":"Whole-body ablation of ORP6 (Osbpl6-/- mice) results in dysregulation of systemic and brain lipid homeostasis, with elevated brain desmosterol and amyloid-beta oligomers (AβOs). In astrocytes, ORP6 knockdown altered expression of cholesterol metabolism genes, promoted accumulation of esterified cholesterol in lipid droplets, reduced cholesterol efflux and plasma membrane cholesterol content, and increased amyloid-beta precursor protein (APP) processing.","method":"Osbpl6-/- mouse model, lipidomic analysis, ORP6 siRNA knockdown in astrocytes, cholesterol efflux assay, APP processing assay, lipid droplet staining","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout plus in vitro knockdown with multiple biochemical readouts (lipidomics, cholesterol efflux, APP processing), single lab with orthogonal methods","pmids":["40716750"],"is_preprint":false},{"year":2026,"finding":"PI4K2A physically interacts with ORP6/OSBPL6 as revealed by ER-membrane pulldown mass spectrometry (ER-MS) and immunoprecipitation mass spectrometry (IP-MS). This interaction leads to ORP6-mediated transport of phosphatidylserine (PS) to damaged lysosomal membranes following lysosomal membrane permeabilization (LMP), promoting lysosomal membrane repair. In vivo overexpression of PI4K2A reduced LMP-mediated lipid droplet accumulation and increased neuronal survival in a spinal cord injury model via an OSBPL6- and PS-dependent mechanism.","method":"ER-MS and IP-MS interaction analysis, co-immunoprecipitation, in vivo spinal cord injury mouse model, PI4K2A overexpression with OSBPL6 knockdown, lysosomal membrane permeabilization assays, lipid droplet quantification","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and MS for interaction, in vivo genetic epistasis (PI4K2A effect dependent on OSBPL6), multiple orthogonal methods in single lab","pmids":["41556583"],"is_preprint":false},{"year":2026,"finding":"ORP6 knockdown in oligodendrocytes caused loss of myelin structure in hippocampal neurons in a chronic stress-induced depression mouse model. Upregulation of OSBPL6 or enhancing OSBPL6 transcription improved myelin structure impairments. Restoring cholesterol transport with β-cyclodextrin decreased cholesterol accumulation and improved damaged myelin structure, suggesting ORP6 mediates cholesterol transport in oligodendrocytes to support myelin production.","method":"Single-nucleus RNA sequencing, oligodendrocyte-specific OSBPL6 knockdown (viral), OSBPL6 overexpression in vivo, β-cyclodextrin treatment, myelin structure analysis","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific loss- and gain-of-function with defined structural readout (myelin), but mechanistic link to cholesterol transport is inferred pharmacologically rather than directly measured","pmids":["41605285"],"is_preprint":false},{"year":2026,"finding":"ORP6 regulates neuronal morphology and migration of cerebellar granule cells (CGCs). ORP6 RNAi knockdown and overexpression of two different dominant-negative ORP6 constructs increased neurite number and length in differentiated Neuro-2A cells. ORP6 knockdown in primary CGCs increased neurite number and length and disrupted migration in vitro. In vivo electroporation of a dominant-negative ORP6 into immature CGCs impaired their migration into the granule layer during cerebellar development.","method":"RNAi knockdown, dominant-negative constructs, in vivo electroporation in mouse cerebellum, primary cultured cerebellar granule cell migration assays, neurite morphology quantification","journal":"Biochemistry and biophysics reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo electroporation plus in vitro knockdown and dominant-negative with consistent phenotype across multiple approaches and cell systems","pmids":["42004539"],"is_preprint":false}],"current_model":"ORP6 (OSBPL6) is a sterol/oxysterol-binding ER-localized lipid transfer protein that resides at membrane contact sites (ER-PM and ER-endolysosomal) where it counter-transports PI4P against phosphatidylserine and facilitates non-vesicular cholesterol trafficking; loss of ORP6 causes endosomal cholesterol accumulation, reduced ER cholesterol esterification, impaired lysosomal membrane repair, disrupted myelin cholesterol homeostasis, and defective cerebellar granule cell migration, while its interaction with PI4K2A and ORP3 positions it within a PI4P/PS exchange axis critical for neuronal lipid homeostasis."},"narrative":{"mechanistic_narrative":"OSBPL6 (ORP6) is a sterol/oxysterol-binding lipid transfer protein that operates at membrane contact sites to govern non-vesicular sterol and phospholipid trafficking in the service of cellular cholesterol homeostasis [PMID:17428193, PMID:26941018]. It carries an N-terminal pleckstrin homology domain with plasma-membrane targeting specificity and a C-terminal OSBP-related ligand-binding domain (ORD) that directly binds 25-hydroxycholesterol, with the protein distributing across the ER, endolysosomal network, nuclear envelope, and ER–plasma membrane contact sites [PMID:11483621, PMID:14593528, PMID:17428193, PMID:26941018, PMID:30028970]. At ER–PM contacts in neurons ORP6 mediates counter-transport of PI4P and phosphatidylserine: its localization and PS delivery depend on plasma-membrane PI4P, and dominant-negative ORD-deleted constructs disrupt PS positioning, placing ORP6 within a PI4P/PS exchange axis together with its partner ORP3, with which it also forms homodimers [PMID:30028970, PMID:35518199]. Through these contact-site activities ORP6 drives endosome-to-ER cholesterol movement and esterification; its loss causes endosomal clustering and free-cholesterol accumulation while its overexpression enhances cholesterol efflux, and its expression is induced by liver X receptor and sterol loading [PMID:26941018, PMID:40716750]. ORP6 interacts with PI4K2A to deliver phosphatidylserine to damaged lysosomal membranes, promoting lysosomal membrane repair and neuronal survival after injury [PMID:41556583]. These functions underlie tissue-level roles in the brain, where ORP6 supports myelin cholesterol homeostasis in oligodendrocytes, constrains amyloid-beta precursor protein processing in astrocytes, and is required for cerebellar granule cell neurite morphology and migration during development [PMID:40716750, PMID:41605285, PMID:42004539].","teleology":[{"year":2001,"claim":"Established the domain architecture predicting ORP6 as a sterol-binding protein and linked its expression to cellular sterol status.","evidence":"cDNA/genomic sequencing and Northern blot of sterol-loaded macrophages","pmids":["11483621"],"confidence":"Medium","gaps":["No direct ligand binding demonstrated","No functional assay for transport"]},{"year":2003,"claim":"Resolved where ORP6 acts by mapping endogenous protein to the nuclear envelope and showing PH-domain-driven plasma-membrane targeting versus cytosolic ORD.","evidence":"Peptide-antibody immunostaining, truncation constructs, and subcellular fractionation in cultured cells","pmids":["14593528"],"confidence":"Medium","gaps":["Discrepancy between endogenous nuclear-envelope and cDNA ER/PM localization unresolved","No contact-site assignment"]},{"year":2007,"claim":"Demonstrated that the ORD directly binds sterol, confirming ORP6 as a bona fide oxysterol-binding protein rather than a predicted one.","evidence":"In vitro [3H]25-hydroxycholesterol binding with recombinant protein and live-cell photo-cross-linking","pmids":["17428193"],"confidence":"High","gaps":["Binding affinity and selectivity among sterols not quantified","Did not show sterol transfer activity"]},{"year":2016,"claim":"Connected ORP6 to endosome-to-ER cholesterol flux by showing reciprocal loss/gain-of-function effects on cholesterol esterification and efflux.","evidence":"siRNA knockdown with filipin staining, esterification and efflux assays, LXR agonist treatment","pmids":["26941018"],"confidence":"High","gaps":["Direct cholesterol transfer not reconstituted in vitro","Contact-site tethering partners not identified"]},{"year":2018,"claim":"Placed ORP6 at ER-PM contact sites in a PI4P-turnover role and identified ORP3 binding and ORP6 homodimerization.","evidence":"Deconvolution microscopy, co-IP, siRNA knockdown with PI4P marker imaging, dominant-negative constructs","pmids":["30028970"],"confidence":"High","gaps":["Direction of lipid transport not yet defined","Functional role of homodimerization unclear"]},{"year":2022,"claim":"Defined ORP6 as a PI4P/PS counter-transporter at ER-PM contacts, distinguishing its lipid cargo at this site from cholesterol.","evidence":"PI4KIIIα inhibition, dominant-negative ORP6, PSS1-mutant rescue, and PS/PI4P marker imaging in cerebellar neurons","pmids":["35518199"],"confidence":"High","gaps":["In vitro PS/PI4P transfer not reconstituted","Stoichiometry of counter-transport unknown"]},{"year":2025,"claim":"Demonstrated organismal consequences of ORP6 loss, linking it to brain sterol dysregulation and amyloid pathology.","evidence":"Osbpl6-/- mouse lipidomics plus astrocyte knockdown with efflux, lipid droplet, and APP processing assays","pmids":["40716750"],"confidence":"High","gaps":["Mechanistic link between lipid transport defect and APP processing not fully resolved","Causality of Aβ accumulation versus secondary effects unclear"]},{"year":2026,"claim":"Identified PI4K2A as a partner directing ORP6-mediated PS delivery for lysosomal membrane repair, extending ORP6 function to organelle damage response.","evidence":"ER-MS/IP-MS, co-IP, in vivo spinal cord injury model with PI4K2A overexpression dependent on OSBPL6/PS","pmids":["41556583"],"confidence":"High","gaps":["Direct PS transfer to lysosomal membranes not reconstituted","Recruitment mechanism to damaged membranes undefined"]},{"year":2026,"claim":"Showed cell-type-specific roles for ORP6 in oligodendrocyte myelin cholesterol homeostasis and in cerebellar granule cell neurite morphology and migration.","evidence":"snRNA-seq, cell-type-specific viral knockdown/overexpression, β-cyclodextrin rescue, in vivo electroporation and migration assays","pmids":["41605285","42004539"],"confidence":"High","gaps":["Cholesterol-transport link in oligodendrocytes inferred pharmacologically, not directly measured","Molecular signaling coupling lipid transport to migration not defined"]},{"year":null,"claim":"How ORP6's distinct cargoes (sterol versus PI4P/PS) and its multiple contact-site localizations are coordinated and selected in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted transfer assay comparing sterol vs PS/PI4P","No structural model of cargo selection","No human disease mutation linkage in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,3,6]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[3,6,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,6,8]}],"complexes":[],"partners":["ORP3","OSBPL6","PI4K2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZF3","full_name":"Oxysterol-binding protein-related protein 6","aliases":[],"length_aa":934,"mass_kda":106.3,"function":"Regulates cellular transport and efflux of cholesterol (PubMed:26941018). Plays a role in phosphatidylinositol-4-phophate (PI4P) turnover at the neuronal membrane (By similarity). Binds via its PH domain PI4P, phosphatidylinositol-4,5-diphosphate, phosphatidylinositol-3,4,5-triphosphate, and phosphatidic acid (By similarity). Weakly binds 25-hydroxycholesterol (PubMed:17428193)","subcellular_location":"Cytoplasm, cytosol; Endoplasmic reticulum membrane; Nucleus envelope; Cell membrane; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9BZF3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OSBPL6","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STX6","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OSBPL6","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":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":31.4},{"tissue":"tongue","ntpm":19.0}],"url":"https://www.proteinatlas.org/search/OSBPL6"},"hgnc":{"alias_symbol":["ORP6"],"prev_symbol":[]},"alphafold":{"accession":"Q9BZF3","domains":[{"cath_id":"2.30.29.30","chopping":"72-190","consensus_level":"high","plddt":86.377,"start":72,"end":190},{"cath_id":"2.40.160.120","chopping":"572-928","consensus_level":"high","plddt":91.152,"start":572,"end":928}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZF3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZF3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZF3-F1-predicted_aligned_error_v6.png","plddt_mean":70.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OSBPL6","jax_strain_url":"https://www.jax.org/strain/search?query=OSBPL6"},"sequence":{"accession":"Q9BZF3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZF3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZF3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZF3"}},"corpus_meta":[{"pmid":"25122905","id":"PMC_25122905","title":"Characterization of transcriptomes of cochlear inner and outer hair cells.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25122905","citation_count":164,"is_preprint":false},{"pmid":"11483621","id":"PMC_11483621","title":"The OSBP-related protein family in humans.","date":"2001","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/11483621","citation_count":158,"is_preprint":false},{"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":"26830138","id":"PMC_26830138","title":"Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.","date":"2016","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26830138","citation_count":78,"is_preprint":false},{"pmid":"26941018","id":"PMC_26941018","title":"miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux.","date":"2016","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26941018","citation_count":65,"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":"10588946","id":"PMC_10588946","title":"Family of human oxysterol binding protein (OSBP) homologues. 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ORP6 mRNA was upregulated ~2-fold in acetylated LDL-loaded human macrophages, suggesting sterol-regulated expression.\",\n      \"method\": \"cDNA sequencing, genomic structure analysis, Northern blot analysis of macrophage transcriptomes\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — structural characterization from cDNA sequence and a single expression experiment; no in vitro functional assay for ORP6 specifically\",\n      \"pmids\": [\"11483621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ORP6 protein localizes primarily to the nuclear envelope in endogenous F9 embryonic carcinoma cells. When expressed from cDNA in cultured cells, ORP6 distributes between cytosol and ER membranes, with a minor portion at the plasma membrane. The N-terminal portion containing the PH domain has strong plasma membrane targeting specificity, while the C-terminal half remains largely cytosolic. ORP6 gene expression is induced upon differentiation of F9 cells into parietal endoderm.\",\n      \"method\": \"Monospecific peptide antibody immunostaining, truncated construct expression in cultured cells, subcellular fractionation, cDNA hybridization\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by antibody and truncation constructs, two orthogonal methods (immunostaining + fractionation), single lab\",\n      \"pmids\": [\"14593528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ORP6 binds 25-hydroxycholesterol in live cells. Photo-cross-linking experiments with [3H]photo-25-hydroxycholesterol in live COS7 cells demonstrated that the ORD (OSBP-related ligand-binding domain) of ORP6 binds sterol. Both truncated ORD-only constructs and full-length ORP6 were cross-linked with photo-25OH.\",\n      \"method\": \"In vitro [3H]25-hydroxycholesterol binding assay with purified recombinant proteins; live cell photo-cross-linking with [3H]photo-25-hydroxycholesterol\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with recombinant protein plus live-cell photo-cross-linking, two orthogonal methods, demonstrated for ORP6 directly\",\n      \"pmids\": [\"17428193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ORP6 localizes to the endolysosomal network and endoplasmic reticulum. OSBPL6 contains dual membrane- and ER-targeting motifs. Knockdown of OSBPL6 causes aberrant clustering of endosomes, accumulation of free cholesterol in endosomal structures, and reduced cholesterol esterification at the ER. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. ORP6 expression is transcriptionally regulated by liver X receptor and in response to cholesterol loading.\",\n      \"method\": \"Subcellular localization studies, siRNA knockdown with filipin staining and cholesterol esterification assays, ORP6 overexpression with cholesterol efflux assays, LXR agonist treatment\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined biochemical readouts (cholesterol esterification, efflux), multiple orthogonal methods, supported by localization data\",\n      \"pmids\": [\"26941018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ORP6 localizes to the ER and ER-plasma membrane (ER-PM) contact sites in cerebellar granule neurons, co-localizing with the ER-PM contact site marker extended synaptotagmin 2 (E-Syt2). ORP6 physically interacts with ORP3 (via the intermediate region of ORP6) and forms a homodimer (ORP6-ORP6 interaction) as demonstrated by co-immunoprecipitation. Co-expression with ORP3 (but not ORP5) altered ORP6 distribution into neuronal processes. Knockdown of ORP6 shifted the PI4P marker from the Golgi to the plasma membrane, indicating ORP6 is involved in PI4P turnover at ER-PM contact sites.\",\n      \"method\": \"Deconvolution microscopy, co-immunoprecipitation, siRNA knockdown, PI4P marker (GFP-FAPP-PH) live imaging, dominant-negative construct expression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for binding partners, direct localization with functional readout (PI4P redistribution upon knockdown), multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30028970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ORP6 mediates cholesterol transfer from endosomes to the ER at endosomal-organelle membrane contact sites, contributing to regulation of cholesterol homeostasis.\",\n      \"method\": \"Review summarizing experimental findings from referenced studies (ORP6 mentioned alongside ORP1L and ORP5 as mediating endosome-to-ER cholesterol transfer)\",\n      \"journal\": \"Current opinion in lipidology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper summarizing others' findings, no primary experiment described for ORP6 specifically in this paper\",\n      \"pmids\": [\"29629999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ORP6 is involved in the counter-transport of phosphatidylinositol-4-phosphate (PI4P) and phosphatidylserine (PS) at ER-PM contact sites in neurons. Knockdown of ORP6 shifted PS marker localization but not filipin (cholesterol) in cerebellar neurons. A PI4KIIIα inhibitor that reduces PM PI4P suppressed ORP6 localization and PS marker at the PM. Overexpression of dominant-negative ORP6 (lacking ORD) shifted the PS marker away from PM. Introduction of full-length ORP6 (but not dominant-negative) rescued PS marker redistribution to PM caused by mutant PSS1 overexpression.\",\n      \"method\": \"Deconvolution microscopy of primary cultured cerebellar neurons, PI4KIIIα inhibitor treatment, mutant PSS1 overexpression, dominant-negative ORP6 constructs, PS marker (GFP-LactC2) and PI4P marker imaging\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (pharmacological inhibition, dominant-negative, rescue experiment), direct lipid marker readouts, single lab\",\n      \"pmids\": [\"35518199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Whole-body ablation of ORP6 (Osbpl6-/- mice) results in dysregulation of systemic and brain lipid homeostasis, with elevated brain desmosterol and amyloid-beta oligomers (AβOs). In astrocytes, ORP6 knockdown altered expression of cholesterol metabolism genes, promoted accumulation of esterified cholesterol in lipid droplets, reduced cholesterol efflux and plasma membrane cholesterol content, and increased amyloid-beta precursor protein (APP) processing.\",\n      \"method\": \"Osbpl6-/- mouse model, lipidomic analysis, ORP6 siRNA knockdown in astrocytes, cholesterol efflux assay, APP processing assay, lipid droplet staining\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout plus in vitro knockdown with multiple biochemical readouts (lipidomics, cholesterol efflux, APP processing), single lab with orthogonal methods\",\n      \"pmids\": [\"40716750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PI4K2A physically interacts with ORP6/OSBPL6 as revealed by ER-membrane pulldown mass spectrometry (ER-MS) and immunoprecipitation mass spectrometry (IP-MS). This interaction leads to ORP6-mediated transport of phosphatidylserine (PS) to damaged lysosomal membranes following lysosomal membrane permeabilization (LMP), promoting lysosomal membrane repair. In vivo overexpression of PI4K2A reduced LMP-mediated lipid droplet accumulation and increased neuronal survival in a spinal cord injury model via an OSBPL6- and PS-dependent mechanism.\",\n      \"method\": \"ER-MS and IP-MS interaction analysis, co-immunoprecipitation, in vivo spinal cord injury mouse model, PI4K2A overexpression with OSBPL6 knockdown, lysosomal membrane permeabilization assays, lipid droplet quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and MS for interaction, in vivo genetic epistasis (PI4K2A effect dependent on OSBPL6), multiple orthogonal methods in single lab\",\n      \"pmids\": [\"41556583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ORP6 knockdown in oligodendrocytes caused loss of myelin structure in hippocampal neurons in a chronic stress-induced depression mouse model. Upregulation of OSBPL6 or enhancing OSBPL6 transcription improved myelin structure impairments. Restoring cholesterol transport with β-cyclodextrin decreased cholesterol accumulation and improved damaged myelin structure, suggesting ORP6 mediates cholesterol transport in oligodendrocytes to support myelin production.\",\n      \"method\": \"Single-nucleus RNA sequencing, oligodendrocyte-specific OSBPL6 knockdown (viral), OSBPL6 overexpression in vivo, β-cyclodextrin treatment, myelin structure analysis\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific loss- and gain-of-function with defined structural readout (myelin), but mechanistic link to cholesterol transport is inferred pharmacologically rather than directly measured\",\n      \"pmids\": [\"41605285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ORP6 regulates neuronal morphology and migration of cerebellar granule cells (CGCs). ORP6 RNAi knockdown and overexpression of two different dominant-negative ORP6 constructs increased neurite number and length in differentiated Neuro-2A cells. ORP6 knockdown in primary CGCs increased neurite number and length and disrupted migration in vitro. In vivo electroporation of a dominant-negative ORP6 into immature CGCs impaired their migration into the granule layer during cerebellar development.\",\n      \"method\": \"RNAi knockdown, dominant-negative constructs, in vivo electroporation in mouse cerebellum, primary cultured cerebellar granule cell migration assays, neurite morphology quantification\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo electroporation plus in vitro knockdown and dominant-negative with consistent phenotype across multiple approaches and cell systems\",\n      \"pmids\": [\"42004539\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ORP6 (OSBPL6) is a sterol/oxysterol-binding ER-localized lipid transfer protein that resides at membrane contact sites (ER-PM and ER-endolysosomal) where it counter-transports PI4P against phosphatidylserine and facilitates non-vesicular cholesterol trafficking; loss of ORP6 causes endosomal cholesterol accumulation, reduced ER cholesterol esterification, impaired lysosomal membrane repair, disrupted myelin cholesterol homeostasis, and defective cerebellar granule cell migration, while its interaction with PI4K2A and ORP3 positions it within a PI4P/PS exchange axis critical for neuronal lipid homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OSBPL6 (ORP6) is a sterol/oxysterol-binding lipid transfer protein that operates at membrane contact sites to govern non-vesicular sterol and phospholipid trafficking in the service of cellular cholesterol homeostasis [#2, #3]. It carries an N-terminal pleckstrin homology domain with plasma-membrane targeting specificity and a C-terminal OSBP-related ligand-binding domain (ORD) that directly binds 25-hydroxycholesterol, with the protein distributing across the ER, endolysosomal network, nuclear envelope, and ER–plasma membrane contact sites [#0, #1, #2, #3, #4]. At ER–PM contacts in neurons ORP6 mediates counter-transport of PI4P and phosphatidylserine: its localization and PS delivery depend on plasma-membrane PI4P, and dominant-negative ORD-deleted constructs disrupt PS positioning, placing ORP6 within a PI4P/PS exchange axis together with its partner ORP3, with which it also forms homodimers [#4, #6]. Through these contact-site activities ORP6 drives endosome-to-ER cholesterol movement and esterification; its loss causes endosomal clustering and free-cholesterol accumulation while its overexpression enhances cholesterol efflux, and its expression is induced by liver X receptor and sterol loading [#3, #7]. ORP6 interacts with PI4K2A to deliver phosphatidylserine to damaged lysosomal membranes, promoting lysosomal membrane repair and neuronal survival after injury [#8]. These functions underlie tissue-level roles in the brain, where ORP6 supports myelin cholesterol homeostasis in oligodendrocytes, constrains amyloid-beta precursor protein processing in astrocytes, and is required for cerebellar granule cell neurite morphology and migration during development [#7, #9, #10].\"\n}\n\nGiven the budget, I'll provide the full JSON:\n\n{\n  \"mechanistic_narrative\": \"OSBPL6 (ORP6) is a sterol/oxysterol-binding lipid transfer protein that operates at membrane contact sites to govern non-vesicular sterol and phospholipid trafficking in the service of cellular cholesterol homeostasis [#2, #3]. It carries an N-terminal pleckstrin homology domain with plasma-membrane targeting specificity and a C-terminal OSBP-related ligand-binding domain (ORD) that directly binds 25-hydroxycholesterol, with the protein distributing across the ER, endolysosomal network, nuclear envelope, and ER–plasma membrane contact sites [#0, #1, #2, #3, #4]. At ER–PM contacts in neurons ORP6 mediates counter-transport of PI4P and phosphatidylserine: its localization and PS delivery depend on plasma-membrane PI4P, and dominant-negative ORD-deleted constructs disrupt PS positioning, placing ORP6 within a PI4P/PS exchange axis together with its partner ORP3, with which it also forms homodimers [#4, #6]. Through these contact-site activities ORP6 drives endosome-to-ER cholesterol movement and esterification; its loss causes endosomal clustering and free-cholesterol accumulation while its overexpression enhances cholesterol efflux, and its expression is induced by liver X receptor and sterol loading [#3, #7]. ORP6 interacts with PI4K2A to deliver phosphatidylserine to damaged lysosomal membranes, promoting lysosomal membrane repair and neuronal survival after injury [#8]. These functions underlie tissue-level roles in the brain, where ORP6 supports myelin cholesterol homeostasis in oligodendrocytes, constrains amyloid-beta precursor protein processing in astrocytes, and is required for cerebellar granule cell neurite morphology and migration during development [#7, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the domain architecture predicting ORP6 as a sterol-binding protein and linked its expression to cellular sterol status.\",\n      \"evidence\": \"cDNA/genomic sequencing and Northern blot of sterol-loaded macrophages\",\n      \"pmids\": [\"11483621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ligand binding demonstrated\", \"No functional assay for transport\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved where ORP6 acts by mapping endogenous protein to the nuclear envelope and showing PH-domain-driven plasma-membrane targeting versus cytosolic ORD.\",\n      \"evidence\": \"Peptide-antibody immunostaining, truncation constructs, and subcellular fractionation in cultured cells\",\n      \"pmids\": [\"14593528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy between endogenous nuclear-envelope and cDNA ER/PM localization unresolved\", \"No contact-site assignment\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that the ORD directly binds sterol, confirming ORP6 as a bona fide oxysterol-binding protein rather than a predicted one.\",\n      \"evidence\": \"In vitro [3H]25-hydroxycholesterol binding with recombinant protein and live-cell photo-cross-linking\",\n      \"pmids\": [\"17428193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity and selectivity among sterols not quantified\", \"Did not show sterol transfer activity\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected ORP6 to endosome-to-ER cholesterol flux by showing reciprocal loss/gain-of-function effects on cholesterol esterification and efflux.\",\n      \"evidence\": \"siRNA knockdown with filipin staining, esterification and efflux assays, LXR agonist treatment\",\n      \"pmids\": [\"26941018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cholesterol transfer not reconstituted in vitro\", \"Contact-site tethering partners not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ORP6 at ER-PM contact sites in a PI4P-turnover role and identified ORP3 binding and ORP6 homodimerization.\",\n      \"evidence\": \"Deconvolution microscopy, co-IP, siRNA knockdown with PI4P marker imaging, dominant-negative constructs\",\n      \"pmids\": [\"30028970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction of lipid transport not yet defined\", \"Functional role of homodimerization unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined ORP6 as a PI4P/PS counter-transporter at ER-PM contacts, distinguishing its lipid cargo at this site from cholesterol.\",\n      \"evidence\": \"PI4KIIIα inhibition, dominant-negative ORP6, PSS1-mutant rescue, and PS/PI4P marker imaging in cerebellar neurons\",\n      \"pmids\": [\"35518199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro PS/PI4P transfer not reconstituted\", \"Stoichiometry of counter-transport unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated organismal consequences of ORP6 loss, linking it to brain sterol dysregulation and amyloid pathology.\",\n      \"evidence\": \"Osbpl6-/- mouse lipidomics plus astrocyte knockdown with efflux, lipid droplet, and APP processing assays\",\n      \"pmids\": [\"40716750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between lipid transport defect and APP processing not fully resolved\", \"Causality of Aβ accumulation versus secondary effects unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified PI4K2A as a partner directing ORP6-mediated PS delivery for lysosomal membrane repair, extending ORP6 function to organelle damage response.\",\n      \"evidence\": \"ER-MS/IP-MS, co-IP, in vivo spinal cord injury model with PI4K2A overexpression dependent on OSBPL6/PS\",\n      \"pmids\": [\"41556583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PS transfer to lysosomal membranes not reconstituted\", \"Recruitment mechanism to damaged membranes undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed cell-type-specific roles for ORP6 in oligodendrocyte myelin cholesterol homeostasis and in cerebellar granule cell neurite morphology and migration.\",\n      \"evidence\": \"snRNA-seq, cell-type-specific viral knockdown/overexpression, β-cyclodextrin rescue, in vivo electroporation and migration assays\",\n      \"pmids\": [\"41605285\", \"42004539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cholesterol-transport link in oligodendrocytes inferred pharmacologically, not directly measured\", \"Molecular signaling coupling lipid transport to migration not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ORP6's distinct cargoes (sterol versus PI4P/PS) and its multiple contact-site localizations are coordinated and selected in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reconstituted transfer assay comparing sterol vs PS/PI4P\", \"No structural model of cargo selection\", \"No human disease mutation linkage in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [3, 6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ORP3\", \"OSBPL6\", \"PI4K2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}