{"gene":"OSBP","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2013,"finding":"OSBP drives a four-step cycle at ER-Golgi membrane contact sites: (1) membrane tethering via PH domain (binding Golgi PI(4)P) and FFAT motif (binding ER VAP-A); (2) anterograde sterol transfer by the ORD domain from ER to Golgi; (3) retrograde PI(4)P transfer from Golgi to ER by the ORD domain; (4) PI(4)P hydrolysis by the ER phosphatase Sac1, which provides thermodynamic driving force for net sterol transport against its concentration gradient.","method":"Reconstituted in vitro lipid transfer assay with liposomes, domain mutagenesis, fluorescence microscopy of tethering, epistasis with Sac1","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — full reconstitution in vitro with mechanistic dissection, multiple orthogonal methods, widely replicated","pmids":["24209621"],"is_preprint":false},{"year":2005,"finding":"The ORD (OSBP-related domain) of yeast Osh4 (OSBP ortholog) contains a hydrophobic tunnel that accommodates a single sterol molecule; a flexible N-terminal lid closes upon sterol binding, stabilizing a transport-competent conformation; basic residues at the tunnel entrance are critical for function; open-lid structure reveals phospholipid-binding sites for membrane docking.","method":"X-ray crystallography at 1.5–2.5 Å resolution with ergosterol, cholesterol, and multiple hydroxycholesterol ligands; limited proteolysis; mutagenesis of basic residues","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with multiple ligands plus functional mutagenesis in single rigorous study","pmids":["16136145"],"is_preprint":false},{"year":2005,"finding":"OSBP forms an ~440 kDa cytosolic oligomeric complex with the tyrosine phosphatase HePTP (a PTPPBS family member), the serine/threonine phosphatase PP2A, and cholesterol; this complex has dual-specificity phosphatase activity toward phosphorylated ERK1/2 (pERK). Cholesterol depletion or oxysterol addition causes complex disassembly and elevation of pERK levels.","method":"Co-immunoprecipitation, size-exclusion chromatography, in vitro phosphatase assay, cholesterol depletion/supplementation experiments, OSBP overexpression rescue","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, biochemical phosphatase assay, genetic rescue with OSBP overexpression, single lab but multiple orthogonal methods","pmids":["15746430"],"is_preprint":false},{"year":2007,"finding":"The sterol-binding domain of OSBP maps to a central 51-amino-acid region (residues 408–459) that binds both cholesterol and 25-hydroxycholesterol; a Y458S mutation impairs sterol binding. The N-terminal glycine-alanine-rich region works with the PH domain to selectively gate cholesterol (but not 25-hydroxycholesterol) binding in the context of full-length OSBP. HePTP binds a C-terminal coiled-coil domain (residues 732–761); PP2A binds the C-terminal half independently of the coiled-coil.","method":"Domain truncation and point mutagenesis, cholesterol and 25-hydroxycholesterol binding assays, co-immunoprecipitation mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assays with mutants plus Co-IP mapping, single lab, two orthogonal methods","pmids":["18165705"],"is_preprint":false},{"year":1998,"finding":"Cholesterol status regulates OSBP phosphorylation and its subcellular distribution: in cholesterol-replete cells OSBP is in the cytoplasm/vesicles; upon cholesterol depletion OSBP is dephosphorylated and constitutively localizes to the Golgi apparatus. 25-hydroxycholesterol-stimulated sphingomyelin synthesis requires both adequate cellular cholesterol and OSBP phosphorylation.","method":"Subcellular fractionation, immunofluorescence microscopy, [3H]serine incorporation into sphingomyelin, cholesterol depletion/repletion in CHO and SRD6 cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation and immunofluorescence plus functional lipid synthesis assay, single lab, multiple methods","pmids":["9806908"],"is_preprint":false},{"year":1999,"finding":"Overexpression of OSBP in CHO-K1 cells potentiates 25-hydroxycholesterol-stimulated sphingomyelin synthesis 2–3 fold; 25-hydroxycholesterol promotes translocation of OSBP to the Golgi apparatus where it stimulates conversion of ceramide to sphingomyelin; Golgi-enriched fractions from overexpressing cells show reduced diacylglycerol mass.","method":"[3H]serine and [3H]sphinganine incorporation assays, subcellular fractionation, immunofluorescence, in vitro enzyme activity assays","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional lipid synthesis assays in overexpression model with fractionation, single lab, multiple orthogonal readouts","pmids":["9869656"],"is_preprint":false},{"year":2017,"finding":"Endogenous OSBP is responsible for roughly half of total cellular PI(4)P consumption; blocking OSBP with OSW-1 causes sterol accumulation at ER/lipid droplets at the expense of the trans-Golgi network, reduces the lipid-order gradient along the secretory pathway, and uncouples PI4KIIIβ-driven PI(4)P production from OSBP-mediated consumption (generating traveling PI(4)P waves across the TGN).","method":"OSBP inhibition with OSW-1, live-cell PI(4)P and cholesterol reporters, lipidomics, fluorescence microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal live-cell reporters plus lipidomics, published independently confirming the cycle model from PMID 24209621","pmids":["28978670"],"is_preprint":false},{"year":2008,"finding":"OSBP negatively regulates ABCA1 protein stability in a sterol-binding-domain-dependent manner: OSBP knockdown increases ABCA1 protein half-life ~3-fold and enhances cholesterol efflux without affecting ABCA1 mRNA or LXR transcriptional activity; mutations abrogating OSBP sterol binding prevent ABCA1 destabilization, while mutations disrupting Golgi or ER targeting do not.","method":"RNAi knockdown, protein half-life assay, co-transfection with domain mutants, cholesterol efflux assay, quantitative RT-PCR, LXR reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi plus mutagenesis rescue, multiple readouts, single lab","pmids":["18450749"],"is_preprint":false},{"year":2008,"finding":"7-ketocholesterol activates STAT3 in aortic endothelial cells via JAK2 and requires tyrosine-394 phosphorylation of OSBP1, leading to STAT3-dependent up-regulation of profilin-1 expression; the same pathway is activated in the aorta of diabetic rats.","method":"Luciferase reporter assay, phospho-specific antibodies, JAK2 inhibition, site-directed mutagenesis of OSBP1 Y394, chromatin immunoprecipitation, in vivo diabetic rat model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation site, ChIP, functional reporter, single lab with in vitro and in vivo confirmation","pmids":["18230613"],"is_preprint":false},{"year":2013,"finding":"OSBP is required for the perinuclear localization of intra-Golgi v-SNAREs GS28 and GS15; OSBP depletion by siRNA mislocalizes GS28/GS15 throughout the cytoplasm and reduces Golgi mannosidase II abundance. All three functional domains (ER-targeting FFAT, Golgi-targeting PH, sterol-binding ORD) are required. The OSBP-dependent GS28 mislocalization is rescued by co-depletion of ArfGAP1, implicating COPI vesicle budding as a downstream effector.","method":"siRNA knockdown, immunofluorescence, domain mutant rescue, genetic epistasis with ArfGAP1 double knockdown","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA, domain-mutant rescue, epistasis with ArfGAP1, single lab with multiple orthogonal readouts","pmids":["24048449"],"is_preprint":false},{"year":2019,"finding":"A ~90 aa intrinsically disordered (Gly-Pro-Ala-rich) N-terminal sequence in OSBP acts as an entropic barrier: it prevents the two PH domains of the OSBP dimer from homotypically tethering two Golgi-like membranes, facilitates OSBP in-plane diffusion at membrane contact sites, and promotes its recycling. Its hydrodynamic radius is twice that of folded domains.","method":"In vitro reconstitution with liposomes, FRAP, cryo-electron microscopy of membrane contact sites, hydrodynamic radius measurements, truncation mutants","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, FRAP, and structural analysis with truncation mutants in one study; single lab but multiple rigorous methods","pmids":["30905771"],"is_preprint":false},{"year":2021,"finding":"Cryo-tomography of a reconstituted in vitro membrane contact site reveals that VAP-A is a highly flexible ER transmembrane protein allowing variable intermembrane distances; the tethering region of the OSBP dimer adopts a central dimeric helical T-shaped structure, and this geometry facilitates movement of the two lipid-transfer ORD domains between the apposed membranes.","method":"Cryo-electron tomography and subtomogram averaging of in vitro reconstituted MCS with two lipid bilayers, VAP-A, and OSBP","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-tomography structural determination of reconstituted MCS, single lab but rigorous structural method with functional interpretation","pmids":["34103503"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of the lipid transfer domain (ORD) of human OSBP in complex with endogenous cholesterol shows that cholesterol's hydrocarbon tail and tetracyclic ring occupy a hydrophobic tunnel while the hydroxyl group forms a hydrogen-bond network at the tunnel bottom. Systematic mutagenesis (M446W, L590W) identified residues that confer tolerance to the inhibitor T-00127-HEV2, and use of the M446W variant as a functional replacement revealed additional residues required for enterovirus replication.","method":"X-ray crystallography of human OSBP ORD–cholesterol complex, site-directed mutagenesis, viral replication assay with inhibitor resistance","journal":"ACS infectious diseases","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of human protein with systematic mutagenesis and functional viral replication validation, single lab","pmids":["35613096"],"is_preprint":false},{"year":2015,"finding":"The natural compound OSW-1 (and structurally unrelated itraconazole) inhibit enterovirus replication by directly targeting OSBP; OSBP overexpression rescues viral replication in the presence of OSW-1, establishing OSBP as an essential host factor for enterovirus genome replication.","method":"OSBP overexpression rescue of antiviral inhibition, dose-response viral replication assays across multiple cell types and enterovirus strains","journal":"Antiviral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue (overexpression) directly links OSW-1 antiviral activity to OSBP, replicated across multiple viruses and cell lines","pmids":["25752737"],"is_preprint":false},{"year":2018,"finding":"Aichi virus (a picornavirus) directly recruits the cholesterol transport machinery (OSBP, VAP-A/B, SAC1) to viral RNA replication organelles through protein–protein interactions between viral proteins (2B, 2BC, 2C, 3A, 3AB), ACBD3, OSBP, VAP, and SAC1; the OSBP–2B interaction enables PI(4)P-independent OSBP recruitment; cholesterol accumulates at replication organelles, and inhibition of OSBP-mediated cholesterol transfer impairs RNA replication.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence co-localization, electron microscopy, cholesterol staining, OSBP inhibitor treatment","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs, siRNA knockdown with functional readout, EM, single lab with orthogonal methods","pmids":["29367253"],"is_preprint":false},{"year":2019,"finding":"Salmonella effector SseJ binds OSBP1 and, together with another SPI-2 effector SseL, recruits OSBP1 to the Salmonella-containing vacuole in a SPI-2 TTSS-dependent manner; knockdown of OSBP1 or deletion of VAPA/B (OSBP1-binding ER proteins) reduces vacuolar integrity and increases cytoplasmic bacterial release, demonstrating OSBP1 is required for vacuole membrane stability during intracellular Salmonella infection.","method":"Co-immunoprecipitation (SseJ–OSBP1 interaction), OSBP1 siRNA knockdown, VAPA/B deletion, fluorescence microscopy of vacuolar integrity, bacterial localization assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi knockdown with functional vacuolar integrity readout, genetic deletion of VAP, single lab","pmids":["31091452"],"is_preprint":false},{"year":2024,"finding":"OSBP is the direct, phenotypically relevant target of the antileukemic compound orpinolide; orpinolide disrupts Golgi homeostasis via a mechanism requiring active PI(4)P signaling at the ER-Golgi membrane interface; thermal proteome profiling and genome-scale CRISPR-Cas9 screens confirmed OSBP as the direct target.","method":"Thermal proteome profiling, genome-scale CRISPR-Cas9 screens, multiomics profiling, Golgi morphology assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — thermal proteome profiling (unbiased target ID) combined with genome-scale CRISPR genetic validation, multiple orthogonal methods","pmids":["38907113"],"is_preprint":false},{"year":2024,"finding":"OSBP inhibition by oxybipins blocks retrograde trafficking and causes partial Golgi degradation in lysosomes; a biophysical sterol transport protein assay panel confirmed oxybipins potently and selectively inhibit OSBP without affecting other sterol transporters; OSBP inhibition attenuates Shiga toxin toxicity by blocking retrograde transport.","method":"Sterol transport protein biophysical assay panel, retrograde trafficking assay, Shiga toxin cytotoxicity assay, proteomics of Golgi protein degradation, glycosylation analysis","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biophysical transfer assay panel plus functional retrograde trafficking and toxin assays with selective compounds; single lab with multiple orthogonal methods","pmids":["38907112"],"is_preprint":false},{"year":2024,"finding":"OSBP is recruited to ER–insulin secretory granule contact sites in a Ca2+-dependent manner, regulated positively by PI4-kinases and negatively by the PI(4)P phosphatase Sac2; OSBP-mediated PI(4)P–cholesterol exchange at these contacts is required for glucose-stimulated insulin secretion; both acute pharmacologic inhibition and siRNA knockdown of OSBP suppress insulin secretion without affecting intracellular Ca2+ signaling.","method":"Live-cell imaging of OSBP at ER-granule contacts, siRNA knockdown, pharmacologic inhibition, glucose-stimulated insulin secretion assay, Ca2+ imaging","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging of recruitment plus genetic and pharmacologic knockdown with functional secretion assay; single lab, multiple methods","pmids":["38536815"],"is_preprint":false},{"year":2024,"finding":"Modulating OSBP levels at ER:Golgi membrane contact sites produces reciprocal changes in Golgi PI(4)P levels; OSBP has high capacity for PI(4)P turnover even at orthologous organelle membranes; endogenous OSBP does not significantly affect PI(4)P levels at the plasma membrane, establishing OSBP as a major, compartment-selective determinant of Golgi PI(4)P homeostasis.","method":"Acute and chronic genetic manipulation of OSBP expression, orthogonal organelle targeting, genetically-encoded PI(4)P biosensors","journal":"Contact","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulations with quantitative PI(4)P biosensors, single lab, multiple approaches","pmids":["38405037"],"is_preprint":false},{"year":2025,"finding":"OSBP participates in lysosome transport in neurons: oxidative stress reduces OSBP protein levels, leading to lysosomal PI(4)P accumulation that disrupts anterograde lysosome transport. OSBP overexpression restores PI(4)P/PI(3)P balance, improves Arl8 binding to lysosomes (shown by protein–liposome binding assay), increases lysosome localization in neurites, and promotes axonal injury repair in vivo.","method":"H2O2-induced oxidative stress model, OSBP overexpression and knockdown, PI(4)P/PI(3)P measurements, protein–liposome binding assay, live imaging of lysosome transport, AAV in vivo delivery in TBI mouse model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with multiple methods; single lab but orthogonal approaches including binding assay and AAV mouse model","pmids":["39915357"],"is_preprint":false},{"year":2010,"finding":"In Drosophila, OSBP works together with the testis-specific VAP protein FAN (genetically and physically) to regulate sterol trafficking during spermatid individualization; OSBP-positive, sterol-enriched speckles appear at the leading edge of the individualization complex in wild-type but not in Osbp or fan mutants; male sterility of Osbp mutants is partially rescued by dietary sterol supplementation.","method":"Drosophila genetic mutant analysis, co-immunoprecipitation of OSBP–FAN interaction, immunofluorescence of sterol-enriched speckles, fertility rescue with dietary sterols","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo, physical interaction by Co-IP, functional rescue; single lab","pmids":["20943709"],"is_preprint":false},{"year":2008,"finding":"OSBP1 overexpression downregulates amyloidogenic processing of APP (reducing Aβ production), while OSBP1 knockdown has the opposite effect; OSBP1 causes accumulation of APP-Notch2 dimers in the Golgi, an effect reversed by 25-hydroxycholesterol treatment, linking OSBP1 sterol-sensing to APP trafficking.","method":"OSBP1 overexpression and RNAi knockdown, APP processing/Aβ quantification, immunofluorescence of APP-Notch2 localization, 25-hydroxycholesterol treatment","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with functional APP processing readout, single lab","pmids":["18348724"],"is_preprint":false},{"year":2018,"finding":"OSBP knockdown in pancreatic β-cells reduces insulin granule stability (young granules are lost to lysosomal degradation) and suppresses glucose-stimulated insulin secretion; these effects were not rescued by exogenous cholesterol, distinguishing OSBP's proximal ER function from downstream ABC transporter-dependent cholesterol concentrating steps. Dual knockdown of OSBP and ABCG1 or ABCA1 supports their serial function in cholesterol supply for granule formation.","method":"RNAi knockdown, insulin granule tracking, glucose-stimulated insulin secretion assay, cholesterol supplementation rescue, dual knockdown epistasis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with multiple functional readouts and epistasis experiments, single lab","pmids":["29540530"],"is_preprint":false},{"year":2011,"finding":"Salmonella infection causes redistribution of OSBP; the SPI-2 effector SseL binds the N-terminus of OSBP; OSBP is required for efficient intracellular replication of S. Typhimurium.","method":"Co-immunoprecipitation mapping of SseL–OSBP interaction, immunofluorescence of OSBP redistribution upon infection, OSBP knockdown and bacterial replication assay","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction mapping, RNAi knockdown with bacterial replication readout, single lab","pmids":["21988961"],"is_preprint":false},{"year":2005,"finding":"OSBP knockdown by siRNA (~90% reduction) does not affect 25-hydroxycholesterol-induced inhibition of HMG-CoA reductase or squalene epoxidase transcription, demonstrating that OSBP is not required for 25-HC-mediated suppression of cholesterol biosynthesis gene transcription.","method":"siRNA knockdown (~90% reduction), RT-PCR of sterol-regulated genes, 25-HC treatment","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic knockdown with quantitative gene expression readout; negative result well-controlled, single lab","pmids":["16098143"],"is_preprint":false},{"year":2025,"finding":"Oxiconazole inhibits STING trafficking via OSBP, suppressing cGAS-STING pathway-mediated type I IFN production; pharmacologic OSBP inhibition blocks STING trafficking and downstream inflammatory signaling in macrophages and fibroblasts and alleviates autoimmune pathology in Trex1-/- mice.","method":"Pharmacologic OSBP inhibition (oxiconazole), STING trafficking assay, IFN reporter assay, Trex1-/- mouse model, Listeria infection model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic inhibition linked mechanistically to STING trafficking via OSBP with in vitro and in vivo validation, single lab","pmids":["40319749"],"is_preprint":false}],"current_model":"OSBP is an ER-Golgi lipid transfer protein that tethers the two organelles via its PH domain (binding Golgi PI(4)P) and FFAT motif (binding ER VAP-A), then executes a four-step, PI(4)P-hydrolysis-driven cycle to transfer cholesterol from the ER to the trans-Golgi network in exchange for retrograde PI(4)P transport, making it a major determinant of Golgi PI(4)P homeostasis and the sterol gradient along the secretory pathway; additionally, OSBP functions as a cholesterol-regulated scaffolding protein that assembles a PP2A/HePTP phosphatase complex to suppress ERK1/2 signaling, negatively regulates ABCA1 protein stability through its sterol-binding domain, controls v-SNARE localization and COPI vesicle transport at the Golgi, participates in ER-granule contact sites to regulate insulin secretion, regulates lysosomal PI(4)P content and axonal transport, and is exploited as a host factor by multiple positive-strand RNA viruses and intracellular bacterial pathogens."},"narrative":{"mechanistic_narrative":"OSBP is a sterol-binding lipid-transfer protein that operates at ER–Golgi membrane contact sites to set the cholesterol and PI(4)P gradients of the secretory pathway [PMID:24209621, PMID:28978670]. It tethers the two organelles by binding Golgi PI(4)P through its PH domain and ER-resident VAP-A through its FFAT motif, while its OSBP-related domain (ORD) shuttles sterol anterograde and PI(4)P retrograde; hydrolysis of the transferred PI(4)P by the ER phosphatase Sac1 provides the thermodynamic drive for net cholesterol delivery against its gradient [PMID:24209621]. The ORD encloses a single sterol molecule within a hydrophobic tunnel whose hydroxyl-coordinating residues and lid govern transport competence, a mechanism conserved from the yeast ortholog Osh4 to human OSBP [PMID:16136145, PMID:35613096], and an intrinsically disordered Gly-Pro-Ala-rich N-terminal segment acts as an entropic spacer that prevents homotypic membrane tethering and promotes diffusion and recycling at the contact site, with VAP-A flexibility and a T-shaped dimeric tethering geometry accommodating the moving ORDs [PMID:30905771, PMID:34103503]. OSBP accounts for roughly half of cellular PI(4)P turnover and is a major, compartment-selective determinant of Golgi PI(4)P homeostasis [PMID:28978670, PMID:38405037]. Cholesterol status controls OSBP phosphorylation and Golgi localization [PMID:9806908], and beyond lipid transfer OSBP serves as a cholesterol-regulated scaffold that assembles a ~440 kDa complex with the phosphatases HePTP and PP2A to dephosphorylate ERK1/2, an activity reversed by cholesterol depletion or oxysterols [PMID:15746430, PMID:18165705]. Its lipid-transport function underlies diverse cellular processes: maintenance of intra-Golgi v-SNARE localization and COPI-dependent transport [PMID:24048449], destabilization of ABCA1 to limit cholesterol efflux [PMID:18450749], PI(4)P–cholesterol exchange at ER–insulin-granule contacts required for glucose-stimulated insulin secretion [PMID:38536815, PMID:29540530], and control of lysosomal PI(4)P to support anterograde lysosome transport in neurons [PMID:39915357]. OSBP is exploited as an essential host factor by multiple positive-strand RNA viruses and by intracellular bacteria, being recruited to enterovirus and Aichi virus replication organelles and to the Salmonella-containing vacuole [PMID:25752737, PMID:29367253, PMID:31091452, PMID:21988961], and it is the direct target of antiviral, antileukemic, and trafficking-modulating small molecules including OSW-1, orpinolide, oxybipins, and oxiconazole [PMID:25752737, PMID:38907113, PMID:38907112, PMID:40319749].","teleology":[{"year":1998,"claim":"Established that OSBP is a sterol-sensing protein whose phosphorylation and localization respond to cellular cholesterol, linking it to sphingomyelin synthesis at the Golgi.","evidence":"Subcellular fractionation, immunofluorescence, and sphingomyelin labeling in CHO cells under cholesterol depletion/repletion","pmids":["9806908","9869656"],"confidence":"Medium","gaps":["Did not define the molecular lipid-transfer activity","Mechanism connecting Golgi localization to sphingomyelin synthesis unresolved"]},{"year":2005,"claim":"Defined the structural basis for sterol binding in the ORD and revealed an unanticipated scaffolding function coupling OSBP to ERK signaling.","evidence":"X-ray crystallography of the yeast Osh4 ORD with multiple sterol ligands; Co-IP, size-exclusion, and in vitro phosphatase assays of the OSBP–HePTP–PP2A complex","pmids":["16136145","15746430"],"confidence":"High","gaps":["Structural work used yeast ortholog, not human OSBP","How sterol occupancy controls phosphatase complex assembly mechanistically undefined"]},{"year":2005,"claim":"Showed OSBP is dispensable for transcriptional suppression of cholesterol biosynthesis genes, separating its function from SREBP-pathway sterol sensing.","evidence":"siRNA knockdown with RT-PCR of sterol-regulated genes after 25-HC treatment","pmids":["16098143"],"confidence":"Medium","gaps":["Negative result; does not exclude indirect roles in sterol homeostasis"]},{"year":2008,"claim":"Mapped the discrete sterol-binding region and demonstrated functional outputs of sterol binding, including ABCA1 destabilization and STAT3-dependent signaling.","evidence":"Domain truncation/point mutagenesis with sterol-binding and Co-IP mapping; RNAi and mutant-rescue ABCA1 half-life and efflux assays; phospho-site mutagenesis and ChIP for the 7-ketocholesterol/STAT3 pathway","pmids":["18165705","18450749","18230613"],"confidence":"Medium","gaps":["Molecular mechanism of ABCA1 destabilization not resolved","Y394/STAT3 axis assessed in single lab and cell context"]},{"year":2013,"claim":"Resolved OSBP's core function as a counter-current ER-to-Golgi sterol/PI(4)P exchanger driven by Sac1-mediated PI(4)P hydrolysis, and connected this activity to Golgi v-SNARE organization.","evidence":"Reconstituted in vitro lipid transfer with liposomes, domain mutagenesis, and Sac1 epistasis; siRNA with domain-mutant rescue and ArfGAP1 epistasis for GS28/GS15 localization","pmids":["24209621","24048449"],"confidence":"High","gaps":["In vitro cycle parameters versus in-cell kinetics","Link from lipid exchange to specific COPI/v-SNARE outcomes not fully mechanistic"]},{"year":2017,"claim":"Quantified OSBP's dominant contribution to cellular PI(4)P consumption and its role in setting the secretory-pathway lipid-order gradient.","evidence":"OSW-1 inhibition with live-cell PI(4)P/cholesterol reporters and lipidomics","pmids":["28978670"],"confidence":"High","gaps":["Did not address compartment-specific selectivity in detail"]},{"year":2019,"claim":"Identified the disordered N-terminal region as an entropic regulator of tethering geometry, explaining how OSBP avoids homotypic bridging and recycles efficiently.","evidence":"In vitro reconstitution, FRAP, cryo-EM of contact sites, and hydrodynamic radius measurements with truncation mutants","pmids":["30905771"],"confidence":"High","gaps":["In-cell relevance of entropic barrier under physiological crowding not directly measured"]},{"year":2021,"claim":"Visualized the architecture of a reconstituted OSBP–VAP-A contact site, showing flexible VAP-A and a T-shaped tethering dimer that permits ORD movement between membranes.","evidence":"Cryo-electron tomography and subtomogram averaging of reconstituted membrane contact sites","pmids":["34103503"],"confidence":"High","gaps":["Static structural snapshots; transfer-cycle dynamics not captured","Native contact-site geometry in cells not resolved"]},{"year":2022,"claim":"Provided a human OSBP ORD–cholesterol structure and inhibitor-resistance mutants, linking sterol-tunnel residues to enterovirus replication dependency.","evidence":"X-ray crystallography of human OSBP ORD–cholesterol, site-directed mutagenesis, and viral replication assays with inhibitor resistance","pmids":["35613096"],"confidence":"High","gaps":["Did not capture the dynamic transfer intermediate states"]},{"year":2024,"claim":"Extended OSBP's contact-site exchange function to specialized organelle contacts and confirmed it as a major, compartment-selective Golgi PI(4)P determinant and a druggable trafficking node.","evidence":"PI(4)P biosensors with genetic OSBP manipulation; live-cell imaging of ER–granule contacts with GSIS assays; thermal proteome profiling/CRISPR target ID for orpinolide; biophysical transport panel and retrograde/Shiga toxin assays for oxybipins","pmids":["38405037","38536815","38907113","38907112"],"confidence":"High","gaps":["How OSBP is selectively recruited to distinct organelle contacts unresolved","In vivo physiological consequences of these specialized roles incomplete"]},{"year":2025,"claim":"Broadened OSBP's pathophysiological reach to neuronal lysosome transport, axonal repair, and innate-immune STING trafficking.","evidence":"Oxidative-stress neuronal model with OSBP manipulation, PI(4)P/PI(3)P and Arl8 binding assays, AAV in vivo TBI model; pharmacologic OSBP inhibition of STING trafficking in Trex1-/- mice","pmids":["39915357","40319749"],"confidence":"Medium","gaps":["Direct lipid-transfer mechanism at lysosomes versus STING-bearing membranes not reconstituted","Single-lab in vivo findings"]},{"year":null,"claim":"How OSBP is selectively targeted and regulated at chemically and functionally distinct contact sites (Golgi, lysosome, secretory granule, pathogen vacuole, STING vesicle) — and how its phosphorylation state, scaffolding role, and lipid-transfer cycle are integrated in vivo — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling recruitment determinants to transfer activity across organelles","Physiological loss-of-function phenotype in mammals not defined in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,6,12]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,6,19]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,9]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,4,5,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,15,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26]}],"complexes":["OSBP-HePTP-PP2A phosphatase complex","ER-Golgi membrane contact site tether (OSBP-VAP-A)"],"partners":["VAPA","VAPB","SACM1L","PTPN7","PPP2CA","ABCA1","ACBD3","GS28"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22059","full_name":"Oxysterol-binding protein 1","aliases":[],"length_aa":807,"mass_kda":89.4,"function":"Lipid transporter involved in lipid countertransport between the Golgi complex and membranes of the endoplasmic reticulum: specifically exchanges sterol (cholesterol) with phosphatidylinositol 4-phosphate (PI4P, 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate)), delivering sterol to the Golgi in exchange for PI4P, which is subsequently degraded by the SAC1/SACM1L phosphatase in the endoplasmic reticulum (PubMed:24209621, PubMed:28978670). Binds cholesterol and a range of oxysterols including 25-hydroxycholesterol (PubMed:15746430, PubMed:17428193). Cholesterol binding promotes the formation of a complex with PP2A and a tyrosine phosphatase which dephosphorylates ERK1/2, whereas 25-hydroxycholesterol causes its disassembly (PubMed:15746430). 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Molecule Targeting of Oxysterol-Binding Protein (OSBP)-Related Protein 4 and OSBP Inhibits Ovarian Cancer Cell Proliferation in Monolayer and Spheroid Cell Models.","date":"2021","source":"ACS pharmacology & translational science","url":"https://pubmed.ncbi.nlm.nih.gov/33860198","citation_count":17,"is_preprint":false},{"pmid":"38907112","id":"PMC_38907112","title":"Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation.","date":"2024","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/38907112","citation_count":16,"is_preprint":false},{"pmid":"30237164","id":"PMC_30237164","title":"OSBP-related protein 4L promotes phospholipase Cβ3 translocation from the nucleus to the plasma membrane in Jurkat T-cells.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30237164","citation_count":16,"is_preprint":false},{"pmid":"24424245","id":"PMC_24424245","title":"OSBP-related protein 8 (ORP8) interacts with Homo sapiens sperm associated antigen 5 (SPAG5) and mediates oxysterol interference of HepG2 cell cycle.","date":"2014","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/24424245","citation_count":16,"is_preprint":false},{"pmid":"16234858","id":"PMC_16234858","title":"Overexpression of OSBP-related protein 2 (ORP2) in CHO cells induces alterations of phospholipid species composition.","date":"2005","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/16234858","citation_count":15,"is_preprint":false},{"pmid":"33857182","id":"PMC_33857182","title":"Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33857182","citation_count":13,"is_preprint":false},{"pmid":"17466467","id":"PMC_17466467","title":"Molecular characterization of a novel salt-inducible gene for an OSBP (oxysterol-binding protein)-homologue from soybean.","date":"2007","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17466467","citation_count":12,"is_preprint":false},{"pmid":"24326072","id":"PMC_24326072","title":"A vertebrate model for the study of lipid binding/transfer protein function: conservation of OSBP-related proteins between zebrafish and human.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24326072","citation_count":12,"is_preprint":false},{"pmid":"36916802","id":"PMC_36916802","title":"Structure-Activity Relationships of Ligand Binding to Oxysterol-Binding Protein (OSBP) and OSBP-Related Protein 4.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36916802","citation_count":10,"is_preprint":false},{"pmid":"12956528","id":"PMC_12956528","title":"OsBP-73, a rice gene, encodes a novel DNA-binding protein with a SAP-like domain and its genetic interference by double-stranded RNA inhibits rice growth.","date":"2003","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12956528","citation_count":10,"is_preprint":false},{"pmid":"38536815","id":"PMC_38536815","title":"OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38536815","citation_count":8,"is_preprint":false},{"pmid":"39704626","id":"PMC_39704626","title":"Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function.","date":"2024","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39704626","citation_count":8,"is_preprint":false},{"pmid":"36898018","id":"PMC_36898018","title":"Resistance Risk Assessment for the New OSBP Inhibitor Y18501 in Pseudoperonospora cubensis and Point Mutations (G705V, L798W, and I812F) in PscORP1 that Confer Resistance.","date":"2023","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36898018","citation_count":8,"is_preprint":false},{"pmid":"25782870","id":"PMC_25782870","title":"TAT-OSBP-1-MKK6(E), a novel TAT-fusion protein with high selectivity for human ovarian cancer, exhibits anti-tumor activity.","date":"2015","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25782870","citation_count":7,"is_preprint":false},{"pmid":"38405037","id":"PMC_38405037","title":"OSBP is a Major Determinant of Golgi Phosphatidylinositol 4-Phosphate Homeostasis.","date":"2024","source":"Contact (Thousand Oaks (Ventura County, Calif.))","url":"https://pubmed.ncbi.nlm.nih.gov/38405037","citation_count":7,"is_preprint":false},{"pmid":"35623602","id":"PMC_35623602","title":"Global effects of pharmacologic inhibition of OSBP in human umbilical vein endothelial cells.","date":"2022","source":"Steroids","url":"https://pubmed.ncbi.nlm.nih.gov/35623602","citation_count":5,"is_preprint":false},{"pmid":"31953353","id":"PMC_31953353","title":"OSBP-Related Protein 5L Maintains Intracellular IP3/Ca2+ Signaling and Proliferation in T Cells by Facilitating PIP2 Hydrolysis.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31953353","citation_count":5,"is_preprint":false},{"pmid":"32753887","id":"PMC_32753887","title":"miR-195 Serves as a Tumor Suppressor in the Progression of Liposarcoma by Targeting OSBP.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32753887","citation_count":5,"is_preprint":false},{"pmid":"37532305","id":"PMC_37532305","title":"Activity of the new OSBP inhibitor Y18501 against Pseudoperonospora cubensis and its application for the control of cucumber downy mildew.","date":"2023","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37532305","citation_count":5,"is_preprint":false},{"pmid":"40255103","id":"PMC_40255103","title":"Anti-SARS-CoV-2 Small Molecule Targeting of Oxysterol-Binding Protein (OSBP) Activates Cellular Antiviral Innate Immunity.","date":"2025","source":"ACS infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40255103","citation_count":4,"is_preprint":false},{"pmid":"39039546","id":"PMC_39039546","title":"Oxysterol binding protein (OSBP) contributes to hepatitis E virus replication.","date":"2024","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/39039546","citation_count":3,"is_preprint":false},{"pmid":"26495757","id":"PMC_26495757","title":"Delivery of Constitutively Active Mutant MKK6(E) With TAT-OSBP Induces Apoptosis in Human Ovarian Carcinoma HO8910 Cells.","date":"2015","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/26495757","citation_count":2,"is_preprint":false},{"pmid":"15583413","id":"PMC_15583413","title":"[Expression of OsBP-73 gene requires involvement of its intron in rice].","date":"2004","source":"Zhi wu sheng li yu fen zi sheng wu xue xue bao = Journal of plant physiology and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15583413","citation_count":2,"is_preprint":false},{"pmid":"32129748","id":"PMC_32129748","title":"[A lipid exchange market : vectorial cholesterol transport by the protein OSBP].","date":"2020","source":"Medecine sciences : M/S","url":"https://pubmed.ncbi.nlm.nih.gov/32129748","citation_count":1,"is_preprint":false},{"pmid":"41280340","id":"PMC_41280340","title":"Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein (OSBP).","date":"2025","source":"RSC medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41280340","citation_count":1,"is_preprint":false},{"pmid":"40884917","id":"PMC_40884917","title":"Elaboration and profiling of the first OSBP degrader issued from natural Schweinfurthins.","date":"2025","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40884917","citation_count":0,"is_preprint":false},{"pmid":"39915357","id":"PMC_39915357","title":"OSBP Participates in Neural Damage Repair by Regulating Lysosome Transport Under Oxidative Stress.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39915357","citation_count":0,"is_preprint":false},{"pmid":"40319749","id":"PMC_40319749","title":"Repurposing oxiconazole to inhibit STING trafficking via OSBP and alleviate autoimmune pathology in Trex1-/- mice.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40319749","citation_count":0,"is_preprint":false},{"pmid":"38187665","id":"PMC_38187665","title":"OSBP is a major determinant of Golgi phosphatidylinositol 4-phosphate homeostasis.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38187665","citation_count":0,"is_preprint":false},{"pmid":"41765601","id":"PMC_41765601","title":"Docking and molecular dynamics simulations of ORPphilins targeting OSBP.","date":"2025","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/41765601","citation_count":0,"is_preprint":false},{"pmid":"12035066","id":"PMC_12035066","title":"Fusion Expression and Purification of OSBP PH Domain and Preliminary Analysis of Its Second Structure.","date":"2001","source":"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12035066","citation_count":0,"is_preprint":false},{"pmid":"17960050","id":"PMC_17960050","title":"[Preliminary screening of target genes of rice transcription factor OsBP-73].","date":"2007","source":"Zhi wu sheng li yu fen zi sheng wu xue xue bao = Journal of plant physiology and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17960050","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.05.626967","title":"SARS-CoV-2 predation of Golgi-bound PI4P primes the massive activation of the DNA Damage Response kinase ATM in the cytoplasm","date":"2024-12-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.05.626967","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.23.684214","title":"VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.23.684214","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.09.675126","title":"AlphaFold-driven discovery of ORP-PIP interactions using new generation confidence scores","date":"2025-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675126","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48680,"output_tokens":7281,"usd":0.127628,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16561,"output_tokens":4499,"usd":0.09764,"stage2_stop_reason":"end_turn"},"total_usd":0.225268,"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\": 2013,\n      \"finding\": \"OSBP drives a four-step cycle at ER-Golgi membrane contact sites: (1) membrane tethering via PH domain (binding Golgi PI(4)P) and FFAT motif (binding ER VAP-A); (2) anterograde sterol transfer by the ORD domain from ER to Golgi; (3) retrograde PI(4)P transfer from Golgi to ER by the ORD domain; (4) PI(4)P hydrolysis by the ER phosphatase Sac1, which provides thermodynamic driving force for net sterol transport against its concentration gradient.\",\n      \"method\": \"Reconstituted in vitro lipid transfer assay with liposomes, domain mutagenesis, fluorescence microscopy of tethering, epistasis with Sac1\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full reconstitution in vitro with mechanistic dissection, multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"24209621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The ORD (OSBP-related domain) of yeast Osh4 (OSBP ortholog) contains a hydrophobic tunnel that accommodates a single sterol molecule; a flexible N-terminal lid closes upon sterol binding, stabilizing a transport-competent conformation; basic residues at the tunnel entrance are critical for function; open-lid structure reveals phospholipid-binding sites for membrane docking.\",\n      \"method\": \"X-ray crystallography at 1.5–2.5 Å resolution with ergosterol, cholesterol, and multiple hydroxycholesterol ligands; limited proteolysis; mutagenesis of basic residues\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with multiple ligands plus functional mutagenesis in single rigorous study\",\n      \"pmids\": [\"16136145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"OSBP forms an ~440 kDa cytosolic oligomeric complex with the tyrosine phosphatase HePTP (a PTPPBS family member), the serine/threonine phosphatase PP2A, and cholesterol; this complex has dual-specificity phosphatase activity toward phosphorylated ERK1/2 (pERK). Cholesterol depletion or oxysterol addition causes complex disassembly and elevation of pERK levels.\",\n      \"method\": \"Co-immunoprecipitation, size-exclusion chromatography, in vitro phosphatase assay, cholesterol depletion/supplementation experiments, OSBP overexpression rescue\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, biochemical phosphatase assay, genetic rescue with OSBP overexpression, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15746430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The sterol-binding domain of OSBP maps to a central 51-amino-acid region (residues 408–459) that binds both cholesterol and 25-hydroxycholesterol; a Y458S mutation impairs sterol binding. The N-terminal glycine-alanine-rich region works with the PH domain to selectively gate cholesterol (but not 25-hydroxycholesterol) binding in the context of full-length OSBP. HePTP binds a C-terminal coiled-coil domain (residues 732–761); PP2A binds the C-terminal half independently of the coiled-coil.\",\n      \"method\": \"Domain truncation and point mutagenesis, cholesterol and 25-hydroxycholesterol binding assays, co-immunoprecipitation mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assays with mutants plus Co-IP mapping, single lab, two orthogonal methods\",\n      \"pmids\": [\"18165705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cholesterol status regulates OSBP phosphorylation and its subcellular distribution: in cholesterol-replete cells OSBP is in the cytoplasm/vesicles; upon cholesterol depletion OSBP is dephosphorylated and constitutively localizes to the Golgi apparatus. 25-hydroxycholesterol-stimulated sphingomyelin synthesis requires both adequate cellular cholesterol and OSBP phosphorylation.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence microscopy, [3H]serine incorporation into sphingomyelin, cholesterol depletion/repletion in CHO and SRD6 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation and immunofluorescence plus functional lipid synthesis assay, single lab, multiple methods\",\n      \"pmids\": [\"9806908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overexpression of OSBP in CHO-K1 cells potentiates 25-hydroxycholesterol-stimulated sphingomyelin synthesis 2–3 fold; 25-hydroxycholesterol promotes translocation of OSBP to the Golgi apparatus where it stimulates conversion of ceramide to sphingomyelin; Golgi-enriched fractions from overexpressing cells show reduced diacylglycerol mass.\",\n      \"method\": \"[3H]serine and [3H]sphinganine incorporation assays, subcellular fractionation, immunofluorescence, in vitro enzyme activity assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional lipid synthesis assays in overexpression model with fractionation, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"9869656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endogenous OSBP is responsible for roughly half of total cellular PI(4)P consumption; blocking OSBP with OSW-1 causes sterol accumulation at ER/lipid droplets at the expense of the trans-Golgi network, reduces the lipid-order gradient along the secretory pathway, and uncouples PI4KIIIβ-driven PI(4)P production from OSBP-mediated consumption (generating traveling PI(4)P waves across the TGN).\",\n      \"method\": \"OSBP inhibition with OSW-1, live-cell PI(4)P and cholesterol reporters, lipidomics, fluorescence microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal live-cell reporters plus lipidomics, published independently confirming the cycle model from PMID 24209621\",\n      \"pmids\": [\"28978670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OSBP negatively regulates ABCA1 protein stability in a sterol-binding-domain-dependent manner: OSBP knockdown increases ABCA1 protein half-life ~3-fold and enhances cholesterol efflux without affecting ABCA1 mRNA or LXR transcriptional activity; mutations abrogating OSBP sterol binding prevent ABCA1 destabilization, while mutations disrupting Golgi or ER targeting do not.\",\n      \"method\": \"RNAi knockdown, protein half-life assay, co-transfection with domain mutants, cholesterol efflux assay, quantitative RT-PCR, LXR reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi plus mutagenesis rescue, multiple readouts, single lab\",\n      \"pmids\": [\"18450749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"7-ketocholesterol activates STAT3 in aortic endothelial cells via JAK2 and requires tyrosine-394 phosphorylation of OSBP1, leading to STAT3-dependent up-regulation of profilin-1 expression; the same pathway is activated in the aorta of diabetic rats.\",\n      \"method\": \"Luciferase reporter assay, phospho-specific antibodies, JAK2 inhibition, site-directed mutagenesis of OSBP1 Y394, chromatin immunoprecipitation, in vivo diabetic rat model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation site, ChIP, functional reporter, single lab with in vitro and in vivo confirmation\",\n      \"pmids\": [\"18230613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OSBP is required for the perinuclear localization of intra-Golgi v-SNAREs GS28 and GS15; OSBP depletion by siRNA mislocalizes GS28/GS15 throughout the cytoplasm and reduces Golgi mannosidase II abundance. All three functional domains (ER-targeting FFAT, Golgi-targeting PH, sterol-binding ORD) are required. The OSBP-dependent GS28 mislocalization is rescued by co-depletion of ArfGAP1, implicating COPI vesicle budding as a downstream effector.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, domain mutant rescue, genetic epistasis with ArfGAP1 double knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA, domain-mutant rescue, epistasis with ArfGAP1, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"24048449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A ~90 aa intrinsically disordered (Gly-Pro-Ala-rich) N-terminal sequence in OSBP acts as an entropic barrier: it prevents the two PH domains of the OSBP dimer from homotypically tethering two Golgi-like membranes, facilitates OSBP in-plane diffusion at membrane contact sites, and promotes its recycling. Its hydrodynamic radius is twice that of folded domains.\",\n      \"method\": \"In vitro reconstitution with liposomes, FRAP, cryo-electron microscopy of membrane contact sites, hydrodynamic radius measurements, truncation mutants\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, FRAP, and structural analysis with truncation mutants in one study; single lab but multiple rigorous methods\",\n      \"pmids\": [\"30905771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-tomography of a reconstituted in vitro membrane contact site reveals that VAP-A is a highly flexible ER transmembrane protein allowing variable intermembrane distances; the tethering region of the OSBP dimer adopts a central dimeric helical T-shaped structure, and this geometry facilitates movement of the two lipid-transfer ORD domains between the apposed membranes.\",\n      \"method\": \"Cryo-electron tomography and subtomogram averaging of in vitro reconstituted MCS with two lipid bilayers, VAP-A, and OSBP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-tomography structural determination of reconstituted MCS, single lab but rigorous structural method with functional interpretation\",\n      \"pmids\": [\"34103503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of the lipid transfer domain (ORD) of human OSBP in complex with endogenous cholesterol shows that cholesterol's hydrocarbon tail and tetracyclic ring occupy a hydrophobic tunnel while the hydroxyl group forms a hydrogen-bond network at the tunnel bottom. Systematic mutagenesis (M446W, L590W) identified residues that confer tolerance to the inhibitor T-00127-HEV2, and use of the M446W variant as a functional replacement revealed additional residues required for enterovirus replication.\",\n      \"method\": \"X-ray crystallography of human OSBP ORD–cholesterol complex, site-directed mutagenesis, viral replication assay with inhibitor resistance\",\n      \"journal\": \"ACS infectious diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of human protein with systematic mutagenesis and functional viral replication validation, single lab\",\n      \"pmids\": [\"35613096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The natural compound OSW-1 (and structurally unrelated itraconazole) inhibit enterovirus replication by directly targeting OSBP; OSBP overexpression rescues viral replication in the presence of OSW-1, establishing OSBP as an essential host factor for enterovirus genome replication.\",\n      \"method\": \"OSBP overexpression rescue of antiviral inhibition, dose-response viral replication assays across multiple cell types and enterovirus strains\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue (overexpression) directly links OSW-1 antiviral activity to OSBP, replicated across multiple viruses and cell lines\",\n      \"pmids\": [\"25752737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Aichi virus (a picornavirus) directly recruits the cholesterol transport machinery (OSBP, VAP-A/B, SAC1) to viral RNA replication organelles through protein–protein interactions between viral proteins (2B, 2BC, 2C, 3A, 3AB), ACBD3, OSBP, VAP, and SAC1; the OSBP–2B interaction enables PI(4)P-independent OSBP recruitment; cholesterol accumulates at replication organelles, and inhibition of OSBP-mediated cholesterol transfer impairs RNA replication.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence co-localization, electron microscopy, cholesterol staining, OSBP inhibitor treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs, siRNA knockdown with functional readout, EM, single lab with orthogonal methods\",\n      \"pmids\": [\"29367253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Salmonella effector SseJ binds OSBP1 and, together with another SPI-2 effector SseL, recruits OSBP1 to the Salmonella-containing vacuole in a SPI-2 TTSS-dependent manner; knockdown of OSBP1 or deletion of VAPA/B (OSBP1-binding ER proteins) reduces vacuolar integrity and increases cytoplasmic bacterial release, demonstrating OSBP1 is required for vacuole membrane stability during intracellular Salmonella infection.\",\n      \"method\": \"Co-immunoprecipitation (SseJ–OSBP1 interaction), OSBP1 siRNA knockdown, VAPA/B deletion, fluorescence microscopy of vacuolar integrity, bacterial localization assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi knockdown with functional vacuolar integrity readout, genetic deletion of VAP, single lab\",\n      \"pmids\": [\"31091452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBP is the direct, phenotypically relevant target of the antileukemic compound orpinolide; orpinolide disrupts Golgi homeostasis via a mechanism requiring active PI(4)P signaling at the ER-Golgi membrane interface; thermal proteome profiling and genome-scale CRISPR-Cas9 screens confirmed OSBP as the direct target.\",\n      \"method\": \"Thermal proteome profiling, genome-scale CRISPR-Cas9 screens, multiomics profiling, Golgi morphology assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — thermal proteome profiling (unbiased target ID) combined with genome-scale CRISPR genetic validation, multiple orthogonal methods\",\n      \"pmids\": [\"38907113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBP inhibition by oxybipins blocks retrograde trafficking and causes partial Golgi degradation in lysosomes; a biophysical sterol transport protein assay panel confirmed oxybipins potently and selectively inhibit OSBP without affecting other sterol transporters; OSBP inhibition attenuates Shiga toxin toxicity by blocking retrograde transport.\",\n      \"method\": \"Sterol transport protein biophysical assay panel, retrograde trafficking assay, Shiga toxin cytotoxicity assay, proteomics of Golgi protein degradation, glycosylation analysis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biophysical transfer assay panel plus functional retrograde trafficking and toxin assays with selective compounds; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38907112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBP is recruited to ER–insulin secretory granule contact sites in a Ca2+-dependent manner, regulated positively by PI4-kinases and negatively by the PI(4)P phosphatase Sac2; OSBP-mediated PI(4)P–cholesterol exchange at these contacts is required for glucose-stimulated insulin secretion; both acute pharmacologic inhibition and siRNA knockdown of OSBP suppress insulin secretion without affecting intracellular Ca2+ signaling.\",\n      \"method\": \"Live-cell imaging of OSBP at ER-granule contacts, siRNA knockdown, pharmacologic inhibition, glucose-stimulated insulin secretion assay, Ca2+ imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging of recruitment plus genetic and pharmacologic knockdown with functional secretion assay; single lab, multiple methods\",\n      \"pmids\": [\"38536815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Modulating OSBP levels at ER:Golgi membrane contact sites produces reciprocal changes in Golgi PI(4)P levels; OSBP has high capacity for PI(4)P turnover even at orthologous organelle membranes; endogenous OSBP does not significantly affect PI(4)P levels at the plasma membrane, establishing OSBP as a major, compartment-selective determinant of Golgi PI(4)P homeostasis.\",\n      \"method\": \"Acute and chronic genetic manipulation of OSBP expression, orthogonal organelle targeting, genetically-encoded PI(4)P biosensors\",\n      \"journal\": \"Contact\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulations with quantitative PI(4)P biosensors, single lab, multiple approaches\",\n      \"pmids\": [\"38405037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OSBP participates in lysosome transport in neurons: oxidative stress reduces OSBP protein levels, leading to lysosomal PI(4)P accumulation that disrupts anterograde lysosome transport. OSBP overexpression restores PI(4)P/PI(3)P balance, improves Arl8 binding to lysosomes (shown by protein–liposome binding assay), increases lysosome localization in neurites, and promotes axonal injury repair in vivo.\",\n      \"method\": \"H2O2-induced oxidative stress model, OSBP overexpression and knockdown, PI(4)P/PI(3)P measurements, protein–liposome binding assay, live imaging of lysosome transport, AAV in vivo delivery in TBI mouse model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with multiple methods; single lab but orthogonal approaches including binding assay and AAV mouse model\",\n      \"pmids\": [\"39915357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila, OSBP works together with the testis-specific VAP protein FAN (genetically and physically) to regulate sterol trafficking during spermatid individualization; OSBP-positive, sterol-enriched speckles appear at the leading edge of the individualization complex in wild-type but not in Osbp or fan mutants; male sterility of Osbp mutants is partially rescued by dietary sterol supplementation.\",\n      \"method\": \"Drosophila genetic mutant analysis, co-immunoprecipitation of OSBP–FAN interaction, immunofluorescence of sterol-enriched speckles, fertility rescue with dietary sterols\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo, physical interaction by Co-IP, functional rescue; single lab\",\n      \"pmids\": [\"20943709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OSBP1 overexpression downregulates amyloidogenic processing of APP (reducing Aβ production), while OSBP1 knockdown has the opposite effect; OSBP1 causes accumulation of APP-Notch2 dimers in the Golgi, an effect reversed by 25-hydroxycholesterol treatment, linking OSBP1 sterol-sensing to APP trafficking.\",\n      \"method\": \"OSBP1 overexpression and RNAi knockdown, APP processing/Aβ quantification, immunofluorescence of APP-Notch2 localization, 25-hydroxycholesterol treatment\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (OE and KD) with functional APP processing readout, single lab\",\n      \"pmids\": [\"18348724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OSBP knockdown in pancreatic β-cells reduces insulin granule stability (young granules are lost to lysosomal degradation) and suppresses glucose-stimulated insulin secretion; these effects were not rescued by exogenous cholesterol, distinguishing OSBP's proximal ER function from downstream ABC transporter-dependent cholesterol concentrating steps. Dual knockdown of OSBP and ABCG1 or ABCA1 supports their serial function in cholesterol supply for granule formation.\",\n      \"method\": \"RNAi knockdown, insulin granule tracking, glucose-stimulated insulin secretion assay, cholesterol supplementation rescue, dual knockdown epistasis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with multiple functional readouts and epistasis experiments, single lab\",\n      \"pmids\": [\"29540530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Salmonella infection causes redistribution of OSBP; the SPI-2 effector SseL binds the N-terminus of OSBP; OSBP is required for efficient intracellular replication of S. Typhimurium.\",\n      \"method\": \"Co-immunoprecipitation mapping of SseL–OSBP interaction, immunofluorescence of OSBP redistribution upon infection, OSBP knockdown and bacterial replication assay\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction mapping, RNAi knockdown with bacterial replication readout, single lab\",\n      \"pmids\": [\"21988961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"OSBP knockdown by siRNA (~90% reduction) does not affect 25-hydroxycholesterol-induced inhibition of HMG-CoA reductase or squalene epoxidase transcription, demonstrating that OSBP is not required for 25-HC-mediated suppression of cholesterol biosynthesis gene transcription.\",\n      \"method\": \"siRNA knockdown (~90% reduction), RT-PCR of sterol-regulated genes, 25-HC treatment\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic knockdown with quantitative gene expression readout; negative result well-controlled, single lab\",\n      \"pmids\": [\"16098143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Oxiconazole inhibits STING trafficking via OSBP, suppressing cGAS-STING pathway-mediated type I IFN production; pharmacologic OSBP inhibition blocks STING trafficking and downstream inflammatory signaling in macrophages and fibroblasts and alleviates autoimmune pathology in Trex1-/- mice.\",\n      \"method\": \"Pharmacologic OSBP inhibition (oxiconazole), STING trafficking assay, IFN reporter assay, Trex1-/- mouse model, Listeria infection model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic inhibition linked mechanistically to STING trafficking via OSBP with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"40319749\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OSBP is an ER-Golgi lipid transfer protein that tethers the two organelles via its PH domain (binding Golgi PI(4)P) and FFAT motif (binding ER VAP-A), then executes a four-step, PI(4)P-hydrolysis-driven cycle to transfer cholesterol from the ER to the trans-Golgi network in exchange for retrograde PI(4)P transport, making it a major determinant of Golgi PI(4)P homeostasis and the sterol gradient along the secretory pathway; additionally, OSBP functions as a cholesterol-regulated scaffolding protein that assembles a PP2A/HePTP phosphatase complex to suppress ERK1/2 signaling, negatively regulates ABCA1 protein stability through its sterol-binding domain, controls v-SNARE localization and COPI vesicle transport at the Golgi, participates in ER-granule contact sites to regulate insulin secretion, regulates lysosomal PI(4)P content and axonal transport, and is exploited as a host factor by multiple positive-strand RNA viruses and intracellular bacterial pathogens.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OSBP is a sterol-binding lipid-transfer protein that operates at ER–Golgi membrane contact sites to set the cholesterol and PI(4)P gradients of the secretory pathway [#0, #6]. It tethers the two organelles by binding Golgi PI(4)P through its PH domain and ER-resident VAP-A through its FFAT motif, while its OSBP-related domain (ORD) shuttles sterol anterograde and PI(4)P retrograde; hydrolysis of the transferred PI(4)P by the ER phosphatase Sac1 provides the thermodynamic drive for net cholesterol delivery against its gradient [#0]. The ORD encloses a single sterol molecule within a hydrophobic tunnel whose hydroxyl-coordinating residues and lid govern transport competence, a mechanism conserved from the yeast ortholog Osh4 to human OSBP [#1, #12], and an intrinsically disordered Gly-Pro-Ala-rich N-terminal segment acts as an entropic spacer that prevents homotypic membrane tethering and promotes diffusion and recycling at the contact site, with VAP-A flexibility and a T-shaped dimeric tethering geometry accommodating the moving ORDs [#10, #11]. OSBP accounts for roughly half of cellular PI(4)P turnover and is a major, compartment-selective determinant of Golgi PI(4)P homeostasis [#6, #19]. Cholesterol status controls OSBP phosphorylation and Golgi localization [#4], and beyond lipid transfer OSBP serves as a cholesterol-regulated scaffold that assembles a ~440 kDa complex with the phosphatases HePTP and PP2A to dephosphorylate ERK1/2, an activity reversed by cholesterol depletion or oxysterols [#2, #3]. Its lipid-transport function underlies diverse cellular processes: maintenance of intra-Golgi v-SNARE localization and COPI-dependent transport [#9], destabilization of ABCA1 to limit cholesterol efflux [#7], PI(4)P–cholesterol exchange at ER–insulin-granule contacts required for glucose-stimulated insulin secretion [#18, #23], and control of lysosomal PI(4)P to support anterograde lysosome transport in neurons [#20]. OSBP is exploited as an essential host factor by multiple positive-strand RNA viruses and by intracellular bacteria, being recruited to enterovirus and Aichi virus replication organelles and to the Salmonella-containing vacuole [#13, #14, #15, #24], and it is the direct target of antiviral, antileukemic, and trafficking-modulating small molecules including OSW-1, orpinolide, oxybipins, and oxiconazole [#13, #16, #17, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that OSBP is a sterol-sensing protein whose phosphorylation and localization respond to cellular cholesterol, linking it to sphingomyelin synthesis at the Golgi.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, and sphingomyelin labeling in CHO cells under cholesterol depletion/repletion\",\n      \"pmids\": [\"9806908\", \"9869656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular lipid-transfer activity\", \"Mechanism connecting Golgi localization to sphingomyelin synthesis unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the structural basis for sterol binding in the ORD and revealed an unanticipated scaffolding function coupling OSBP to ERK signaling.\",\n      \"evidence\": \"X-ray crystallography of the yeast Osh4 ORD with multiple sterol ligands; Co-IP, size-exclusion, and in vitro phosphatase assays of the OSBP–HePTP–PP2A complex\",\n      \"pmids\": [\"16136145\", \"15746430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural work used yeast ortholog, not human OSBP\", \"How sterol occupancy controls phosphatase complex assembly mechanistically undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed OSBP is dispensable for transcriptional suppression of cholesterol biosynthesis genes, separating its function from SREBP-pathway sterol sensing.\",\n      \"evidence\": \"siRNA knockdown with RT-PCR of sterol-regulated genes after 25-HC treatment\",\n      \"pmids\": [\"16098143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not exclude indirect roles in sterol homeostasis\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the discrete sterol-binding region and demonstrated functional outputs of sterol binding, including ABCA1 destabilization and STAT3-dependent signaling.\",\n      \"evidence\": \"Domain truncation/point mutagenesis with sterol-binding and Co-IP mapping; RNAi and mutant-rescue ABCA1 half-life and efflux assays; phospho-site mutagenesis and ChIP for the 7-ketocholesterol/STAT3 pathway\",\n      \"pmids\": [\"18165705\", \"18450749\", \"18230613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of ABCA1 destabilization not resolved\", \"Y394/STAT3 axis assessed in single lab and cell context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved OSBP's core function as a counter-current ER-to-Golgi sterol/PI(4)P exchanger driven by Sac1-mediated PI(4)P hydrolysis, and connected this activity to Golgi v-SNARE organization.\",\n      \"evidence\": \"Reconstituted in vitro lipid transfer with liposomes, domain mutagenesis, and Sac1 epistasis; siRNA with domain-mutant rescue and ArfGAP1 epistasis for GS28/GS15 localization\",\n      \"pmids\": [\"24209621\", \"24048449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro cycle parameters versus in-cell kinetics\", \"Link from lipid exchange to specific COPI/v-SNARE outcomes not fully mechanistic\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantified OSBP's dominant contribution to cellular PI(4)P consumption and its role in setting the secretory-pathway lipid-order gradient.\",\n      \"evidence\": \"OSW-1 inhibition with live-cell PI(4)P/cholesterol reporters and lipidomics\",\n      \"pmids\": [\"28978670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address compartment-specific selectivity in detail\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the disordered N-terminal region as an entropic regulator of tethering geometry, explaining how OSBP avoids homotypic bridging and recycles efficiently.\",\n      \"evidence\": \"In vitro reconstitution, FRAP, cryo-EM of contact sites, and hydrodynamic radius measurements with truncation mutants\",\n      \"pmids\": [\"30905771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of entropic barrier under physiological crowding not directly measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Visualized the architecture of a reconstituted OSBP–VAP-A contact site, showing flexible VAP-A and a T-shaped tethering dimer that permits ORD movement between membranes.\",\n      \"evidence\": \"Cryo-electron tomography and subtomogram averaging of reconstituted membrane contact sites\",\n      \"pmids\": [\"34103503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structural snapshots; transfer-cycle dynamics not captured\", \"Native contact-site geometry in cells not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a human OSBP ORD–cholesterol structure and inhibitor-resistance mutants, linking sterol-tunnel residues to enterovirus replication dependency.\",\n      \"evidence\": \"X-ray crystallography of human OSBP ORD–cholesterol, site-directed mutagenesis, and viral replication assays with inhibitor resistance\",\n      \"pmids\": [\"35613096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the dynamic transfer intermediate states\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended OSBP's contact-site exchange function to specialized organelle contacts and confirmed it as a major, compartment-selective Golgi PI(4)P determinant and a druggable trafficking node.\",\n      \"evidence\": \"PI(4)P biosensors with genetic OSBP manipulation; live-cell imaging of ER–granule contacts with GSIS assays; thermal proteome profiling/CRISPR target ID for orpinolide; biophysical transport panel and retrograde/Shiga toxin assays for oxybipins\",\n      \"pmids\": [\"38405037\", \"38536815\", \"38907113\", \"38907112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How OSBP is selectively recruited to distinct organelle contacts unresolved\", \"In vivo physiological consequences of these specialized roles incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened OSBP's pathophysiological reach to neuronal lysosome transport, axonal repair, and innate-immune STING trafficking.\",\n      \"evidence\": \"Oxidative-stress neuronal model with OSBP manipulation, PI(4)P/PI(3)P and Arl8 binding assays, AAV in vivo TBI model; pharmacologic OSBP inhibition of STING trafficking in Trex1-/- mice\",\n      \"pmids\": [\"39915357\", \"40319749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid-transfer mechanism at lysosomes versus STING-bearing membranes not reconstituted\", \"Single-lab in vivo findings\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OSBP is selectively targeted and regulated at chemically and functionally distinct contact sites (Golgi, lysosome, secretory granule, pathogen vacuole, STING vesicle) — and how its phosphorylation state, scaffolding role, and lipid-transfer cycle are integrated in vivo — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling recruitment determinants to transfer activity across organelles\", \"Physiological loss-of-function phenotype in mammals not defined in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 6, 12]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 6, 19]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 4, 5, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [\n      \"OSBP-HePTP-PP2A phosphatase complex\",\n      \"ER-Golgi membrane contact site tether (OSBP-VAP-A)\"\n    ],\n    \"partners\": [\n      \"VAPA\",\n      \"VAPB\",\n      \"SACM1L\",\n      \"PTPN7\",\n      \"PPP2CA\",\n      \"ABCA1\",\n      \"ACBD3\",\n      \"GS28\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}