Oxysterol-binding protein-related protein 6 · UniProt Q9BZF3
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).
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
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
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
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
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
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
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
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
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
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 2001 | 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. | cDNA sequencing, genomic structure analysis, Northern blot analysis of macrophage transcriptomes | Journal of lipid research | Medium | 11483621 |
| 2003 | 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. | Monospecific peptide antibody immunostaining, truncated construct expression in cultured cells, subcellular fractionation, cDNA hybridization | Cell and tissue research | Medium | 14593528 |
| 2007 | 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. | In vitro [3H]25-hydroxycholesterol binding assay with purified recombinant proteins; live cell photo-cross-linking with [3H]photo-25-hydroxycholesterol | The Biochemical journal | High | 17428193 |
| 2016 | 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. | Subcellular localization studies, siRNA knockdown with filipin staining and cholesterol esterification assays, ORP6 overexpression with cholesterol efflux assays, LXR agonist treatment | Arteriosclerosis, thrombosis, and vascular biology | High | 26941018 |
| 2018 | 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. | Deconvolution microscopy, co-immunoprecipitation, siRNA knockdown, PI4P marker (GFP-FAPP-PH) live imaging, dominant-negative construct expression | Experimental cell research | High | 30028970 |
| 2018 | ORP6 mediates cholesterol transfer from endosomes to the ER at endosomal-organelle membrane contact sites, contributing to regulation of cholesterol homeostasis. | Review summarizing experimental findings from referenced studies (ORP6 mentioned alongside ORP1L and ORP5 as mediating endosome-to-ER cholesterol transfer) | Current opinion in lipidology | Low | 29629999 |
| 2022 | 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. | 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 | Biochemistry and biophysics reports | High | 35518199 |
| 2025 | 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. | Osbpl6-/- mouse model, lipidomic analysis, ORP6 siRNA knockdown in astrocytes, cholesterol efflux assay, APP processing assay, lipid droplet staining | Journal of lipid research | High | 40716750 |
| 2026 | 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. | 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 | Autophagy | High | 41556583 |
| 2026 | 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. | Single-nucleus RNA sequencing, oligodendrocyte-specific OSBPL6 knockdown (viral), OSBPL6 overexpression in vivo, β-cyclodextrin treatment, myelin structure analysis | Journal of advanced research | Medium | 41605285 |
| 2026 | 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. | RNAi knockdown, dominant-negative constructs, in vivo electroporation in mouse cerebellum, primary cultured cerebellar granule cell migration assays, neurite morphology quantification | Biochemistry and biophysics reports | High | 42004539 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 2014 | Characterization of transcriptomes of cochlear inner and outer hair cells. | The Journal of neuroscience : the official journal of the Society for Neuroscience | 164 | 25122905 |
| 2001 | The OSBP-related protein family in humans. | Journal of lipid research | 158 | 11483621 |
| 2007 | The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. | The Biochemical journal | 127 | 17428193 |
| 2016 | Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3. | Molecular psychiatry | 78 | 26830138 |
| 2016 | miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux. | Arteriosclerosis, thrombosis, and vascular biology | 65 | 26941018 |
| 2003 | Subfamily III of mammalian oxysterol-binding protein (OSBP) homologues: the expression and intracellular localization of ORP3, ORP6, and ORP7. | Cell and tissue research | 51 | 14593528 |
| 1999 | Family of human oxysterol binding protein (OSBP) homologues. A novel member implicated in brain sterol metabolism. | Journal of lipid research | 39 | 10588946 |
| 2020 | Epigenetics of Skeletal Muscle-Associated Genes in the ASB, LRRC, TMEM, and OSBPL Gene Families. | Epigenomes | 32 | 34968235 |
| 2019 | Multi-population GWAS and enrichment analyses reveal novel genomic regions and promising candidate genes underlying bovine milk fatty acid composition. | BMC genomics | 30 | 30841852 |
| 2014 | Copy number variants in short children born small for gestational age. | Hormone research in paediatrics | 29 | 25300501 |
| 2018 | Cholesterol transfer at endosomal-organelle membrane contact sites. | Current opinion in lipidology | 28 | 29629999 |
| 2018 | Oxysterol-binding protein-related protein (ORP) 6 localizes to the ER and ER-plasma membrane contact sites and is involved in the turnover of PI4P in cerebellar granule neurons. | Experimental cell research | 25 | 30028970 |
| 2006 | Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia. | European journal of human genetics : EJHG | 16 | 17149386 |
| 2022 | The involvement of oxysterol-binding protein related protein (ORP) 6 in the counter-transport of phosphatidylinositol-4-phosphate (PI4P) and phosphatidylserine (PS) in neurons. | Biochemistry and biophysics reports | 9 | 35518199 |
| 2023 | Identification of Candidate Genes Associated with Yak Body Size Using a Genome-Wide Association Study and Multiple Populations of Information. | Animals : an open access journal from MDPI | 7 | 37174506 |
| 2023 | Genome-wide association study identifies variants associated with semen volume in white-feathered broilers. | Animal genetics | 6 | 37705287 |
| 2025 | Oxysterol-binding protein ORP6 regulates lipid metabolism and brain Aβ production. | Journal of lipid research | 1 | 40716750 |
| 2025 | Identification of key lipid metabolism-related genes in kidney fibrosis: implications for chronic kidney disease management. | Frontiers in physiology | 1 | 41049486 |
| 2026 | The PI4K2A-OSBPL6/ORP6-PS axis mediates lysosomal membrane repair to restore neuronal lipid homeostasis and promote neuronal survival after spinal cord injury. | Autophagy | 0 | 41556583 |
| 2026 | Role of Oxysterol-Binding Protein Family in Cholesterol Metabolism and Cancer Progression: A Review. | Medical science monitor : international medical journal of experimental and clinical research | 0 | 41560326 |
| 2026 | OSBPL6 protects against demyelination and behavioral disorder via promoting cholesterol transport in oligodendrocyte. | Journal of advanced research | 0 | 41605285 |
| 2026 | Oxysterol-binding protein-related protein 6 regulates neuronal morphology and migration of cerebellar granule cells during cerebellar development in vivo. | Biochemistry and biophysics reports | 0 | 42004539 |
| 2025 | Genetic haplotypes in VWA8, OSBPL6, and ADAMTS9-AS2 are associated with immune-related adverse effects in ICI-treated patients with cancer. | Journal for immunotherapy of cancer | 0 | 41151836 |
| 2025 | In silico characterization of the OSBPL6 gene and its potential role in ascites syndrome in broiler chickens. | Research in veterinary science | 0 | 41317444 |
No submissions yet.