Affinage

OSBPL11

Oxysterol-binding protein-related protein 11 · UniProt Q9BXB4

Length
747 aa
Mass
83.6 kDa
Annotated
2026-06-10
23 papers in source corpus 10 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OSBPL11 (ORP11) is a sterol- and phosphoinositide-binding lipid transfer protein that operates at endoplasmic reticulum membrane contact sites to control cellular lipid distribution (PMID:36071159, PMID:39106189). It localizes to the Golgi complex and late endosomes through N-terminal targeting determinants, while its C-terminal ORD domain binds sterol ligands such as 25-hydroxycholesterol (PMID:20599956, PMID:17428193). ORP11 functions obligately as a heterodimer with ORP9, which recruits it to membranes; loss of ORP9 abolishes ORP11 Golgi association (PMID:20599956). At ER–trans-Golgi network contacts the ORP9–ORP11 complex exchanges phosphatidylserine for PI(4)P, extracting Golgi PI4P to support sphingomyelin synthesis and to restrain OSBP-mediated cholesterol transport (PMID:37735529, PMID:39106189). Upon lysosomal membrane permeabilization, ORP11 is additionally recruited to damaged lysosomes via PI4K2A-generated PI4P, forming ER–lysosome contacts that deliver phosphatidylserine and cholesterol for membrane repair (PMID:36071159). Consistent with these transport roles, ORP11 maintains intracellular cholesterol distribution: a homozygous Arg171Trp variant causes free cholesterol accumulation in patient fibroblasts, and ORP11 cooperates with BMP in late-endosomal cholesterol efflux in macrophages (PMID:28051070, PMID:31136841). Its lipid transport activity also acts upstream of APC/C-dependent cyclin B1 degradation to influence mitotic cell fate (PMID:41313943).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 Medium

    Established that ORP11 is a genuine sterol-binding protein, defining its ORD domain as a functional ligand-binding pocket rather than a structural vestige.

    Evidence In vitro [3H]25OH binding with recombinant protein plus live-cell photo-cross-linking with [3H]photo-25OH in COS7 cells

    PMID:17428193

    Open questions at the time
    • Did not establish a transport function for the bound sterol
    • Cellular site of sterol binding not resolved
  2. 2010 Medium

    Defined ORP11's subcellular addresses (Golgi and late endosomes) and its domain architecture, and showed it acts as an obligate heterodimer with ORP9 that is required for membrane targeting.

    Evidence Fluorescence microscopy with organelle markers, truncation mutants, yeast two-hybrid, and ORP9 siRNA silencing in HEK293 cells

    PMID:20599956

    Open questions at the time
    • The lipid species transported was not identified
    • Functional consequence of dimerization beyond localization unknown
  3. 2012 Medium

    Linked ORP11 to physiological lipid storage by showing it is required for adipocyte differentiation and triglyceride accumulation.

    Evidence siRNA knockdown during SGBS adipocyte differentiation with qRT-PCR and triglyceride measurement

    PMID:23028956

    Open questions at the time
    • Molecular mechanism connecting ORP11 to adipogenic gene expression not defined
    • Direct lipid transport activity not measured
  4. 2017 Medium

    Provided human-genetic evidence that ORP11 function is required for normal intracellular cholesterol distribution.

    Evidence Filipin cholesterol staining of fibroblasts and biopsies from patients homozygous for the Arg171Trp variant

    PMID:28051070

    Open questions at the time
    • Cellular pathway by which the variant disrupts cholesterol handling not defined
    • Variant present in clinically unaffected sibling, leaving genotype-phenotype relationship unclear
  5. 2019 Medium

    Placed ORP11 in late-endosomal cholesterol egress, showing it cooperates with BMP to support cholesterol efflux and protect against oxLDL-induced apoptosis.

    Evidence Stable shRNA knockdown in RAW264.7 macrophages with oxysterol lipidomics, cholesterol efflux assays, and ABCG1 immunoblotting

    PMID:31136841

    Open questions at the time
    • Direct physical interaction with BMP not demonstrated
    • Mechanism of ABCG1 regulation not established
  6. 2022 High

    Revealed a stress-response role: ORP11 is recruited to damaged lysosomes via PI4K2A-generated PI4P to form ER-lysosome contacts that transfer lipids for membrane repair.

    Evidence Unbiased proteomics of damaged lysosomes, live imaging, and lipid transport assays after LMP induction

    PMID:36071159

    Open questions at the time
    • Relative contributions of ORP9/ORP10/ORP11/OSBP not dissected
    • Quantitative repair kinetics attributable to ORP11 alone unknown
  7. 2023 High

    Defined the directional lipid logic at the TGN, showing ORP9-ORP11 extracts PI4P to suppress OSBP-mediated cholesterol delivery.

    Evidence Genetic knockout, live imaging, lipid mass spectrometry, and epistasis with ORP9/GRAMD1 depletion

    PMID:37735529

    Open questions at the time
    • Regulation of contact-site assembly not defined
    • Counter-cargo for PI4P extraction not specified in this study
  8. 2024 High

    Identified the transported lipid pair, establishing ORP9-ORP11 as a PS/PI(4)P exchanger whose activity sustains Golgi sphingomyelin synthesis.

    Evidence Genome-scale LTP knockout screen, whole-cell lipidomics, co-localization, and lipid transfer assays

    PMID:39106189

    Open questions at the time
    • Structural basis of PS/PI4P selectivity not resolved
    • Regulation linking exchange to sphingomyelin synthase activity unclear
  9. 2025 Medium

    Connected ORP11 lipid transport to mitotic cell-fate decisions, placing its activity upstream of APC/C-mediated cyclin B1 degradation.

    Evidence siRNA knockdown, structure-function rescue with lipid-transport mutants, cyclin B1 immunoblotting, and proTAME APC/C inhibition with cell-fate tracking

    PMID:41313943

    Open questions at the time
    • Molecular link between membrane lipid transport and APC/C activity not defined
    • Site of action during mitosis not localized
  10. 2025 Low

    Proposed ORP11 as a vitamin D binding protein with whole-animal metabolic consequences.

    Evidence In vitro binding assays, molecular docking, and OSBPL11 knockdown mouse metabolic phenotyping

    PMID:40492082

    Open questions at the time
    • Binding lacks mutagenesis validation and relies partly on docking
    • Mouse phenotype not connected to a defined molecular pathway
    • Physiological relevance of vitamin D binding not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ORP11/ORP9 lipid exchange is mechanistically coupled to downstream effects on sphingomyelin synthase, ABCG1-dependent efflux, and APC/C remains unresolved.
  • No structure of the ORP9-ORP11 complex on membranes
  • Causal chain from lipid imbalance to cyclin B1 degradation undefined
  • Regulation of contact-site recruitment across organelles not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0140104 molecular carrier activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 3 GO:0005768 endosome 2 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 1
Complex memberships
ORP9-ORP11 heterodimer

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 ORP11 localizes to the Golgi complex and late endosomes (co-localizing with GFP-Rab9, TGN46, GFP-Rab7, and a medial-trans-Golgi marker), and the N-terminal fragment (aa 1-292) contains the membrane-targeting determinants. The C-terminal ligand-binding domain (aa 273-747) is cytosolic. Fluorescence microscopy with GFP-tagged organelle markers, subcellular fractionation, overexpression of truncation mutants in HEK293 cells Experimental cell research Medium 20599956
2010 ORP11 forms a heterodimer with ORP9 via interaction between aa 98-372 of ORP9 and aa 154-292 of ORP11. Overexpressed ORP9 recruits EGFP-ORP11 to membranes, and ORP9 silencing inhibits ORP11 Golgi association, establishing the ORP9-ORP11 dimer as a functional unit. Yeast two-hybrid screen, overexpression and co-localization in HEK293 cells, ORP9 siRNA silencing Experimental cell research Medium 20599956
2007 ORP11 (via its ORD domain) binds 25-hydroxycholesterol in live cells, as shown by photo-cross-linking with [3H]photo-25OH, indicating it is a sterol-binding protein with a conserved ligand-binding pocket. In vitro [3H]25OH-binding assay with recombinant proteins; live cell photo-cross-linking with [3H]photo-25OH in COS7 cells The Biochemical journal Medium 17428193
2022 Upon lysosomal membrane permeabilization (LMP), ORP11 (along with ORP9, ORP10, and OSBP) is recruited to damaged lysosomes via lysosomal phosphatidylinositol-4-phosphate generated by PI4K2A, forming new ER-lysosome membrane contact sites that mediate ER-to-lysosome transfer of phosphatidylserine and cholesterol to support lysosomal repair. Unbiased proteomics of damaged lysosomes, live imaging, functional lipid transport assays, LMP induction in cell culture Nature High 36071159
2023 ORP11 (with ORP9) localizes at ER-trans-Golgi network contact sites via interaction between ORP9's tandem α-helices and ORP10/ORP11. The ORP9-ORP11 complex extracts PI4P from the TGN to prevent its overaccumulation, thereby suppressing OSBP-mediated cholesterol transport to the Golgi. Genetic knockout, live fluorescence imaging, lipid mass spectrometry, epistasis experiments in cells depleted of ORP9 and/or GRAMD1s Nature communications High 37735529
2024 The ORP9-ORP11 heterodimer localizes at ER-trans-Golgi membrane contact sites and exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Loss of either ORP9 or ORP11 causes phospholipid imbalances in the Golgi that result in lowered sphingomyelin synthesis. Gene knockout library targeting 90 LTPs, whole-cell lipidomics, co-localization imaging, lipid transfer assays eLife High 39106189
2019 ORP11 knockdown in RAW264.7 macrophages abrogates the protective action of bis(monoacylglycero)phosphate (BMP) against oxidized LDL-induced apoptosis, causes accumulation of free cholesterol, decreases cholesterol efflux, and reduces ABCG1 expression, demonstrating that ORP11 cooperates with BMP in intracellular cholesterol trafficking at the late endosome. Stable shRNA knockdown in RAW264.7 macrophages, lipidomics (oxysterol measurement), cholesterol efflux assays, western blotting for ABCG1 Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 31136841
2012 ORP11 silencing in differentiating SGBS adipocytes reduces adiponectin and aP2 mRNA expression and markedly decreases cellular triglyceride storage, demonstrating a functional role for ORP11 in adipocyte differentiation and lipid accumulation. siRNA knockdown during SGBS adipocyte differentiation, qRT-PCR, triglyceride content measurement PloS one Medium 23028956
2025 OSBPL11 knockdown accelerates mitotic slippage and represses cell death during mitotic arrest (induced by the Eg5 inhibitor STLC or paclitaxel), with decreased cyclin B1 levels in knockdown mitotic cells. Rescue with wild-type OSBPL11 but not lipid transport/binding mutants restores normal cell fate, and the APC/C inhibitor proTAME reverses the knockdown phenotype, placing OSBPL11's lipid transport activity upstream of APC/C-mediated cyclin B1 degradation. siRNA knockdown, rescue with wild-type and mutant OSBPL11, cyclin B1 immunoblotting, APC/C inhibition with proTAME, cell fate tracking Biochemical and biophysical research communications Medium 41313943
2025 In vitro binding assays and molecular docking showed that OSBPL11 is a vitamin D binding protein capable of binding vitamin D metabolites (25-hydroxyvitamin D). OSBPL11 knockdown in mice results in increased fat mass, reduced triglycerides, and improved glucose tolerance. In vitro binding assays, molecular docking, OSBPL11 knockdown mouse model with metabolic phenotyping medRxiv (preprint) / Inflammation Low 40492082
2017 Homozygous Arg171Trp variant in OSBPL11 causes intracellular cholesterol accumulation in skin fibroblasts and skin biopsy cells, demonstrating that functional OSBPL11 is required for normal intracellular cholesterol distribution. This effect was also seen in a clinically unaffected sibling homozygous for the variant, suggesting OSBPL11 loss-of-function causes a cholesterol trafficking defect without overt neurological disease. Filipin staining for free cholesterol in skin fibroblasts and biopsies from patients and carrier sibling with homozygous OSBPL11 variant European journal of human genetics Medium 28051070

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 A phosphoinositide signalling pathway mediates rapid lysosomal repair. Nature 287 36071159
2013 Oxysterol-binding proteins: sterol and phosphoinositide sensors coordinating transport, signaling and metabolism. Progress in lipid research 145 23830809
2007 The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. The Biochemical journal 127 17428193
2022 Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11. Journal of nanobiotechnology 60 35012554
2023 Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites. Nature communications 43 37735529
2010 OSBP-related protein 11 (ORP11) dimerizes with ORP9 and localizes at the Golgi-late endosome interface. Experimental cell research 39 20599956
2020 Epigenetics of Skeletal Muscle-Associated Genes in the ASB, LRRC, TMEM, and OSBPL Gene Families. Epigenomes 32 34968235
2009 Association of OSBPL11 gene polymorphisms with cardiovascular disease risk factors in obesity. Obesity (Silver Spring, Md.) 31 19325544
2019 Analysis of the Zika and Japanese Encephalitis Virus NS5 Interactomes. Journal of proteome research 25 31199156
2017 Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A. European journal of human genetics : EJHG 24 28051070
2012 OSBP-related proteins (ORPs) in human adipose depots and cultured adipocytes: evidence for impacts on the adipocyte phenotype. PloS one 21 23028956
2019 Bis(monoacylglycero)phosphate regulates oxysterol binding protein-related protein 11 dependent sterol trafficking. Biochimica et biophysica acta. Molecular and cell biology of lipids 14 31136841
2021 Global Proximity Interactome of the Human Macroautophagy Pathway. Autophagy 10 34524948
2019 Serum and tissue proteomic signatures of patients with hepatocellular carcinoma using 2‑D gel electrophoresis. Molecular medicine reports 10 31173207
2024 The ORP9-ORP11 dimer promotes sphingomyelin synthesis. eLife 9 39106189
2012 Mixture designs to assess composition-structure-property relationships in SiO₂-CaO-ZnO-La₂O₃-TiO₂-MgO-SrO-Na₂O glasses: potential materials for embolization. Journal of biomaterials applications 9 22863846
2024 Transcriptome in Liver of Periparturient Dairy Cows Differs between Supplementation of Rumen-Protected Niacin and Rumen-Protected Nicotinamide. Metabolites 3 38535310
2026 AlphaFold-driven discovery of oxysterol-binding protein-related protein-phosphoinositide 3-, 4-, and 5-phosphatase interactions using new generation confidence scores. Protein science : a publication of the Protein Society 0 41983709
2025 High level expression of OSBPL11 is associated with atherosclerosis and Alzheimer's disease. Inflammation 0 40407857
2025 OSBPL11 is an African-specific locus associated with 25-hydroxyvitamin D concentrations and cardiometabolic health. medRxiv : the preprint server for health sciences 0 40492082
2025 Rosai-Dorfman Disease With Novel BRAF Fusion Involving the Central Nervous System. International journal of surgical pathology 0 40831220
2025 Suppression of the lipid-transport activity of OSBPL11 weakens the cytotoxicity of SAC-activating drugs by promoting mitotic slippage. Biochemical and biophysical research communications 0 41313943
2025 Urinary total arsenic, arsenic species, and arsenic methylation capacity: an integrative profiling analysis of microRNAs in plasma and leukocytes. Environmental pollution (Barking, Essex : 1987) 0 41443549

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