Affinage

OSBPL11

Oxysterol-binding protein-related protein 11 · UniProt Q9BXB4

Length
747 aa
Mass
83.6 kDa
Annotated
2026-04-29
23 papers in source corpus 10 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OSBPL11 (ORP11) is a lipid transfer protein that operates at membrane contact sites to exchange phospholipids and sterols between organelles, with central roles in Golgi sphingomyelin synthesis, cholesterol homeostasis, and lysosomal membrane repair. It forms a functional heterodimer with ORP9 through its N-terminal domain and localizes to ER–trans-Golgi network and ER–lysosome contact sites, where it catalyzes the counter-transport of phosphatidylserine and phosphatidylinositol-4-phosphate; loss of ORP11 causes Golgi phospholipid imbalance, reduced sphingomyelin production, and cholesterol accumulation (PMID:39106189, PMID:37735529, PMID:20599956). Upon lysosomal membrane damage, ORP11 is recruited by PI4K2A-generated PI(4)P to damaged lysosomes, where it transfers phosphatidylserine and cholesterol from the ER to support rapid membrane repair (PMID:36071159). Its ligand-binding domain binds oxysterols including 25-hydroxycholesterol, and its lipid transport activity is required to suppress APC/C-mediated cyclin B1 degradation during mitotic arrest, linking lipid transfer to cell-cycle control (PMID:17428193, PMID:41313943).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 High

    Establishing that ORP11 directly binds oxysterols resolved the question of whether this OSBP family member possesses an intrinsic sterol-binding activity, placing it among the lipid-sensing/transport ORPs.

    Evidence Photo-crosslinking with radiolabeled 25-hydroxycholesterol in live COS7 cells and in vitro binding with recombinant protein

    PMID:17428193

    Open questions at the time
    • Full ligand selectivity profile (e.g., phospholipids) was not tested
    • Structural basis of sterol binding was not resolved
  2. 2010 High

    Mapping ORP11 to the Golgi and late endosomes, and identifying its obligate heterodimerization with ORP9 via the N-terminal domain, established the ORP9–ORP11 unit as the functional species and explained how ORP11 reaches target membranes.

    Evidence GFP-tagged organelle markers, EM, truncation mutants, yeast two-hybrid, and ORP9 siRNA in HEK293 cells

    PMID:20599956

    Open questions at the time
    • Stoichiometry and structure of the heterodimer were not determined
    • Whether ORP11 can function independently of ORP9 at endosomes remained unclear
  3. 2012 Medium

    Demonstrating that ORP11 silencing impairs adipocyte triglyceride storage and adipogenic marker expression revealed a physiological role for ORP11 lipid transport in adipogenesis.

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

    PMID:23028956

    Open questions at the time
    • Which lipid species ORP11 transfers in adipocytes was not identified
    • In vivo confirmation in animal models was lacking
  4. 2017 Medium

    A patient homozygous OSBPL11 p.Arg171Trp variant causing intracellular cholesterol accumulation in fibroblasts provided human genetic evidence that ORP11 is required for normal cholesterol trafficking.

    Evidence Exome sequencing with functional cholesterol accumulation assay in patient skin fibroblasts and biopsies

    PMID:28051070

    Open questions at the time
    • The mutation maps to the ORP9-interaction region but its effect on dimerization was not tested
    • No large cohort replication or disease phenotype fully delineated
  5. 2019 Medium

    Showing that ORP11 knockdown abrogates BMP-mediated cholesterol efflux protection and increases oxysterol toxicity in macrophages extended ORP11's cholesterol trafficking role to foam-cell biology and atherosclerosis-relevant pathways.

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

    PMID:31136841

    Open questions at the time
    • Direct lipid transfer activity at endosomes was not measured
    • In vivo relevance in atherosclerotic models not tested
  6. 2022 High

    Unbiased proteomics of damaged lysosomes revealed that ORP11 is recruited by PI4K2A-generated PI(4)P to form ER–lysosome contacts that transfer PS and cholesterol for rapid membrane repair, uncovering a new organelle-repair function.

    Evidence Proteomics of LMP-damaged lysosomes, live-cell imaging, lipid transfer assays, and functional rescue (PITT pathway)

    PMID:36071159

    Open questions at the time
    • Relative contributions of ORP9–ORP11 versus ORP11 alone at damaged lysosomes were not dissected
    • Structural basis of PI(4)P-driven recruitment not resolved
  7. 2023 High

    Demonstrating that the ORP9–ORP11 complex antagonizes OSBP-mediated cholesterol transport to the Golgi established an epistatic framework in which ORP11 shapes Golgi cholesterol levels through counter-regulation of parallel lipid transfer pathways.

    Evidence Genetic knockout, co-localization imaging, lipid measurements, GRAMD1 epistasis, SREBP-2 signaling in multiple cell lines

    PMID:37735529

    Open questions at the time
    • Whether ORP10 and ORP11 are redundant partners for ORP9 at the TGN was not fully resolved
    • Quantitative lipid flux measurements between pathways were not performed
  8. 2024 High

    A systematic CRISPR lipidomics screen confirmed ORP11 as the PS/PI(4)P exchanger at ER–TGN contacts and showed that its loss reduces Golgi sphingomyelin synthesis, directly linking its counter-transport activity to downstream sphingolipid metabolism.

    Evidence CRISPR KO of 90 LTP genes, whole-cell lipidomics, lipid transfer assays, co-localization imaging

    PMID:39106189

    Open questions at the time
    • How PS delivery specifically regulates sphingomyelin synthase activity was not elucidated
    • Potential compensatory roles of other LTPs were not fully excluded
  9. 2025 Medium

    Linking ORP11 lipid transport to suppression of APC/C-dependent cyclin B1 degradation during mitotic arrest revealed an unexpected cell-cycle regulatory function, dependent on both lipid binding and transfer activities.

    Evidence siRNA knockdown with mutant rescue, cyclin B1 immunoblot, APC/C inhibitor epistasis, SAC-activating drug treatment

    PMID:41313943

    Open questions at the time
    • The specific lipid species whose transport controls APC/C activity was not identified
    • Mechanism by which membrane lipid composition influences APC/C–cyclin B1 axis is unknown
    • Single-lab finding awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ORP11 lipid transfer activity is allosterically regulated, whether ORP11 and ORP9 have distinct or overlapping lipid cargo preferences in vivo, and the molecular mechanism connecting lipid transport to APC/C-mediated cell-cycle control remain open questions.
  • No high-resolution structure of the ORP9–ORP11 heterodimer exists
  • In vivo physiological consequences of ORP11 loss in mammalian models are poorly characterized
  • Mechanism linking lipid composition to APC/C regulation is entirely unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0140104 molecular carrier activity 2
Localization
GO:0005794 Golgi apparatus 4 GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005768 endosome 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-382551 Transport of small molecules 4 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
ORP9PI4K2ARAB7RAB9
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 (OSBPL11) localizes to the Golgi complex and late endosomes (co-localizing with Rab7, Rab9, and TGN46), with membrane targeting determinants residing in its N-terminal domain (aa 1-292). The N-terminal fragment shows enhanced localization on Rab7- and Rab9-positive late endosomes, while the C-terminal ligand-binding domain (aa 273-747) is cytosolic. Fluorescence microscopy with GFP-tagged organelle markers, electron microscopy, and truncation mutant analysis in HEK293 cells Experimental cell research High 20599956
2010 ORP11 (OSBPL11) dimerizes with ORP9 through its N-terminal region (aa 154-292 of ORP11 interacting with aa 98-372 of ORP9). Overexpressed ORP9 recruits EGFP-ORP11 to membranes, and ORP9 silencing inhibits ORP11 Golgi association, defining ORP9-ORP11 as a functional dimeric unit. Yeast two-hybrid screen, co-expression and membrane recruitment assay, ORP9 siRNA silencing in HEK293 cells Experimental cell research High 20599956
2007 ORP11 (OSBPL11) binds 25-hydroxycholesterol in a conserved sterol-binding pocket, as demonstrated by photo-crosslinking with [3H]photo-25-hydroxycholesterol in live COS7 cells using the full-length protein and the isolated OSBP-related ligand-binding domain. Live cell photo-crosslinking with radiolabeled photo-25-hydroxycholesterol; in vitro sterol binding assay with recombinant proteins The Biochemical journal High 17428193
2022 Upon lysosomal membrane permeabilization (LMP), ORP11 (OSBPL11) is recruited to damaged lysosomes by lysosomal phosphatidylinositol-4-phosphate (generated by PI4K2A), where it forms membrane contact sites between damaged lysosomes and the ER, catalyzing ER-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal membrane repair. Unbiased proteomics of LMP-damaged lysosomes, live-cell imaging, lipid transfer assays, and functional rescue experiments (PITT pathway analysis) Nature High 36071159
2024 The ORP9-ORP11 heterodimer localizes at ER-trans-Golgi network membrane contact sites, where it exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Loss of ORP11 causes phospholipid imbalances in the Golgi that result in lowered sphingomyelin synthesis. CRISPR knockout lipidomics screen (90 LTP gene library), whole-cell lipidomics, co-localization imaging, lipid transfer assays eLife High 39106189
2023 ORP9 localizes to the TGN via interaction between its tandem α-helices and ORP10/ORP11, and suppresses OSBP-mediated PI4P-driven cholesterol transport to the Golgi. Cells lacking ORP9 exhibit cholesterol accumulation at the Golgi, indicating that the ORP9-ORP11 complex regulates non-vesicular cholesterol transport at ER-Golgi contact sites. Genetic knockout, co-localization imaging, lipid measurements, epistasis with GRAMD1s, SREBP-2 signaling readout Nature communications High 37735529
2019 ORP11 (OSBPL11) cooperates with bis(monoacylglycero)phosphate (BMP) in intracellular cholesterol trafficking in macrophages. ORP11 knockdown abrogates BMP-mediated protection against oxidized LDL-induced apoptosis, increases free cholesterol, reduces cholesterol efflux, and is associated with increased 7-oxysterol production and decreased ABCG1 expression. Stable shRNA knockdown of ORP11 in RAW264.7 macrophages, cholesterol and oxysterol measurements, apoptosis assays, ABCG1 expression analysis Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 31136841
2012 ORP11 (OSBPL11) is induced during adipogenic differentiation of SGBS adipocytes, and ORP11 silencing results in downregulation of adiponectin and aP2 mRNA and markedly decreased cellular triglyceride storage, demonstrating a functional role in adipocyte differentiation and lipid metabolism. siRNA silencing of ORP11 in differentiating SGBS adipocytes, qRT-PCR for adipogenic markers, triglyceride quantification PloS one Medium 23028956
2025 OSBPL11 represses mitotic slippage and promotes cell death during mitotic arrest in a manner dependent on both its lipid transport and lipid binding activities. OSBPL11 knockdown decreases cyclin B1 levels during mitotic arrest via APC/C-dependent mechanisms, and this effect can be rescued by wild-type OSBPL11 but not by lipid transport/binding mutants. siRNA knockdown, mutant overexpression rescue, cyclin B1 immunoblot, APC/C inhibitor (proTAME) epistasis, SAC-activating drug (STLC, paclitaxel) treatment assays Biochemical and biophysical research communications Medium 41313943
2025 OSBPL11 functions as a vitamin D binding protein, with in vitro binding assays and molecular docking demonstrating binding of vitamin D metabolites to OSBPL11. OSBPL11 knockdown mice display increased fat, 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 A homozygous missense variant (p.Arg171Trp) in OSBPL11 causes intracellular cholesterol accumulation in skin fibroblasts and biopsies, demonstrating that OSBPL11 plays a role in intracellular cholesterol trafficking. Human genetics (exome sequencing) combined with functional verification via cholesterol accumulation assay in patient skin fibroblasts/biopsies 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 270 36071159
2013 Oxysterol-binding proteins: sterol and phosphoinositide sensors coordinating transport, signaling and metabolism. Progress in lipid research 143 23830809
2007 The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. The Biochemical journal 126 17428193
2022 Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11. Journal of nanobiotechnology 59 35012554
2023 Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites. Nature communications 39 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 31 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 23 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 13 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