OSBPL10

OSBPL10 encodes ORP10, a lipid transfer protein that controls cellular lipid distribution with consequences for hepatic lipid metabolism, lysosomal integrity, and tumor biology (PMID:19554302, PMID:41794746). In hepatoma cells, ORP10 suppresses lipogenesis and VLDL output, restraining cholesterol and triglyceride synthesis and apolipoprotein B100 secretion (PMID:19554302). Mechanistically, ORP10 transfers phosphatidylserine to lysosomes to repair lysosomal membranes, an activity that restores autophagic flux and limits ferroptosis and oxidative stress in injured neurons (PMID:41794746). This lysosomal-repair function operates in cooperation with VAPA/VAPB and ATG2A to drive lipophagy and lipid mobilization, supporting tumor growth in pancreatic ductal adenocarcinoma (PMID:42003919). OSBPL10 is transcriptionally induced by HIF-1α under hypoxia and acts through direct binding to CNBP to influence pancreatic cancer proliferation, metastasis, and macrophage M1→M2 polarization (PMID:39329194), and it is also required to support dengue virus replication in macrophage-like cells (PMID:28241052).

1. 2009 Medium

   Establishing the first cellular function of ORP10 showed it acts as a negative regulator of hepatic lipid synthesis rather than a passive lipid binder.

   Evidence siRNA silencing in Huh7 hepatoma cells with radiolabeled lipid incorporation assays and ApoB100 secretion measurement

   PMID:19554302

   Open questions at the time

   • Did not identify the lipid transfer reaction or molecular partner responsible for lipogenic suppression
   • Mechanism linking ORP10 to ApoB100 secretion not resolved
2. 2009 Low

   Imaging placed ORP10 on microtubules, hinting at a role in intracellular transport or organelle positioning.

   Evidence Co-localization imaging of ORP10 with microtubules in Huh7 cells

   PMID:19554302

   Open questions at the time

   • Single imaging-based observation with no functional consequence linked
   • No demonstration that microtubule association is required for any ORP10 activity
3. 2017 Medium

   Loss-of-function screening revealed OSBPL10 is required by a virus, expanding its role beyond lipid metabolism into host-pathogen interaction.

   Evidence Two independent shRNAs in THP-1 macrophage-like cells followed by DENV2 infection and viral replication quantification

   PMID:28241052

   Open questions at the time

   • Molecular step in the viral life cycle requiring OSBPL10 not defined
   • Whether lipid transfer activity underlies the pro-viral effect untested
4. 2024 Medium

   Defining an upstream and downstream axis showed OSBPL10 is a HIF-1α target that signals via direct CNBP binding to drive pancreatic cancer phenotypes and macrophage polarization.

   Evidence HIF-1α promoter interaction assay, Co-IP with mass spectrometry, western blot, and functional cell assays in pancreatic cancer cells

   PMID:39329194

   Open questions at the time

   • Co-IP/MS not reciprocally validated
   • Mechanism connecting CNBP regulation to metastasis and M1→M2 polarization not fully resolved
5. 2026 Medium

   Identifying phosphatidylserine delivery to lysosomes established the concrete lipid transfer activity of OSBPL10 and tied it to lysosomal membrane repair, autophagy, and protection from ferroptosis.

   Evidence Western blotting, immunofluorescence, molecular docking, lipid synthesis inhibitor rescue, RNA-seq, CSF ELISA, and an in vivo mouse spinal cord injury model

   PMID:41794746

   Open questions at the time

   • Direct in vitro reconstitution of PS transfer not shown
   • Lysosomal membrane contact site machinery for PS delivery not detailed
6. 2026 Medium

   Mapping co-factors placed OSBPL10's lysosomal repair within a VAPA/VAPB–ATG2A axis driving lipophagy and tumor growth, unifying its lysosomal and lipid-mobilization roles.

   Evidence Immunofluorescence, single-cell transcriptomics, orthotopic/subcutaneous xenografts, and lysosomal function inhibition in PDAC

   PMID:42003919

   Open questions at the time

   • Direct physical interaction stoichiometry among OSBPL10, VAPA/VAPB and ATG2A not quantified
   • Whether contact-site assembly is constitutive or repair-triggered unknown

• How OSBPL10's microtubule association, hepatic lipogenic suppression, viral support, and lysosomal PS transfer mechanistically converge on a single lipid transfer mechanism remains unresolved.
• No unified biochemical model connecting the distinct cellular contexts
• Structural basis of lipid selectivity and membrane targeting uncharacterized