The ORP9-ORP11 dimer promotes sphingomyelin synthesis
eLife, vol. 12
Abstract
Numerous lipids are heterogeneously distributed among organelles. Most lipid trafficking between organelles is achieved by a group of lipid transfer proteins (LTPs) that carry lipids using their hydrophobic cavities. The human genome encodes many intracellular LTPs responsible for lipid trafficking and the function of many LTPs in defining cellular lipid levels and distributions is unclear. Here, we created a gene knockout library targeting 90 intracellular LTPs and performed whole-cell lipidomics analysis. This analysis confirmed known lipid disturbances and identified new ones caused by the loss of LTPs. Among these, we found major sphingolipid imbalances in ORP9 and ORP11 knockout cells, two proteins of previously unknown function in sphingolipid metabolism. ORP9 and ORP11 form a heterodimer to localize at the ER- trans -Golgi membrane contact sites, where the dimer exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Consequently, loss of either protein causes phospholipid imbalances in the Golgi apparatus that result in lowered sphingomyelin synthesis at this organelle. Overall, our LTP knockout library toolbox identifies various proteins in control of cellular lipid levels, including the ORP9-ORP11 heterodimer, which exchanges PS and PI(4)P at the ER-Golgi membrane contact site as a critical step in sphingomyelin synthesis in the Golgi apparatus.
Authors 8
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Leiden University Medical Center · Oncode Institute
Affiliation as printed
Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center
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Leiden University Medical Center · Oncode Institute
Affiliation as printed
Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center
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Leiden University Medical Center · Oncode Institute
Affiliation as printed
Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center
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Leiden University Medical Center
Affiliation as printed
Centre for Proteomics and Metabolomics, Leiden University Medical Center
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Leiden University Medical Center
Affiliation as printed
Electron Microscopy Facility, Cell and Chemical Biology, Leiden University Medical Center
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Leiden University Medical Center
Affiliation as printed
Electron Microscopy Facility, Cell and Chemical Biology, Leiden University Medical Center
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Leiden University Medical Center
Affiliation as printed
Centre for Proteomics and Metabolomics, Leiden University Medical Center
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Leiden University Medical Center · Oncode Institute
Affiliation as printed
Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center
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