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Cited by 8Sphingolipid Metabolism and SignalingLipid metabolism and biosynthesisCellular transport and secretion

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The ORP9-ORP11 dimer promotes sphingomyelin synthesis

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Cabukusta, Birol, Borst Pauwels, Shalom, Akkermans, Jimmy JLL, Blomberg, Niek, Mulder, Aat A, Koning, Roman I, Giera, Martin, Neefjes, Jacques·2024·eLife
DOI 10.7554/elife.91345PMC PMC11302984

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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.

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Metadata

Authors
Cabukusta, B., Borst Pauwels, S., Akkermans, J. J., Blomberg, N., Mulder, A. A., Koning, R. I., Giera, M., & Neefjes, J.
Affiliations
  • Leiden University Medical Center (NL)
  • Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center
Corresponding author
Cabukusta, Birol
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-08-06
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.91345
PMC
PMC11302984
OpenAlex
W4387169175
Cited by
8
References
4
Citations by year
2026: 5 · 2025: 3
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Oncode Institute
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Spinoza 00897590)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
lipid transfer proteins, sphingomyelin synthesis, sphingolipid metabolism, phosphatidylserine, phosphatidylinositol 4-phosphate, Golgi apparatus, lipid trafficking
MeSH terms
Oxysterol Binding Proteins, Carrier Proteins, Endoplasmic Reticulum, Golgi Apparatus, Humans, Receptors, Steroid, Sphingomyelins, Phosphatidylinositol Phosphates, Protein Multimerization, Gene Knockout Techniques

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