Journal
CURRENT BIOLOGY
Volume 30, Issue 19, Pages 3775-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2020.07.059
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Funding
- Basque Government
- HHMI fellowship from the Jane Coffin Childs Memorial Fund for Medical Research
- Swiss National Science Foundation [163966]
- Swiss National Supercomputing Centre (CSCS) [s726, s842]
- NCCR Chemical Biology [183561, 184949, 185898]
- Swiss National Science Foundation
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Sphingolipids play important roles in physiology and cell biology, but a systematic examination of their functions is lacking. We performed a genome-wide CRISPRi screen in sphingolipid-depleted human cells and identified hypersensitive mutants in genes of membrane trafficking and lipid biosynthesis, including ether lipid synthesis. Systematic lipidomic analysis showed a coordinate regulation of ether lipids with sphingolipids, suggesting an adaptation and functional compensation. Biophysical experiments on model membranes show common properties of these structurally diverse lipids that also share a known function as glycosylphosphatidylinositol (GPI) anchors in different kingdoms of life. Molecular dynamics simulations show a selective enrichment of ether phosphatidylcholine around p24 proteins, which are receptors for the export of GPI-anchored proteins and have been shown to bind a specific sphingomyelin species. Our results support a model of convergent evolution of proteins and lipids, based on their physico-chemical properties, to regulate GPI-anchored protein transport and maintain homeostasis in the early secretory pathway.
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