Publication 325

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  1. Jiménez-Rojo, N.; Leonetti, M. D.; Zoni, V.; Colom, A.; Feng, S.; Iyengar, N. R.; Matile, S.; Roux, A.; Vanni, S.; Weissman, J. S.; Riezman, H. “Conserved Functions of Ether Lipids and Sphingolipids in the Early Secretory Pathway” Curr. Biol. 2020, 30, 3775-3787.e7

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.

DOI: 10.1016/j.cub.2020.07.059 

open archive unige:141206 • pdf