Conserved functions of ether lipids and sphingolipids in the early secretory pathway

Jiménez-Rojo, Noemi; Leonetti, Manuel D.; Zoni, Valeria; Colom, Adai; Feng, Suihan; Iyengar, Namrata R.; Matile, Stefan; Roux, Aurélien; Vanni, Stefano; Weissman, Jonathan S.; Riezman, Howard

doi:10.1016/j.cub.2020.07.059

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Conserved functions of ether lipids and sphingolipids in the early secretory pathway

Jiménez-Rojo, Noemi NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland -
Leonetti, Manuel D. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA - Howard Hughes Medical Institute, San Francisco, CA 94158, USA -
Zoni, Valeria Department of Biology, University of Fribourg, Fribourg, Switzerland
Colom, Adai NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland
Feng, Suihan NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland
Iyengar, Namrata R. Institute of Protein Biochemistry (IBP), Italian National Research Council (CNR), Napoli, Italy
Matile, Stefan NCCR Chemical Biology, Department of Organic Chemistry, University of Geneva, 1211 Geneva, Switzerlan
Roux, Aurélien NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland
Vanni, Stefano Department of Biology, University of Fribourg, Fribourg, Switzerland
Weissman, Jonathan S. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA - Howard Hughes Medical Institute, San Francisco, CA 94158, USA
Riezman, Howard NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland -

05.10.2020

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Current Biology. - 2020, vol. 30, no. 19, p. 3775-3787.e7

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

Language