Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor

Author:

Altuzar Janathan1ORCID,Notbohm Judith1ORCID,Stein Frank2,Haberkant Per2,Hempelmann Pia1ORCID,Heybrock Saskia3,Worsch Jutta1ORCID,Saftig Paul3,Höglinger Doris1

Affiliation:

1. Heidelberg University Biochemistry Center, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany

2. European Molecular Biology Laboratory, 69117 Heidelberg, Germany

3. Institute of Biochemistry, Christian-Albrechts-Universität Kiel, 24118 Kiel, Germany

Abstract

Lysosomes are catabolic organelles involved in macromolecular digestion, and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to common neurodegenerative diseases, many of which have lipid accumulation phenotypes. The mechanism of lipid efflux from lysosomes is well understood for cholesterol, while the export of other lipids, particularly sphingosine, is less well studied. To overcome this knowledge gap, we have developed functionalized sphingosine and cholesterol probes that allow us to follow their metabolism, protein interactions, and their subcellular localization. These probes feature a modified cage group for lysosomal targeting and controlled release of the active lipids with high temporal precision. An additional photocrosslinkable group allowed for the discovery of lysosomal interactors for both sphingosine and cholesterol. In this way, we found that two lysosomal cholesterol transporters, NPC1 and to a lesser extent LIMP-2/SCARB2, bind to sphingosine and showed that their absence leads to lysosomal sphingosine accumulation which hints at a sphingosine transport role of both proteins. Furthermore, artificial elevation of lysosomal sphingosine levels impaired cholesterol efflux, consistent with sphingosine and cholesterol sharing a common export mechanism.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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