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Sphingosine kinases regulate ER contacts with late endocytic organelles and cholesterol trafficking

Palladino, Elisa ND; Bernas, Tytus; Green, Christopher D; Weigel, Cynthia; Singh, Sandeep K; Senkal, Can E; Martello, Andrea; ... Spiegel, Sarah; + view all (2022) Sphingosine kinases regulate ER contacts with late endocytic organelles and cholesterol trafficking. Proceedings of the National Academy of Sciences , 119 (39) , Article e2204396119. 10.1073/pnas.2204396119. Green open access

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Abstract

Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.

Type: Article
Title: Sphingosine kinases regulate ER contacts with late endocytic organelles and cholesterol trafficking
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2204396119
Publisher version: https://doi.org/10.1073/pnas.2204396119
Language: English
Additional information: Copyright © 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). See: https://creativecommons.org/licenses/by-nc-nd/4.0/
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10156343
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