Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

Journal of Cell Science
Brendan T FinicleAimee L Edinger

Abstract

Endogenous sphingolipids (ceramide) and related synthetic molecules (FTY720, SH-BC-893) reduce nutrient access by decreasing cell surface expression of a subset of nutrient transporter proteins. Here, we report that these sphingolipids disrupt endocytic recycling by inactivating the small GTPase ARF6. Consistent with reported roles for ARF6 in maintaining the tubular recycling endosome, MICAL-L1-positive tubules were lost from sphingolipid-treated cells. We propose that ARF6 inactivation may occur downstream of PP2A activation since: (1) sphingolipids that fail to activate PP2A did not reduce ARF6-GTP levels; (2) a structurally unrelated PP2A activator disrupted tubular recycling endosome morphology and transporter localization; and (3) overexpression of a phosphomimetic mutant of the ARF6 GEF GRP1 prevented nutrient transporter loss. ARF6 inhibition alone was not toxic; however, the ARF6 inhibitors SecinH3 and NAV2729 dramatically enhanced the killing of cancer cells by SH-BC-893 without increasing toxicity to peripheral blood mononuclear cells, suggesting that ARF6 inactivation contributes to the anti-neoplastic actions of sphingolipids. Taken together, these studies provide mechanistic insight into how ceramide and sphingoli...Continue Reading

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Citations

Nov 30, 2018·Molecular & Cellular Proteomics : MCP·Peter KubiniokPierre Thibault
Aug 22, 2020·Journal of Lipid and Atherosclerosis·Scott A Summers
Jul 23, 2020·Nature Metabolism·Scott A SummersWilliam L Holland
Jun 6, 2020·Scientific Reports·Christian M GarridoKwang-Jin Cho
Mar 1, 2019·Molecular & Cellular Proteomics : MCP·Peter KubiniokPierre Thibault
May 22, 2020·ACS Medicinal Chemistry Letters·Sylvestre P J T BacholletStephen Hanessian

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