Abstract
Sphingosine-1-phosphate is a signaling molecule involved in the control of cell migration, differentiation, survival and other physiological processes. This sphingolipid metabolite can be degraded by the action of sphingosine-1-phosphate lyase (SPL) to form hexadecenal and ethanolamine phosphate. The importance of SPL-mediated ethanolamine phosphate formation has been characterized in only few cell types. We show that in the protozoan parasite Trypanosoma brucei, expression of TbSpl is essential for cell survival. Ablation of TbSpl expression increased sphingosine-1-phosphate levels and reduced de novo formation and steady-state levels of the glycerophospholipid phosphatidylethanolamine (PE). Growth of TbSpl-depleted parasites could be in part rescued by ethanolamine supplementation to the growth medium, indicating that the main function of TbSpl is to provide ethanolamine phosphate for PE synthesis. In contrast to most cell types analyzed, where SPL localizes to the endoplasmic reticulum, we found by high-resolution microscopy that TbSpl is a mitochondrial protein. In spite of its mitochondrial localization, TbSpl depletion had no apparent effect on mitochondrial morphology but resulted in aggregation of acidocalcisomes. Our results link mitochondria to sphingolipid metabolism and suggest possible roles for PE in acidocalcisome function.
Highlights
Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite involved in the control of cell migration, differentiation and survival, as well as numerous otherphysiological processes
While hexadecenal has been shown to sensitize mitochondria for BAK activation[34] and apoptosis[35], ethanolamine phosphate is generally thought to feed into the PE branch of the Kennedy pathway
We show that inhibition of ethanolamine phosphate formation in T. brucei by depletion of T. brucei SPL (TbSpl) expression leads to reduced de novo synthesis and steady-state levels of PE, resulting in parasite death
Summary
Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite involved in the control of cell migration, differentiation and survival, as well as numerous other (patho-)physiological processes (reviewed in 1–5). Reduced or lack of SPL activity was shown to affect normal immune function, whereas upregulation of SPL activity was reported in several human pathologic conditions 4,25,26. In model organisms, such as Dictyostelium, Drosophila and Caenorhabditis elegans, reduced or deficient SPL expression caused numerous cellular abnormalities, including dysregulation in sphingolipid metabolism. Since the cellular and biochemical alterations could be reversed upon supplementation of parasites with exogenous ethanolamine, the report proposed that the main function of SPL in Leishmania is not to degrade S1P but to produce ethanolamine phosphate for glycerophospholipid synthesis[27]
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