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Trypanosoma brucei bloodstream forms depend upon uptake of myo-inositol for Golgi phosphatidylinositol synthesis and normal cell growth

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Amaia González-Salgado, Michael Steinmann, Louise Laura Major, Erwin Sigel, Jean-Louis Reymond, Terry K Smith, Peter Bütikofer

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Abstract

myo-Inositol is a building block for all inositol-containing phospholipids in eukaryotes. It can be synthesized de novo from glucose-6-phosphate in the cytosol and endoplasmic reticulum. Alternatively, it can be taken up from the environment via Na+- or H+-linked myo-inositol transporters. While Na+-coupled myo-inositol transporters are found exclusively in the plasma membrane, H+-linked myo-inositol transporters are detected in intracellular organelles. In Trypanosoma brucei, the causative agent of human African sleeping sickness, myo-inositol metabolism is compartmentalized. De novo synthesized myo-inositol is used for glycosylphosphatidylinositol production in the endoplasmic reticulum, whereas the myo-inositol taken up from the environment is used for bulk phosphatidylinositol synthesis in the Golgi. We now provide evidence that the Golgi localized T. brucei H+-linked myo-inositol transporter (TbHMIT) is essential in bloodstream forms. Down-regulation of TbHMIT expression by RNA interference blocked phosphatidylinositol production and inhibited growth of parasites in culture. Characterization of the transporter in a heterologous expression system demonstrated a remarkable selectivity of TbHMIT for myo-inositol. It only tolerates a single modification on the inositol ring, such as the removal of a hydroxyl group, or the inversion of stereochemistry at a single hydroxyl group relative to myo-inositol.
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Original languageEnglish
Pages (from-to)616-624
JournalEukaryotic Cell
Volume14
Issue number6
Early online date17 Apr 2015
DOIs
Publication statusPublished - Jun 2015

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