Abstract
Leishmania parasites are trypanosomatid protozoans that cause leishmaniasis affecting millions of people worldwide. Sterols are important components of the plasma and organellar membranes. They also serve as precursors for the synthesis of signaling molecules. Unlike animals, Leishmania does not synthesize cholesterol but makes ergostane-based sterols instead. C-14-demethylase is a key enzyme involved in the biosynthesis of sterols and an important drug target. In Leishmania parasites, the inactivation of C-14-demethylase leads to multiple defects, including increased plasma membrane fluidity, mitochondrion dysfunction, hypersensitivity to stress and reduced virulence. In this study, we revealed a novel role for sterol synthesis in the maintenance of RNA stability and translation. Sterol alteration in C-14-demethylase knockout mutant leads to increased RNA degradation, reduced translation and impaired heat shock response. Thus, sterol biosynthesis in Leishmania plays an unexpected role in global gene regulation.
Highlights
Protozoan parasites of the genus Leishmania cause leishmaniasis infecting 10–12 million people worldwide [1]
We revealed an unexpected role of sterol synthesis in RNA stability and translation
During the last few decades, a substantial amount of research revealed the importance of lipids as signaling molecules regulating many processes and gene expression pathways in the cell
Summary
Protozoan parasites of the genus Leishmania cause leishmaniasis infecting 10–12 million people worldwide [1]. All three forms of leishmaniasis are transmitted through the bite of sand fly vectors (Phlebotomus spp. and Lutzomyia spp.) During their life cycle, these dixenic protozoans alternate between flagellated, extracellular promastigotes, which live in the midgut of sand flies, and non-flagellated amastigotes residing in the phagolysosomal compartment of mammalian macrophages [5]. Sterols are important constituents of the plasma membrane (PM), endoplasmic reticulum (ER) and organellar membranes Because of their rigid and hydrophobic structure, sterols reduce the flexibility of acyl chains of neighboring phospholipids and increase membrane rigidity and tightness [17]. C14DM-null mutant (c14dm− ) has been characterized in Leishmania major LV39 strain [22] This mutant cannot remove the C-14-methyl group from lanosterol or other sterol intermediates. Our study is the first of its kind that links sterol synthesis to the global regulation of gene expression at the level of RNA stability
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