Unexpected Role of Sterol Synthesis in RNA Stability and Translation in Leishmania

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.

Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors

“…However, the importance of C14DM for cell functions goes beyond sterol biosynthesis. L. major C14DM knockout leads to an increase in mRNA degradation and transcription reduction, disrupting gene expression in the defective parasite sterol production [63].…”

Parasitic Infection and Immunity—A Special Biomedicines Issue

“…Discoveries in basic biology may help us to understand the molecular mechanisms employed by protozoan parasites to survive in the host, contributing to the development of new therapeutic drugs. In this Special Issue, Karamysheva and collaborators [ 6 ] revealed new biological aspects of Leishmania spp., and Marucci and colleagues [ 7 ] sequenced four Giardia lamblia viruses and investigated their biological properties.…”

“…Available therapeutic drugs are associated with toxic side effects and the rapid emergence of drug-resistant strains, while prophylactic tools are limited. To reveal the role of lipids in controlling gene expression, Karamysheva and coworkers [ 6 ] studied the C14-demethylase (CD14DM) enzyme, which catalyzes the biosynthesis of ergostane-based sterols. Unlike mammals, Leishmania does not synthesize cholesterol, but ergostane-based sterols, which make CD14DM an interesting drug target.…”