atg5 is essential for atg8-dependent autophagy and mitochondrial homeostasis in leishmania majoratg5 atg8-dependent自噬是至关重要的,在利什曼虫主要线粒体内稳态.pdfVIP

ATG5 Is Essential for ATG8-Dependent Autophagy and Mitochondrial Homeostasis in Leishmania major 1 2 3 3 1 Roderick A. M. Williams , Terry K. Smith , Benjamin Cull , Jeremy C. Mottram , Graham H. Coombs * 1 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom, 2 Schools of Biology Chemistry, The University of St. Andrews, St. Andrews, United Kingdom, 3 Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom Abstract Macroautophagy has been shown to be important for the cellular remodelling required for Leishmania differentiation. We now demonstrate that L. major contains a functional ATG12-ATG5 conjugation system, which is required for ATG8- dependent autophagosome formation. Nascent autophagosomes were found commonly associated with the mitochondrion. L. major mutants lacking ATG5 (Datg5) were viable as promastigotes but were unable to form autophagosomes, had morphological abnormalities including a much reduced flagellum, were less able to differentiate and had greatly reduced virulence to macrophages and mice. Analyses of the lipid metabolome of Datg5 revealed marked elevation of phosphatidylethanolamines (PE) in comparison to wild type parasites. The Datg5 mutants also had increased mitochondrial mass but reduced mitochondrial membrane potential and higher levels of reactive oxygen species. These findings indicate that the lack of ATG5 and autophagy leads to perturbation of the