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Papers In Press, published online ahead of print February 23, 2006
Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow Biomedical Research Centre, Glasgow, Scotland G12 8TA
Corresponding Author: j.mottram{at}udcf.gla.ac.uk
Cellular remodelling during differentiation is essential for life-cycle progression of many unicellular eukaryotic pathogens such as Leishmania, but the mechanisms involved are largely uncharacterised. The role of endosomal sorting in differentiation was analysed in L. major by over-expression of a dominant-negative ATPase VPS4. VPS4E235Q accumulated in vesicles from the endocytic pathway and the mutant L. major was deficient in endosome sorting. Mutant parasites failed to differentiate to the obligate infective metacyclic promastigote form. Furthermore, the autophagy pathway, monitored via the expression of autophagosome marker GFP-ATG8, and shown to normally peak during initiation of metacyclogenesis, was disrupted in the mutants. The defect in late endosome-autophagosome function in the VPS4E235Q parasites made them less able to withstand starvation than wild type L. major. In addition, an L. major ATG4-deficient mutant was found also to be defective in the ability to differentiate. This finding, that transformation to the infective metacyclic form is dependent on late endosome function and, more directly, autophagy, makes L. major a good model for studying the roles of these processes in differentiation.
J. Biol. Chem, 10.1074/jbc.M512307200
Submitted on November 16, 2005
Revised on February 17, 2006
Accepted on February 23, 2006
Endosome sorting and autophagy are essential for differentiation and virulence of Leishmania major
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