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J. Biol. Chem., Vol. 281, Issue 16, 11384-11396, April 21, 2006

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Endosome Sorting and Autophagy Are Essential for Differentiation and Virulence of Leishmania major^*

From the Wellcome Centre for Molecular Parasitology and the Division of Infection & Immunity, Institute of Biomedical and Life Sciences, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, United Kingdom

Cellular remodeling during differentiation is essential for lifecycle progression of many unicellular eukaryotic pathogens such as Leishmania, but the mechanisms involved are largely uncharacterized. The role of endosomal sorting in differentiation was analyzed in Leishmania major by overexpression of a dominant-negative ATPase, VPS4. VPS4^E235Q 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 VPS4^E235Q parasites made them less able to withstand starvation than wild-type L. major. In addition, a 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.

Received for publication, November 16, 2005 , and in revised form, February 17, 2006.

^* This work was supported by the Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and supplemental Table SI.

¹ To whom correspondence should be addressed. Tel.: 44-141-330-3745; Fax: 44-141-330-5422; E-mail: jmottram{at}bio.gla.ac.uk.

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