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J. Biol. Chem., Vol. 283, Issue 6, 3454-3464, February 8, 2008

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Autophagy Is Involved in Nutritional Stress Response and Differentiation in Trypanosoma cruzi^*

Vanina E. Alvarez¹², Gregor Kosec¹, Celso Sant'Anna^¶3, Vito Turk, Juan J. Cazzulo⁴, and Boris Turk⁵

From the Instituto de Investigaciones Biotecnologicas (IIB/INTECH, Universidad Nacional de San Martín/Consejo Nacional de Investigaciones Científicas y Técnicas), 1650 San Martin, Buenos Aires, Argentina, the ^¶Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, Ilha do Fundão, 21949-900 Rio de Janeiro-RJ, Brazil, and the Department of Biochemistry and Molecular and Structural Biology, Joef Stefan Institute, Jamova 39, SI 1000, Ljubljana, Slovenia

Autophagy is the major mechanism used by eukaryotic cells to degrade and recycle proteins and organelles. Bioinformatics analysis of the genome of the protozoan parasite Trypanosoma cruzi revealed the presence of all components of the Atg8 conjugation system, whereas Atg12, Atg5, and Atg10 as the major components of the Atg12 pathway could not be identified. The two TcATG4 (autophagin) homologs present in the genome were found to correctly process the two ATG8 homologs after the conserved Gly residue. Functional studies revealed that both ATG4 homologues but only one T. cruzi ATG8 homolog (TcATG8.1) complemented yeast deletion strains. During starvation of the parasite, TcAtg8.1, but not TcAtg8.2, was found by immunofluorescence to be located in autophagosome-like vesicles. This confirms its function as an Atg8/LC3 homolog and its potential to be used as an autophagosomal marker. Most importantly, autophagy is involved in differentiation between developmental stages of T. cruzi, a process that is essential for parasite maintenance and survival. These findings suggest that the autophagy pathway could represent a target for a novel chemotherapeutic strategy against Chagas disease.

Received for publication, October 11, 2007

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ768297, DQ768298, DQ768299, and DQ768300.

^* This work was supported in part by a grant from Slovene Research Agency P0140 (to V. T.) and by a travel grant from the Secretaría de Ciencia, Tecnología e Innovación Productiva (Argentina) as part of a bilateral cooperation agreement with the Slovenian Research Agency. 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. 1 and 2 and Table 1.

¹ Both authors contributed equally to this work.

² Research Fellow of the Argentinian National Research Council (Consejo Nacional de Investigaciones Científicas y Técnicas).

³ Supported in part by a grant from the Ellison Medical Foundation to the Center for Tropical and Emerging Global Diseases. Electronmicroscopywasperformed in the laboratory of Roberto Docampo, University of Georgia, Athens, GA.

⁴ Member of the Research Career of the Argentinian of the National Research Council (Consejo Nacional de Investigaciones Científicas y Técnicas).

⁵ To whom correspondence should be addressed. Tel.: 386-1-477-37-72; Fax: 386-1-477-3894; E-mail: boris.turk{at}ijs.si.

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