RESUMEN
The genome of Trypanosoma cruzi was surveyed for autophagy-related genes. We have identified all the essential genes except for the Atg12 conjugation system and demonstrated functionality of the putative ATG4 and ATG8 homologs. TcAtg4.1 was primarily involved in the proteolytic processing of TcAtg8.1, the ATG8-homolog that was found to be localized to autophagosomal membranes during starvation. Autophagy was also found to be strongly upregulated during differentiation between developmental stages, a process that is essential for the propagation of the parasite. Based on our work, new strategies for treatment of Chagas disease, a chronic debilitating condition still without suitable chemotherapy, can be envisioned.
Asunto(s)
Autofagia/fisiología , Enfermedad de Chagas/parasitología , Proteínas Protozoarias/fisiología , Trypanosoma cruzi/fisiología , Animales , Enfermedad de Chagas/tratamiento farmacológico , Genes Protozoarios , Interacciones Huésped-Parásitos , Humanos , Insectos Vectores/fisiología , Fagosomas/metabolismo , Proteínas Protozoarias/genética , Trypanosoma cruzi/genéticaRESUMEN
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.