Autophagy in Protozoan Parasites: Trypanosoma Brucei as a Model

Abstract

" To gain further and more complete understanding of the mechanisms and functions of autophagy, both conserved and evolutionarily divergent, study of more divergent model systems is needed. " Autophagy is an intracellular pathway that clears macromolecules, organelles and intracellular pathogens through autophagosomes and lysosomes upon nutrient limitation, infections and other physiological/pathological conditions. Autophagy has been best studied in budding yeast and mammals, revealing highly conserved machineries and physiological importance in development and diseases. In general, autophagy is triggered upon inhibition of TOR, or activation of AMPK; both conserved protein kinases. Phosphorylation and activation of ATG13 lead to activation of ULK1/2 (Atg1 in yeast), which further stimulates autophagic modules including the PtdIns3K complex: VPS34 and Beclin1, and the unbiquition-like conjugation system that includes ATG8 and ATG12. VPS34 produces PtdIns3P at certain cellular locations, which serves as a signal to recruit other proteins for phagophore formation. The phagophores elongate and engulf cytoplasmic components, forming double-membraned autophagosomes. Finally, autophagosomes are transported to and fused with lysosomes, where the engulfed materials are degraded.Most of the autophagy-related genes identified are highly conserved functionally in yeast and mammals, although different regulatory or signaling mechanisms have been found for some molecules, mTOR as an example [1]. The protozoan parasites are evolutionarily divergent, single-celled eukaryotic pathogens including the Plasmodium spp. that causes malaria; Toxoplasma gondii that causes toxoplasmosis; and Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. that cause the tritryp diseases. Together these pathogens cause huge economic and disease burdens globally. Bioinformatics analysis identified only about half of the ATG homologs in these protozoan parasites [2], implying a simple or divergent autophagy pathway in these organisms. To gain further and more complete understanding of the mechanisms and functions of autophagy, both conserved and evolutionarily divergent, study of more divergent model systems is needed. Advantages of T. brucei as a model organism for cell biology studiesAmong the protozoan parasites, T. brucei is one of the most genetically accessible for study in laboratories. Like many parasites, T. brucei undergoes a complex life cycle in the insect vector and mammalian hosts, taking on different developmental forms. Cultivation and differentiation of some life-cycle stages can be achieved in vitro, making T. brucei an ideal organism to study the signaling and cellular remodeling mechanisms during life-cycle differentiation and development. Advanced reverse genetics methods such as inducible expression [3,4] and RNAi [5] allow rapid characterization of protein functions. Additionally, T. brucei possesses a variety of organelles, ubiquitously found in all eukaryotes or uniquely present in trypanosomes, many of them present at ...

Cell death pathways in pathogenic trypanosomatids: lessons of (over)kill

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The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids

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The effect of autophagy on the survival and invasive activity of Eimeria tenella sporozoites

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