Abstract
The precise role of autophagy in P. falciparum remains largely unknown. Although a limited number of autophagy genes have been identified in this apicomplexan, only PfAtg8 has been characterized to a certain extent. On the basis of the expression levels of PfAtg8 and the putative PfAtg5, we report that the basal autophagy in this parasite is quite robust and mediates not only the intraerythrocytic development but also fresh invasion of red blood cells (RBCs) in the subsequent cycles. We demonstrate that the basal autophagy responds to both inducers and inhibitors of autophagy. In addition, the parasite survival upon starvation is temporally governed by the autophagy status. Brief periods of starvation, which induces autophagy, help survival while prolonged starvation decreases autophagy leading to stalled parasite growth and reduced invasion. Thus, starvation-induced autophagy is context dependent. Importantly, we report characterization of another autophagy marker in this parasite, the putative PfAtg5 (Pf3D7_1430400). PfAtg5 is expressed in all the intraerythrocytic stages and partially colocalizes with ER, mitochondria, apicoplast and PfAtg8. It is also present on the double membrane bound vesicles. Altogether, these studies pave way for the detailed dissection of P. falciparum autophagy machinery and insights into molecular and functional characterization of its players for developing new therapeutics as antimalarials.
Highlights
Macroautophagy in eukaryotes is a conserved catabolic process, whereby cytosolic constituents such as proteins and organelles are captured in double membrane vesicles called autophagosomes and are transported to lysosomes for degradation
As 3-MA inhibits PI3Kinase which is upstream of the autophagy pathway and is implicated in other functions, we studied the effect of MRT 68921, the only known specific autophagy inhibitor ULK110
This study experimentally establishes the role of basal and starvation-induced autophagy in mediating P. falciparum development and invasion during its intraerythrocytic stages, demonstrating a prosurvival mechanism unlike reported for other apicomplexans such as Trypanosoma brucei[16], and Toxoplasma gondii[17,18]
Summary
Macroautophagy (hereafter autophagy) in eukaryotes is a conserved catabolic process, whereby cytosolic constituents such as proteins and organelles are captured in double membrane vesicles called autophagosomes and are transported to lysosomes for degradation. The amino acids and other macromolecular constituents generated in lysosomes are recycled to maintain cellular homeostasis[1]. Autophagy serves as a response mechanism for survival under stress conditions such as starvation, hypoxia, high temperatures, differentiation, protein metabolism, etc[2]. The complex life cycle of human malaria parasite P. falciparum consists of three major stages; in mosquito gut, human liver and blood. During its 48 h asexual intraerythrocytic cycle, the parasite development progresses through ring, trophozoite and schizont stages producing upto 32 daughter cells (merozoites) that can reinvade fresh red blood cells.
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