Abstract
The malaria parasite experiences a significant amount of redox stress during its growth in human erythrocytes and heavily relies on secretory functions for pathogenesis. Most certainly, the parasite is equipped with machinery to tackle perturbations in the secretory pathway, like the unfolded protein response pathway in higher eukaryotes. Our bioinformatics analysis revealed the complete absence of genes involved in the canonical unfolded protein response pathway in Plasmodium falciparum. Accordingly, the parasite was unable to up-regulate endoplasmic reticulum (ER) chaperones or ER-associated degradation in response to DTT-mediated ER stress. Global profiling of gene expression upon DTT treatment revealed a network of AP2 transcription factors and their targets being activated. The overall outcome was up-regulation of genes involved in protein export and the sexual stage of the parasite life cycle culminating in gametocytogenesis. Our results suggest that the malaria parasite uses ER stress as a cue to switch to the transmissible sexual stages.
Highlights
Malaria pathogenesis depends on intricate functioning of endoplasmic reticulum (ER) secretory pathway; it lacks canonical unfolded protein response (UPR) machinery to respond to ER stress
ER Stress Induces Gametocytogenesis—Intrigued by the upregulation of transcripts specific to sexual stages of the malaria parasite, we examined whether there was a link between UPR and gametocytogenesis in malaria
The above stress response pathways were originally described in model systems such as yeast and fruit fly, they are relevant to the life cycle of protozoan parasites that cope with the challenging host cell environment for their growth and survival
Summary
Malaria pathogenesis depends on intricate functioning of ER secretory pathway; it lacks canonical UPR machinery to respond to ER stress. Our bioinformatics analysis revealed the complete absence of genes involved in the canonical unfolded protein response pathway in Plasmodium falciparum. The overall outcome was up-regulation of genes involved in protein export and the sexual stage of the parasite life cycle culminating in gametocytogenesis. It aims to increase the folding capacity and thereby decrease the load on the ER [3,4,5] It is mediated by three ER-resident transmembrane proteins, namely IRE1, ATF6, and PERK. It has been reported that P. falciparum-infected erythrocytes efflux glutathione in substantially larger quantities than uninfected erythrocytes (14 –16) This indicates that the parasite resides in an environment that involves extensive oxidative stress so that a large amount of glutathione accumulates in the parasite. Our study sheds light on novel aspects of the ER stress response pathway in P. falciparum where switching over to the sexual stage seems to be the ultimate means to cope with ER stress
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