Released Parasite-Derived Kinases as Novel Targets for Antiparasitic Therapies.

The efficient manipulation of their host cell is an essential feature of intracellular parasites. Most molecular mechanisms governing the subversion of host cell by protozoan parasites involve the release of parasite-derived molecules into the host cell cytoplasm and direct interaction with host proteins. Among these released proteins, kinases are particularly important as they govern the subversion of important host pathways, such as signalling or metabolic pathways. These enzymes, which catalyse the transfer of a phosphate group from ATP onto serine, threonine, tyrosine or histidine residues to covalently modify proteins, are involved in numerous essential biological processes such as cell cycle or transport. Although little is known about the role of most of the released parasite-derived kinases in the host cell, they are examples of kinases hijacking host cellular pathways such as signal transduction or apoptosis, which are essential for immune response evasion as well as parasite survival and development. Here we present the current knowledge on released protozoan kinases and their involvement in host-pathogen interactions. We also highlight the knowledge gaps remaining before considering those kinases - involved in host signalling subversion - as antiparasitic drug targets.

Role of PfGCN5 in nutrient sensing and transcriptional regulation in Plasmodium falciparum.

Malaria is a deadly, infectious disease caused by the parasite Plasmodium, leading to millions of deaths worldwide. Plasmodium requires a coordinated pattern of sequential gene expression for surviving in both invertebrate and vertebrate host environments. As parasites largely depend on host resources, they also develop efficient mechanisms to sense and adapt to variable nutrient conditions in the environment and modulate their virulence. Earlier we have shown that PfGCN5, a histone acetyltransferase, binds to the stress-responsive and virulence-related genes in a poised state and regulates their expression under temperature and artemisinin treatment conditions in P. falciparum. In this study, we show upregulation of PfGCN5 upon nutrient stress condition. With the help of chromatin immunoprecipitation coupled high-throughput sequencing (ChIP-seq) and transcriptomic (RNA-sequencing) analyses, we show that PfGCN5 is associated with the genes that are important for the maintenance of parasite cellular homeostasis upon nutrient stress condition. Furthermore, we identified various metabolic enzymes as interacting partners of PfGCN5 by immunoprecipitation coupled with mass spectroscopy, possibly acting as a sensor of nutrient conditions in the environment. We also demonstrated that PfGCN5 interacts and acetylates PfGAPDH in vitro. Collectively, our data provides important insights into transcriptional deregulation upon nutrient stress condition and elucidate the role of PfGCN5 during nutrient stress condition.