Abstract
Plasmodium falciparum causes the most virulent form of malaria and encodes a large number of molecular chaperones. Because the parasite encounters radically different environments during its lifecycle, many members of this chaperone ensemble may be essential for P. falciparum survival. Therefore, Plasmodium chaperones represent novel therapeutic targets, but to establish the mechanism of action of any developed therapeutics, it is critical to ascertain the functions of these chaperones. To this end, we report the development of a yeast expression system for PfHsp70-1, a P. falciparum cytoplasmic chaperone. We found that PfHsp70-1 repairs mutant growth phenotypes in yeast strains lacking the two primary cytosolic Hsp70s, SSA1 and SSA2, and in strains harboring a temperature sensitive SSA1 allele. PfHsp70-1 also supported chaperone-dependent processes such as protein translocation and ER associated degradation, and ameliorated the toxic effects of oxidative stress. By introducing engineered forms of PfHsp70-1 into the mutant strains, we discovered that rescue requires PfHsp70-1 ATPase activity. Together, we conclude that yeast can be co-opted to rapidly uncover specific cellular activities mediated by malarial chaperones.
Highlights
Malaria is a major worldwide health concern, infecting approximately 250 million people and killing at least one million people annually
A role for P. falciparum Hsp70s in protein transport has been inferred [53], suggesting that Hsp70-1 might functionally substitute for a yeast Hsp70 homolog that is required for protein transport
Because P. falciparum must thrive under oxidative conditions, and because chaperone function in cells is critical under these conditions, we studied the ability of PfHsp70-1 to restore Ssa1-dependent growth in yeast exposed to oxidative stressors
Summary
Malaria is a major worldwide health concern, infecting approximately 250 million people and killing at least one million people annually. Most of those killed by malaria are children. The emergence of drug resistant malarial strains has made the disease significantly more difficult to treat. Widespread resistance to affordable and formerly effective drugs like chloroquine, which inhibits heme detoxification [1], has been well documented. Other new antimalarials are prohibitively expensive and/or are accompanied by adverse side effects [3]. It is critical that novel drug targets are identified and that the mechanism of action of putative new anti-malarials [2] are defined so that compounds with improved efficacy can be developed
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