title: Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death.
abstract: Activation of proteolytic cell death pathways may circumvent drug resistance in deadly protozoan parasites such as Plasmodium falciparum and Leishmania. To this end, it is important to define the cell death pathway(s) in parasites and thus characterize proteases such as metacaspases (MCA), which have been reported to induce cell death in plants and Leishmania parasites. We, therefore, investigated whether the cell death function of MCA is conserved in different protozoan parasite species such as Plasmodium falciparum and Leishmania major, focusing on the substrate specificity and functional role in cell survival as compared to Saccharomyces cerevisae. Our results show that, similarly to Leishmania, Plasmodium MCA exhibits a calcium-dependent, arginine-specific protease activity and its expression in yeast induced growth inhibition as well as an 82% increase in cell death under oxidative stress, a situation encountered by parasites during the host or when exposed to drugs such as artemisins. Furthermore, we show that MCA cell death pathways in both Plasmodium and Leishmania, involve a z-VAD-fmk inhibitable protease. Our data provide evidence that MCA from both Leishmania and Plasmodium falciparum is able to induce cell death in stress conditions, where it specifically activates a downstream enzyme as part of a cell death pathway. This enzymatic activity is also induced by the antimalarial drug chloroquine in erythrocytic stages of Plasmodium falciparum. Interestingly, we found that blocking parasite cell death influences their drug sensitivity, a result which could be used to create therapeutic strategies that by-pass drug resistance mechanisms by acting directly on the innate pathways of protozoan cell death.
authors.affiliation: Malaria Research Unit, ICBMS UMR 5246 CNRS-UCBL1-INSA, Lyon, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Meslin
authors.forename: Abdoul H
authors.initials: AH
authors.lastname: Beavogui
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fasel
authors.forename: Stéphane
authors.initials: S
authors.lastname: Picot
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057056:Cysteine Proteases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008969:Molecular Sequence Data; D016877:Oxidants / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000962:Antimalarials; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016877:Oxidants; D015800:Protozoan Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002738:Chloroquine; D006861:Hydrogen Peroxide; D057056:Cysteine Proteases; D010450:Endopeptidases; D020169:Caspases; D003546:Cysteine Endopeptidases; C569841:MCA-1 protein, Plasmodium falciparum; C034735:arginine protease; D002118:Calcium