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VIEW Open Access Are Protozoan Metacaspases Potential Parasite Killers? Benoît Meslin1, Habib Zalila2, Nicolas Fasel2, Stephane Picot1, Anne-Lise Bienvenu1*

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VIEW Open Access Are Protozoan Metacaspases Potential Parasite Killers? Benoît Meslin1, Habib Zalila2, Nicolas Fasel2, Stephane Picot1, Anne-Lise Bienvenu1* Meslin et al. Parasites & Vectors 2011, 4:26 http://www.parasitesandvectors.com/content/4/1/26 REVIEW Open Access Are protozoan metacaspases potential parasite killers? Benoît Meslin1, Habib Zalila2, Nicolas Fasel2, Stephane Picot1, Anne-Lise Bienvenu1* Abstract Mechanisms concerning life or death decisions in protozoan parasites are still imperfectly understood. Comparison with higher eukaryotes has led to the hypothesis that caspase-like enzymes could be involved in death pathways. This hypothesis was reinforced by the description of caspase-related sequences in the genome of several parasites, including Plasmodium, Trypanosoma and Leishmania. Although several teams are working to decipher the exact role of metacaspases in protozoan parasites, partial, conflicting or negative results have been obtained with respect to the relationship between protozoan metacaspases and cell death. The aim of this paper is to review current knowledge of protozoan parasite metacaspases within a drug targeting perspective. Metacaspases: a twenty-first century history However, it demonstrated the requirement to explore the In the late nineties, Aravind from Bethesda was the first to role of metacaspases, as an aid to determining whether describe orthologues of caspases [1]. This paved the way renaming these enzymes in agreement with their definitive for Uren and colleagues to describe paracaspases from ani- specificity is needed. mals and slime mould, and metacaspases from plants, Although only recently described and their function fungi and protozoa, in the beginning of 21st century [2]. poorly explored, metacaspases could be considered as Caspases are limited to metazoans, while metacaspases are potential targets for new specific treatments against the missing from them: leading to the hypothesis that meta- main protozoan parasites affecting humans. Elucidating caspases resemble ancestral proteases and that caspases their role in physiology is certainly a requirement, but it have diverged through evolution under environmental is clear that addressing this issue could provide new stresses. Approximately a hundred papers were published insights into the fight against tropical diseases. during the first decade of the new century: mostly studying the role of metacaspase in apoptosis in the budding yeast, Structure/Activity of metacaspases Saccharomyces cerevisiae, for example [3,4]. While the Peptidases are classified in the MEROPS database http:// involvement of yeast metacaspase in cell death is well merops.sanger.ac.uk using “clans” and “families” fea- documented [5,6], a non-death role for the yeast metacas- tures. All the sequences in the same clan are evolutiona- pase Yca1p has also been described [7]. More recently, rily-related, determined by similarities in protein tertiary authors have strongly expressed their disagreement with structures and share a similar protein fold [11]. A pepti- the classification of metacaspases as part of the caspases dase clan consists of two letters, the first designating the family [8]. It was argued that the specificity of these catalytic type, for example A for aspartic acid, C for enzymes should determine their classification, rather than cysteine, S for serine. Because some cysteine, serine and any similarities. Other papers with definitive titles (“Are threonine peptidases have similar folds, the letter “P” is metacaspases caspases?” [9] and “Metacaspases are cas- used for clans of mixed catalytic type. Among the pepti- pases. Doubt no more” [10]) were published, demonstrat- dases forming a transient covalent bond between the ing the vitality of the debate. Whether this controversy substrate and the enzyme, serine, threonine and cysteine will address issues of medical importance is debatable. peptidases are well described [12]. Metacaspases (MCA) are cysteine proteases with * Correspondence: [email protected] structural similarity to caspases and a catalytic cysteine- 1Malaria Research Unit, University Lyon 1, 8 Avenue Rockefeller, 69373 Lyon histidine dyad. Caspases and metacaspases are members cedex 08, France Full list of author information is available at the end of the article of the C14 family, clan CD, with probable differences in © 2011 Meslin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Meslin et al. Parasites & Vectors 2011, 4:26 Page 2 of 7 http://www.parasitesandvectors.com/content/4/1/26 substrate specificity [13]. Surprisingly, it was recently mosquito midgut stages of the parasite die naturally by demonstrated that two different type 1 metacaspases apoptosis before gut invasion. This phenomenon was from a plant (Arabidopsis thaliana) differentially regu- prevented by a caspase inhibitor [19]. late superoxide-dependant cell death: AtMC1 is a pro- Metacaspase, as well as clans CA, CD and CE pro- death caspase-like protein while AtMC2 antagonizes this teases have been described in Plasmodium [20]. Clan function [14]. Metacaspases have a highly acidic S1 CA proteases are the best-characterised cysteine pro- pocket leading to a basic specificity for arginine and teases of Plasmodium (Table 1). The major functions of lysine at the P1 position, rather than aspartic acid speci- clan CA proteases, including falcipains, concerned with ficity as seen for caspases [12,15]. hemoglobin hydrolysis and erythrocyte rupture or inva- Differences in substrate specificity between metacas- sion was extensively reviewed a few years ago [21]. pases and caspases lead to uncertainty concerning the However, few studies have been conducted to decipher potential role of protozoan metacaspases in apoptosis- the role of Plasmodium metacaspases [22,23]. like cell death, and it has been proposed that metacas- Three MCAs were described in the genome of the two pases and paracaspases should be separated in a specific major human malaria parasites, P. falciparum (PfMCA1- family in clan CD [9]. Nevertheless, it was recently 3) and P. vivax (PvMCA1-3), and in the murine parasite demonstrated that caspases and metacaspases can both P. berghei (PbMCA1-3). PxMCA1 is the only enzyme target the Tudor Staphylococcal Nuclease (TSN) [16]. that presents the well-characterized histidine and TSN is an evolutionary conserved protein, composed of cysteine catalytic dyad. Patterns of expression seem to a single Tudor domain and five staphylococcal nuclease- differ between PfMCA1 and PbMCA1. PfMCA1 gene like domains, and is involved in a number of transcrip- expression was described in the erythrocytic stage tional and post-transcriptional pathways. Homo sapiens [Meslin et al, unpublished observations], PbMCA1 TSN sequence shows a consensus cleavage site for cas- expression was detected in female gametocytes, in pase-3, and proteolysis of TSN is blocked after treat- oocysts and in sporozoites, but authors [23] failed to ment with the pan-caspase inhibitor zVAD-fmk. demonstrate a significant level of ookinetes apoptosis Although the DAVD caspase-3 cleavage motif is absent compared to other studies [19,24], and did not observe from protozoa, fungi and plants, TSN proteins from the differences between wild-type (WT) and PbMCA1-KO plant Picea abies were found to contain several metacas- ookinetes, leading to the conclusion that functional pase cleavage sites [16]. The ability of caspase from ver- redundancy may exist, probably through PbMCA2/3 tebrate and type 2 metacaspase from plant to cleave the activity. It should be kept in mind that apoptosis of nor- same substrate with a central role in the cell degradome mal parasites may occur in specific conditions that lead provides new evidence that metacaspase could be to a message of death. A more comprehensive study of involved in apoptosis control [16]. the role of metacaspase in Plasmodium biology should be conducted in the presence of one such message. In a Plasmodium Metacaspases recent study, Plasmodium falciparum metacaspase While insecticide-treated bednets, Artemisinin-based expression was measured during parasite culture in combined therapy (ACTs) and climatic changes have vitro, showing a relationship with parasitemia levels and transformed the global impact of malaria in endemic suggesting a role in growth regulation [25]. These preli- areas, this parasitic disease remains a major life-threa- minary results provide some more evidence for a role of tening challenge for millions of people. ACTs are the metacaspase in Plasmodium fitness. drugs of choice for non-severe malaria, but parasite The expression of PfMCA1 C14 peptidase domain in resistance is speculated to appear in the near future yca1 deficient S. cerevisiae led to growth retardation and a [17]. Thus, it is of utmost importance to decipher the drastic yeast cell death [Meslin et al, unpublished observa- mechanisms of parasite growth control, in order to tions]. Interestingly, this phenotype could be blocked by detect new drug targets; potentially not subjected to the addition of the pan caspase inhibitor z-VAD-fmk resistance. Apoptosis-like DNA fragmentation of Plas- while PfMCA1 did not exhibit a caspase-like, but an argi- modium falciparum parasite in response to chloroquine nine protease activity, as reported for other protozoan treatment was described more than a decade ago [18]. It MCAs [Meslin et al, unpublished observations]. PfMCA1
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