Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death.
Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death.
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恶性疟原虫metacaspase PFMCA-1触发Z-VAD-FMK可抑制的蛋白酶以促进细胞死亡。
DOI：
10.1371/journal.pone.0023867
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Picot S
中科院分区：
文献类型：
--
作者：
Meslin B;Beavogui AH;Fasel N;Picot S
蛋白水解细胞死亡途径的激活可能会规避致命的原生动物寄生虫，如恶性疟原虫和利什曼原虫的耐药性。为此，重要的是定义寄生虫中的细胞死亡途径，从而表征蛋白酶，如元天冬酶（MCA），其已被报道在植物和利什曼原虫寄生虫中诱导细胞死亡。因此，我们研究了MCA的细胞死亡功能是否在不同的原生动物寄生虫物种，如恶性疟原虫和利什曼原虫中是保守的，重点是与酿酒酵母相比，在细胞存活中的底物特异性和功能作用。我们的研究结果表明，类似于利什曼原虫，疟原虫MCA表现出钙依赖性，精氨酸特异性蛋白酶活性和其在酵母诱导的生长抑制以及氧化应激下细胞死亡增加82%，这种情况下遇到的寄生虫在宿主或暴露于药物，如青蒿素。此外，我们表明，MCA细胞死亡途径在疟原虫和利什曼原虫，涉及一个z-VAD-favoritable蛋白酶。我们的数据提供的证据表明，MCA从利什曼原虫和恶性疟原虫是能够诱导细胞死亡的应激条件下，它特异性地激活下游酶作为细胞死亡途径的一部分。在恶性疟原虫红细胞期，抗疟药氯喹也能诱导这种酶活性。有趣的是，我们发现阻断寄生虫细胞死亡会影响它们的药物敏感性，这一结果可用于创建治疗策略，通过直接作用于原生动物细胞死亡的先天途径来绕过耐药性机制。
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.
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影响因子：
9
作者：
通讯作者：
--
影响因子：
9
作者：
通讯作者：
--
影响因子：
3.1
作者：
Lim, JH;Gowda, DC;Luckhart, S
通讯作者：
Luckhart, S
影响因子：
16
作者：
Madeo, F;Herker, E;Fröhlich, KU
通讯作者：
Fröhlich, KU
影响因子：
1.5
作者：
Le Chat, Ludovic;Sinden, Robert E.;Dessens, Johannes T.
通讯作者：
Dessens, Johannes T.