Apoptosis is a highly regulated process of cell death in metazoans. Therefore, understanding the biochemical changes associated with apoptosis-like death in Trypanosoma cruzi is key to drug development. PAC-1 was recently shown to induce apoptosis in T. cruzi; with this as motivation, we used quantitative proteomics to unveil alterations of PAC-1-treated versus untreated epimastigotes. The PAC-1 treatment reduced the abundance of putative vesicle-associated membrane protein, putative eukaryotic translation initiation factor 1 eIF1, coatomer subunit beta, putative amastin, and a putative cytoskeleton-associated protein. Apoptosis-like signaling also increases the abundance of proteins associated with actin cytoskeleton remodeling, cell polarization, apoptotic signaling, phosphorylation, methylation, ergosterol biosynthesis, vacuolar proteins associated with autophagy, and flagellum motility. We shortlist seventeen protein targets for possible use in chemotherapy for Chagas disease. Almost all differentially abundant proteins belong to a family of proteins previously associated with apoptosis in metazoans, suggesting that the apoptotic pathway's key functions have been preserved from trypanosomatids and metazoans.

Significance

Approximately 8 million people worldwide are infected with Trypanosoma cruzi. The treatment of Chagas disease comprises drugs with severe side effects, thus limiting their application. Thus, developing new pharmaceutical solutions is relevant, and several molecules targeting apoptosis are therapeutically efficient for parasitic, cardiac, and neurological diseases. Apoptotic processes lead to specific morphological features that have been previously observed in T. cruzi. Here, we investigate changes in epimastigotes' proteomic profile treated with the proapoptotic compound PAC-1, providing data concerning the regulation of both metabolic and cellular processes in nonmetazoan apoptotic cells. We shortlist seventeen protein target candidates for use in chemotherapy for Chagas disease.

中文翻译：

---

用促凋亡化合物PAC-1处理的克氏锥虫锥虫的蛋白质组学变化

凋亡是后生动物中高度受控的细胞死亡过程。因此，了解克氏锥虫细胞凋亡样死亡相关的生化变化是药物开发的关键。最近显示，PAC-1可以诱导克鲁维酵母的凋亡。; 以此为动力，我们使用定量蛋白质组学揭示了经PAC-1处理的前鞭毛体与未处理的鞭毛体的变化。PAC-1处理减少了假定的囊泡相关膜蛋白，假定的真核翻译起始因子1 eIF1，涂层亚基β，假定的amastin和假定的细胞骨架相关蛋白的含量。凋亡样信号转导也增加了与肌动蛋白细胞骨架重塑，细胞极化，细胞凋亡信号转导，磷酸化，甲基化，麦角固醇生物合成，与自噬相关的液泡蛋白和鞭毛运动性相关蛋白的丰度。我们入围了十七种可能用于南美锥虫病化学疗法的蛋白质靶标。

意义

全世界约有80​​0万人感染了克氏锥虫。恰加斯病的治疗包括具有严重副作用的药物，因此限制了它们的应用。因此，开发新的药物解决方案是重要的，并且靶向凋亡的几种分子对于寄生虫，心脏和神经系统疾病在治疗上是有效的。凋亡过程导致特定的形态特征，先前已在克鲁氏锥虫中观察到。在这里，我们研究了用前凋亡化合物PAC-1处理的前鞭毛纲动物的蛋白质组学特征的变化，提供了有关非metazoan凋亡细胞中代谢和细胞过程调节的数据。我们入围了17种蛋白质目标候选物，用于Chagas病的化学疗法。