Structural and Computational Proteomics Laboratory, Carlos Chagas Institute, FIOCRUZ-PR, Curitiba, PR, 80320-290, Brazil.
Structural and Computational Proteomics Laboratory, Carlos Chagas Institute, FIOCRUZ-PR, Curitiba, PR, 80320-290, Brazil.
Biochim Biophys Acta Proteins Proteom. 2021 Feb;1869(2):140582. doi: 10.1016/j.bbapap.2020.140582. Epub 2020 Dec 5.
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.
细胞凋亡是后生动物细胞死亡的一种高度调控的过程。因此，了解与锥虫属 Trypanosoma cruzi 类似凋亡死亡相关的生化变化是药物开发的关键。最近的研究表明，PAC-1 可诱导 T. cruzi 细胞发生凋亡；受此启发，我们使用定量蛋白质组学方法揭示了 PAC-1 处理与未处理的滋养体之间的变化。PAC-1 处理降低了假定囊泡相关膜蛋白、假定真核翻译起始因子 1 eIF1、衣壳蛋白亚基β、假定阿米巴素和假定细胞骨架相关蛋白的丰度。类似凋亡的信号还增加了与肌动蛋白细胞骨架重塑、细胞极化、凋亡信号、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相关的蛋白质的丰度。我们列出了十七个可能用于治疗恰加斯病的化疗的蛋白质靶标。几乎所有差异丰度的蛋白质都属于先前与后生动物细胞凋亡相关的蛋白质家族，这表明凋亡途径的关键功能已在原生动物和后生动物中得到保留。意义：全世界约有 800 万人感染了锥虫属 Trypanosoma cruzi。对恰加斯病的治疗包括使用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相关的，并且几种针对凋亡的分子在寄生虫、心脏和神经疾病方面具有治疗效果。凋亡过程导致了在 T. cruzi 中已经观察到的特定形态特征。在这里，我们研究了用促凋亡化合物 PAC-1 处理滋养体后的蛋白质组图谱变化，提供了关于非后生动物凋亡细胞代谢和细胞过程调节的相关数据。我们列出了十七个可能用于治疗恰加斯病的化疗的蛋白质靶标候选物。
