Extensive Translational Regulation through the Proliferative Transition of Trypanosoma cruzi Revealed by Multi-Omics.
Extensive Translational Regulation through the Proliferative Transition of Trypanosoma cruzi Revealed by Multi-Omics.
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DOI：
10.1128/msphere.00366-21
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发表时间：
2021-10-27
期刊：
影响因子：
4.8
通讯作者：
Duhagon MA
中科院分区：
文献类型：
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作者：
Chávez S;Urbaniak MD;Benz C;Smircich P;Garat B;Sotelo-Silveira JR;Duhagon MA
克氏锥虫是查加斯病的病原体，查加斯病是拉丁美洲一种被忽视的寄生虫病。基因转录控制支配着真核细胞的复制，但在锥虫中不存在；因此，它必须被转录后调控事件所取代。我们利用核糖体图谱和蛋白质组学技术，对用羟基脲同步化的G1/S期上鞭毛体培养物进行研究，以探究克氏锥虫进入复制周期的情况。我们分别鉴定出1784个翻译调控基因（变化＞2，错误发现率[FDR]＜0.05）和653个差异表达蛋白（变化＞1.5，FDR＜0.05）。发现伴随着广泛的蛋白质组变化出现了重大的翻译重塑，而在细胞周期的复制起始阶段转录组基本未受干扰。差异表达基因包含特定的细胞周期过程，这证实了先前的发现，同时揭示了一些经历先前未被注意到的翻译调控的候选细胞周期调节因子。在翻译和蛋白质丰度上表现出协同调控的基因簇具有相关的生物学功能，如细胞骨架组织和线粒体代谢；因此，它们可能代表转录后调节子。协同调控的基因簇的翻译组和蛋白质组在耦合和非耦合方向上都发生变化，这表明需要这两个过程之间复杂的相互作用来实现不同调节子的适当蛋白质水平。这是首次对锥虫的转录组、翻译组和蛋白质组进行同时评估，这代表了缺乏转录控制的范例。研究结果表明，克氏锥虫细胞周期中基因表达的时间顺序主要由翻译组和蛋白质组的变化所控制，这些变化通过针对特定基因组的不同机制进行协调。
重要性：克氏锥虫是一种古老的真核单细胞寄生虫，可导致查加斯病，这是一种可能危及生命的疾病，影响着600万到700万人，主要在拉丁美洲。针对该疾病的抗寄生虫治疗效果不完全且有不良反应；因此，需要改进的药物。我们研究控制寄生虫复制的机制，旨在找出与人类宿主的差异，这对开发针对寄生虫的抗增殖药物很有价值。转录调控对大多数真核生物的复制至关重要，但在锥虫中，由于它们缺乏转录起始控制，必须由后续的基因调控步骤所取代。我们鉴定了在细胞周期进入复制阶段期间mRNA翻译和蛋白质丰度的全基因组重塑。我们发现翻译受到强烈调控，导致特定细胞周期过程的蛋白质水平发生变化，这是首次对锥虫的翻译组和蛋白质组进行同时研究。
Trypanosoma cruzi is the etiological agent for Chagas disease, a neglected parasitic disease in Latin America. Gene transcription control governs the eukaryotic cell replication but is absent in trypanosomatids; thus, it must be replaced by posttranscriptional regulatory events. We investigated the entrance into the T. cruzi replicative cycle using ribosome profiling and proteomics on G1/S epimastigote cultures synchronized with hydroxyurea. We identified 1,784 translationally regulated genes (change > 2, false-discovery rate [FDR] < 0.05) and 653 differentially expressed proteins (change > 1.5, FDR < 0.05), respectively. A major translational remodeling accompanied by an extensive proteome change is found, while the transcriptome remains largely unperturbed at the replicative entrance of the cell cycle. The differentially expressed genes comprise specific cell cycle processes, confirming previous findings while revealing candidate cell cycle regulators that undergo previously unnoticed translational regulation. Clusters of genes showing a coordinated regulation at translation and protein abundance share related biological functions such as cytoskeleton organization and mitochondrial metabolism; thus, they may represent posttranscriptional regulons. The translatome and proteome of the coregulated clusters change in both coupled and uncoupled directions, suggesting that complex cross talk between the two processes is required to achieve adequate protein levels of different regulons. This is the first simultaneous assessment of the transcriptome, translatome, and proteome of trypanosomatids, which represent a paradigm for the absence of transcriptional control. The findings suggest that gene expression chronology along the T. cruzi cell cycle is controlled mainly by translatome and proteome changes coordinated using different mechanisms for specific gene groups. IMPORTANCE Trypanosoma cruzi is an ancient eukaryotic unicellular parasite causing Chagas disease, a potentially life-threatening illness that affects 6 to 7 million people, mostly in Latin America. The antiparasitic treatments for the disease have incomplete efficacy and adverse reactions; thus, improved drugs are needed. We study the mechanisms governing the replication of the parasite, aiming to find differences with the human host, valuable for the development of parasite-specific antiproliferative drugs. Transcriptional regulation is essential for replication in most eukaryotes, but in trypanosomatids, it must be replaced by subsequent gene regulation steps since they lack transcription initiation control. We identified the genome-wide remodeling of mRNA translation and protein abundance during the entrance to the replicative phase of the cell cycle. We found that translation is strongly regulated, causing variation in protein levels of specific cell cycle processes, representing the first simultaneous study of the translatome and proteome in trypanosomatids.
影响因子：
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作者：
Calderano SG;de Melo Godoy PD;da Cunha JP;Elias MC
通讯作者：
Elias MC