Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai400076, India.
Parasitology. 2021 Sep;148(11):1277-1287. doi: 10.1017/S0031182021000937. Epub 2021 Jun 8.
During their complex life cycles, the Apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii employ several layers of regulation of their gene expression. One such layer is mediated at the level of translation through upstream open reading frames (uORFs). As uORFs are found in the upstream regions of a majority of transcripts in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant genes, including var2csa in P. falciparum, and ApiAT1 in T. gondii, that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of these genome-wide datasets, taking into account uORFs associated with each gene, will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.
在复杂的生命周期中，疟原虫和刚地弓形虫等 Apicomplexan 寄生虫通过几个层次的基因表达调控来实现。其中一个层次是通过翻译过程中的上游开放阅读框（uORFs）来介导的。由于 uORFs 存在于这两种寄生虫的大多数转录本的上游区域，因此必须更深入地了解它们在翻译调控中的作用。本综述全面总结了表明这些寄生虫中 uORF 介导的基因调控的研究，并强调了一些具有临床和生理相关性的基因的例子，包括疟原虫中的 var2csa 和刚地弓形虫中的 ApiAT1，它们都表现出 uORF 介导的调控。除了这些例子，还有一些使用生物信息学、转录组学、蛋白质组学和核糖体谱分析的研究也表明 uORFs 可能广泛参与翻译调控。进一步分析这些全基因组数据集，并考虑与每个基因相关的 uORFs，将揭示参与细胞周期进程、应激反应和致病性等关键生物学途径的新基因。本综述中提出的研究的综合证据表明，uORFs 将在这些重要的人类病原体引起的临床疾病期间的基因表达调控中发挥关键作用。
