Laboratory of Molecular Biology of Pathogens, Department of Microbiology, Immunology and Parasitology, Federal University of Sao Paulo, São Paulo, Brazil.
Department of Microbiology, Aggeu Magalhães Institute/FIOCRUZ, Recife, Brazil.
Mol Microbiol. 2021 May;115(5):942-958. doi: 10.1111/mmi.14688. Epub 2021 Feb 10.
Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with mammalian hosts and insect vectors. The parasites must, therefore, survive in different environments, demanding rapid physiological and metabolic changes. These responses depend upon regulation of gene expression, which primarily occurs posttranscriptionally. Altering the composition or conformation of RNA through nucleotide modifications is one posttranscriptional mechanism of regulating RNA fate and function, and modifications including N6-methyladenosine (m6A), N1-methyladenosine (m1A), N5-methylcytidine (m5C), N4-acetylcytidine (ac4C), and pseudouridine (Ψ), dynamically regulate RNA stability and translation in diverse organisms. Little is known about RNA modifications and their machinery in Trypanosomatids, but we hypothesize that they regulate parasite gene expression and are vital for survival. Here, we identified Trypanosomatid homologs for writers of m1A, m5C, ac4C, and Ψ and analyze their evolutionary relationships. We systematically review the evidence for their functions and assess their potential use as therapeutic targets. This work provides new insights into the roles of these proteins in Trypanosomatid parasite biology and treatment of the diseases they cause and illustrates that Trypanosomatids provide an excellent model system to study RNA modifications, their molecular, cellular, and biological consequences, and their regulation and interplay.
锥虫和利什曼原虫寄生虫导致破坏性的热带疾病，造成严重的全球健康后果。这些生物具有复杂的生命周期，有哺乳动物宿主和昆虫媒介。因此，寄生虫必须在不同的环境中生存，要求快速的生理和代谢变化。这些反应取决于基因表达的调节，主要是在后转录水平上。通过核苷酸修饰改变 RNA 的组成或构象是调节 RNA 命运和功能的一种后转录机制，修饰包括 N6-甲基腺苷（m6A）、N1-甲基腺苷（m1A）、N5-甲基胞嘧啶（m5C）、N4-乙酰胞嘧啶（ac4C）和假尿嘧啶（Ψ），在不同的生物体中动态调节 RNA 的稳定性和翻译。关于 RNA 修饰及其在锥虫中的机制知之甚少，但我们假设它们调节寄生虫基因表达，对生存至关重要。在这里，我们鉴定了 m1A、m5C、ac4C 和 Ψ 的锥虫同源物，并分析了它们的进化关系。我们系统地回顾了它们功能的证据，并评估了它们作为治疗靶点的潜在用途。这项工作为这些蛋白在锥虫寄生虫生物学和治疗它们引起的疾病中的作用提供了新的见解，并表明锥虫为研究 RNA 修饰及其分子、细胞和生物学后果以及它们的调节和相互作用提供了一个极好的模型系统。
