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tRNA修饰重编程有助于在Plasmodium falciparum中对艺术素产生抗性

Jennifer L Small-Saunders^1,2, Ameya Sinha^3,4, Talia S Bloxham^5,6

¹Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. jls2302@cumc.columbia.edu.

Nature microbiology

|April 17, 2024

概括

在Plasmodium falciparum中,阿尔特米西宁耐药性可能涉及表观转录学变化. 转移RNA (tRNA) 的低修饰和编码子偏差翻译有助于耐药寄生虫在药物压力下生存.

科学领域:

分子生物学分子生物学
寄生虫学的寄生虫学
遗传学是一个遗传学.

背景情况:

青杆菌 (Plasmodium falciparum) 的抗素 (ART) 耐药性是一个日益严重的公共卫生问题.
鱼样蛋白13 (PfK13) 基因的突变是ART耐药性的主要驱动因素.
假设表观遗传调节,可能涉及表观转录路径,有助于寄生虫静止和抵抗.

研究的目的:

调查转移RNA (tRNA) 修饰重编程和编码子偏差翻译在抗ART的Plasmodium falciparum中所起的作用.
确定特定的表体转录机制,使寄生虫在ART诱导的压力下生存.

主要方法:

对tRNA修饰,蛋白质组形状和在ART敏感和ART耐药环状寄生虫中的密码使用进行比较分析.
研究药物治疗对这些分子机制的影响.
在ARV敏感背景下对PfMnmA基因的条件淘汰,以评估其对ART存活率的影响.

主要成果:

抗ART的寄生虫在药物暴露后在tRNA上表现出mk5s2U的差异性低基因改性.
包括PfK13在内的蛋白质的一个子集受到抗性寄生虫的Lys编码子偏差翻译的调节.
对ART敏感寄生虫中PfMnmA的抑制增加了存活率,这表明低修饰在ART反应中的作用.

结论:

一个涉及tRNAs2U修改重编程和编码器偏差翻译的表皮转录学途径与ART耐药性有关.
这一途径可能代表了在艺术素应激下Plasmodium falciparum的生存机制.
针对这些表体转录基因机制可以提供针对抗ART耐药疟疾的新策略.

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