生物
重编程
翻译(生物学)
密码子使用偏好性
恶性疟原虫
基因敲除
青蒿素
转移RNA
细胞生物学
遗传学
核糖核酸
基因
信使核糖核酸
疟疾
基因组
免疫学
作者
Jennifer L. Small-Saunders,Ameya Sinha,Talia S. Bloxham,Laura M. Hagenah,Guangxin Sun,Peter R. Preiser,Peter C. Dedon,David A. Fidock
出处
期刊:Nature microbiology
日期:2024-04-17
标识
DOI:10.1038/s41564-024-01664-3
摘要
Abstract Plasmodium falciparum artemisinin (ART) resistance is driven by mutations in kelch-like protein 13 (PfK13). Quiescence, a key aspect of resistance, may also be regulated by a yet unidentified epigenetic pathway. Transfer RNA modification reprogramming and codon bias translation is a conserved epitranscriptomic translational control mechanism that allows cells to rapidly respond to stress. We report a role for this mechanism in ART-resistant parasites by combining tRNA modification, proteomic and codon usage analyses in ring-stage ART-sensitive and ART-resistant parasites in response to drug. Post-drug, ART-resistant parasites differentially hypomodify mcm 5 s 2 U on tRNA and possess a subset of proteins, including PfK13, that are regulated by Lys codon-biased translation. Conditional knockdown of the terminal s 2 U thiouridylase, PfMnmA, in an ART-sensitive parasite background led to increased ART survival, suggesting that hypomodification can alter the parasite ART response. This study describes an epitranscriptomic pathway via tRNA s 2 U reprogramming that ART-resistant parasites may employ to survive ART-induced stress.
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