tRNA epitranscriptome determines pathogenicity of the opportunistic pathogen Pseudomonas aeruginosa. tRNA epitranscriptome determines pathogenicity of the opportunistic pathogen Pseudomonas aeruginosa

The overall success of bacterial pathogens depends on the coordinated expression of virulence determinants. Regulatory circuits that drive pathogenesis are complex, multilayered and incompletely understood. Here, we reveal that alterations in tRNA modifications define pathogenic phenotypes in the opportunistic pathogen Pseudomonas aeruginosa. We demonstrate that the enzymatic activity of GidA leads to the introduction of a carboxymethylaminomethyl modification in selected tRNAs. Modifications at the wobble uridine base (cmnm5U34) of the anticodon drives translation of transcripts containing rare codons enriched at specific location. Specifically, in P. aeruginosa the presence of GidA-dependent tRNA modifications modulates expression of genes encoding virulence regulators, leading to a cellular proteomic shift towards pathogenic and well-adapted physiological states. Our approach of profiling the consequences of chemical tRNA modifications is general in concept. It provides a paradigm of how environmentally driven tRNA modifications govern gene expression programs and regulate phenotypic outcomes responsible for bacterial adaption to changing and challenging habitats prevailing in the host niche.

细菌病原菌的整体致病能力，取决于其毒力决定因子的协同表达。介导致病过程的调控通路复杂且具多层级架构，目前尚未被完全阐释。本研究揭示，转运RNA（transfer RNA, tRNA）修饰的改变，可塑造机会致病菌铜绿假单胞菌（Pseudomonas aeruginosa）的致病表型。本研究证实，GidA的酶促活性可在特定tRNA上引入羧甲基氨基甲基修饰。反密码子环的摆动尿苷碱基位点（cmnm5U34）上的该修饰，可驱动携带在特定位点富集的稀有密码子的转录本的翻译过程。具体而言，在铜绿假单胞菌中，依赖GidA的tRNA修饰可调控编码毒力调控因子的基因表达，进而使细胞蛋白质组向致病且高度适配的生理状态发生重塑。本研究用于解析tRNA化学修饰效应的研究思路具备普适性，其为解析环境介导的tRNA修饰如何调控基因表达程序，以及如何调节决定细菌适应宿主微环境中普遍存在的、不断变化且充满挑战的生存生境的表型结果，提供了一个范式模型。