Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Mol Cell. 2022 Sep 15;82(18):3484-3498.e11. doi: 10.1016/j.molcel.2022.08.015. Epub 2022 Sep 6.
ADP-ribosyltransferases (ARTs) were among the first identified bacterial virulence factors. Canonical ART toxins are delivered into host cells where they modify essential proteins, thereby inactivating cellular processes and promoting pathogenesis. Our understanding of ARTs has since expanded beyond protein-targeting toxins to include antibiotic inactivation and DNA damage repair. Here, we report the discovery of RhsP2 as an ART toxin delivered between competing bacteria by a type VI secretion system of Pseudomonas aeruginosa. A structure of RhsP2 reveals that it resembles protein-targeting ARTs such as diphtheria toxin. Remarkably, however, RhsP2 ADP-ribosylates 2'-hydroxyl groups of double-stranded RNA, and thus, its activity is highly promiscuous with identified cellular targets including the tRNA pool and the RNA-processing ribozyme, ribonuclease P. Consequently, cell death arises from the inhibition of translation and disruption of tRNA processing. Overall, our data demonstrate a previously undescribed mechanism of bacterial antagonism and uncover an unprecedented activity catalyzed by ART enzymes.
ADP-核糖基转移酶（ARTs）是首批被鉴定的细菌毒力因子之一。典型的 ART 毒素被输送到宿主细胞中，在那里它们修饰必需的蛋白质，从而使细胞过程失活并促进发病机制。此后，我们对 ART 的理解已经超越了靶向蛋白的毒素，包括抗生素失活和 DNA 损伤修复。在这里，我们报告了 RhsP2 的发现，它是一种由铜绿假单胞菌的 VI 型分泌系统在竞争细菌之间传递的 ART 毒素。RhsP2 的结构表明它类似于靶向蛋白的 ART，如白喉毒素。然而，令人惊讶的是，RhsP2 使双链 RNA 的 2'-羟基发生 ADP-核糖基化，因此，其活性具有高度的混杂性，包括鉴定的细胞靶标，如 tRNA 池和 RNA 处理核酶，核糖核酸酶 P。因此，细胞死亡是由翻译抑制和 tRNA 加工破坏引起的。总的来说，我们的数据证明了细菌拮抗作用的一种以前未描述的机制，并揭示了 ART 酶催化的一种前所未有的活性。
