德国亥姆霍兹感染研究中心Chase L. Beisel小组的一项最新研究显示，RNA触发的Cas12a3切割tRNA尾部来执行细菌免疫。2026年1月7日，国际知名学术期刊《自然》发表了这一成果。

在这里，该课题组人员报道来自型的Cas12a3效应核酸酶。V CRISPR-Cas在识别目标RNA后优先切割tRNA的细菌中的适应性免疫系统。Cas12a3同源物属于两个以前未报道的核酸酶分支之一，它们表现出RNA介导的非靶RNA裂解，且区别于所有其他已知的V型系统。通过基于细胞的生化分析和直接RNA测序，课题组证明了CRISPR RNA对互补靶RNA的识别触发Cas12a3切割多种tRNA的保守5' -CCA-3'尾部，以驱动生长阻滞和抗噬菌体防御。低温电子显微镜结构进一步揭示了一个独特的tRNA装载域，该域将tRNA尾部定位在核酸酶的RuvC活性位点。通过设计模拟tRNA受体茎和尾的合成报告，课题组扩展了当前基于CRISPR的多路RNA检测诊断的能力。总的来说，这些发现揭示了广泛的tRNA失活作为一种以前未被识别的基于CRISPR的免疫策略，拓宽了现有CRISPR工具箱的应用空间。

据介绍，在生命的所有领域，tRNAs介导遗传信息从mRNAs到蛋白质的转移。由于tRNAs的耗竭抑制了翻译，从而抑制了病毒复制，因此tRNAs代表了先天免疫的长期且日益被认识的靶标。

附：英文原文

Title: RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity

Author: Dmytrenko, Oleg, Yuan, Biao, Crosby, Kadin T., Krebel, Max, Chen, Xiye, Nowak, Jakub S., Chramiec-Gbik, Andrzej, Filani, Bamidele, Gribling-Burrer, Anne-Sophie, van der Toorn, Wiep, von Kleist, Max, Achmedov, Tatjana, Smyth, Redmond P., Glatt, Sebastian, Bravo, Jack P. K., Heinz, Dirk W., Jackson, Ryan N., Beisel, Chase L.

Issue&Volume: 2026-01-07

Abstract: In all domains of life, tRNAs mediate the transfer of genetic information from mRNAs to proteins. As their depletion suppresses translation and, consequently, viral replication, tRNAs represent long-standing and increasingly recognized targets of innate immunity1,2,3,4,5. Here we report Cas12a3 effector nucleases from typeV CRISPR–Cas adaptive immune systems in bacteria that preferentially cleave tRNAs after recognition of target RNA. Cas12a3 orthologues belong to one of two previously unreported nuclease clades that exhibit RNA-mediated cleavage of non-target RNA, and are distinct from all other known typeV systems. Through cell-based and biochemical assays and direct RNA sequencing, we demonstrate that recognition of a complementary target RNA by the CRISPR RNA triggers Cas12a3 to cleave the conserved 5′-CCA-3′ tail of diverse tRNAs to drive growth arrest and anti-phage defence. Cryogenic electron microscopy structures further revealed a distinct tRNA-loading domain that positions the tRNA tail in the RuvC active site of the nuclease. By designing synthetic reporters that mimic the tRNA acceptor stem and tail, we expanded the capacity of current CRISPR-based diagnostics for multiplexed RNA detection. Overall, these findings reveal widespread tRNA inactivation as a previously unrecognized CRISPR-based immune strategy that broadens the application space of the existing CRISPR toolbox.

DOI: 10.1038/s41586-025-09852-9

Source: https://www.nature.com/articles/s41586-025-09852-9