article published yes Oleg Dmytrenko author Biao Yuan author Kadin T. Crosby author Max Krebel author Xiye Chen author Jakub S. Nowak author Andrzej Chramiec-Głąbik author Bamidele Filani author Anne-Sophie Gribling-Burrer author Wiep van der Toorn author Max von Kleist author Tatjana Achmedov author Redmond P. Smyth author Sebastian Glatt author Jack Peter Kelly Bravo author 96aecfa5-8931-11ee-af30-aa6a5d6eee0e0000-0003-0456-0753 Dirk W. Heinz author Ryan N. Jackson author Chase L. Beisel author JaBr department 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 type V 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 type V 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. https://research-explorer.ista.ac.at/download/20963/22415/2026_Nature_Dmytrenko.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ Springer Nature2026 eng 0028-0836 1476-4687 4150145910.1038/s41586-025-09852-9 6491312-1321 Dmytrenko, Oleg, Biao Yuan, Kadin T. Crosby, Max Krebel, Xiye Chen, Jakub S. Nowak, Andrzej Chramiec-Głąbik, et al. “RNA-Triggered Cas12a3 Cleaves TRNA Tails to Execute Bacterial Immunity.” <i>Nature</i>. Springer Nature, 2026. <a href="https://doi.org/10.1038/s41586-025-09852-9">https://doi.org/10.1038/s41586-025-09852-9</a>. Dmytrenko O, Yuan B, Crosby KT, et al. RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity. <i>Nature</i>. 2026;649:1312-1321. doi:<a href="https://doi.org/10.1038/s41586-025-09852-9">10.1038/s41586-025-09852-9</a> Dmytrenko O, Yuan B, Crosby KT, Krebel M, Chen X, Nowak JS, Chramiec-Głąbik A, Filani B, Gribling-Burrer A-S, van der Toorn W, von Kleist M, Achmedov T, Smyth RP, Glatt S, Bravo JPK, Heinz DW, Jackson RN, Beisel CL. 2026. RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity. Nature. 649, 1312–1321. Dmytrenko, Oleg, et al. “RNA-Triggered Cas12a3 Cleaves TRNA Tails to Execute Bacterial Immunity.” <i>Nature</i>, vol. 649, Springer Nature, 2026, pp. 1312–21, doi:<a href="https://doi.org/10.1038/s41586-025-09852-9">10.1038/s41586-025-09852-9</a>. Dmytrenko, O., Yuan, B., Crosby, K. T., Krebel, M., Chen, X., Nowak, J. S., … Beisel, C. L. (2026). RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-025-09852-9">https://doi.org/10.1038/s41586-025-09852-9</a> O. Dmytrenko <i>et al.</i>, “RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity,” <i>Nature</i>, vol. 649. Springer Nature, pp. 1312–1321, 2026. O. Dmytrenko, B. Yuan, K.T. Crosby, M. Krebel, X. Chen, J.S. Nowak, A. Chramiec-Głąbik, B. Filani, A.-S. Gribling-Burrer, W. van der Toorn, M. von Kleist, T. Achmedov, R.P. Smyth, S. Glatt, J.P.K. Bravo, D.W. Heinz, R.N. Jackson, C.L. Beisel, Nature 649 (2026) 1312–1321. 209632026-01-08T07:57:17Z2026-07-27T10:36:28Z