---
OA_place: publisher
OA_type: hybrid
PlanS_conform: '1'
_id: '20963'
abstract:
- lang: eng
text: 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.
acknowledgement: 'We thank Ł. Koziej for processing of the initial cryo-EM datasets,
S. Schmelz for support in cryo-EM, A. Gatzemeier for assistance in the purification
of dBa1Cas12a3, R. Rarose for support with the in vitro RNA experiments, M. Kaminski
for providing purified PsmCas13b protein, L. Schönemann for protein purification,
and C. Krempl and S. Backesfor providing the RSV and influenza A transcript-encoding
plasmids. This work was supported through funding by the European Research Council
(101001394 to S.G.; 865973 and 101158249 to C.L.B.), the R. Gaurth Hansen Family
(to R.N.J.), the National Institutes of Health (R35GM138080 to R.N.J.), the PostDoc
Plus Program from the Graduate School of Life Sciences at Julius-Maximilians-Universität
Würzburg (to O.D.), and the Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation) under Germany’s Excellence Strategy–The Berlin Mathematics Research
Center MATH+ (EXC−2046/1, project ID: 390685689 to M.v.K.). Open access funding
provided by Helmholtz-Zentrum für Infektionsforschung GmbH (HZI).'
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Oleg
full_name: Dmytrenko, Oleg
last_name: Dmytrenko
- first_name: Biao
full_name: Yuan, Biao
last_name: Yuan
- first_name: Kadin T.
full_name: Crosby, Kadin T.
last_name: Crosby
- first_name: Max
full_name: Krebel, Max
last_name: Krebel
- first_name: Xiye
full_name: Chen, Xiye
last_name: Chen
- first_name: Jakub S.
full_name: Nowak, Jakub S.
last_name: Nowak
- first_name: Andrzej
full_name: Chramiec-Głąbik, Andrzej
last_name: Chramiec-Głąbik
- first_name: Bamidele
full_name: Filani, Bamidele
last_name: Filani
- first_name: Anne-Sophie
full_name: Gribling-Burrer, Anne-Sophie
last_name: Gribling-Burrer
- first_name: Wiep
full_name: van der Toorn, Wiep
last_name: van der Toorn
- first_name: Max
full_name: von Kleist, Max
last_name: von Kleist
- first_name: Tatjana
full_name: Achmedov, Tatjana
last_name: Achmedov
- first_name: Redmond P.
full_name: Smyth, Redmond P.
last_name: Smyth
- first_name: Sebastian
full_name: Glatt, Sebastian
last_name: Glatt
- first_name: Jack Peter Kelly
full_name: Bravo, Jack Peter Kelly
id: 96aecfa5-8931-11ee-af30-aa6a5d6eee0e
last_name: Bravo
orcid: 0000-0003-0456-0753
- first_name: Dirk W.
full_name: Heinz, Dirk W.
last_name: Heinz
- first_name: Ryan N.
full_name: Jackson, Ryan N.
last_name: Jackson
- first_name: Chase L.
full_name: Beisel, Chase L.
last_name: Beisel
citation:
ama: Dmytrenko O, Yuan B, Crosby KT, et al. RNA-triggered Cas12a3 cleaves tRNA tails
to execute bacterial immunity. Nature. 2026;649:1312-1321. doi:10.1038/s41586-025-09852-9
apa: 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. Nature. Springer Nature. https://doi.org/10.1038/s41586-025-09852-9
chicago: 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.” Nature. Springer Nature, 2026. https://doi.org/10.1038/s41586-025-09852-9.
ieee: O. Dmytrenko et al., “RNA-triggered Cas12a3 cleaves tRNA tails to execute
bacterial immunity,” Nature, vol. 649. Springer Nature, pp. 1312–1321,
2026.
ista: 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.
mla: Dmytrenko, Oleg, et al. “RNA-Triggered Cas12a3 Cleaves TRNA Tails to Execute
Bacterial Immunity.” Nature, vol. 649, Springer Nature, 2026, pp. 1312–21,
doi:10.1038/s41586-025-09852-9.
short: 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.
das_tickbox: '1'
dataavailabilitystatement: 'The Illumina-based PFS screen data and the direct RNA
Nanopore sequencing reads have been deposited into the European Nucleotide Archive
under accession code PRJEB88250 (https://www.ebi.ac.uk/ena/browser/view/PRJEB88250).
Models and associated cryo-EM maps have been deposited into the Electron Microscopy
Data Bank (EMD) and PDB databases with the following accession codes: Ba1Cas12a3
binary complex (EMD-52275; PDB: 9HLX); Ba1Cas12a3 ternary complex (EMD-52287; PDB:
9HM6); Ba1Cas12a3 quaternary complex at pre-cleavage state (EMD-52285; PDB: 9HM4);
and Ba1Cas12a3 quaternary complex at post-cleavage state (EMD-52286; PDB: 9HM5).
Raw gel images are included as Supplementary Fig. 1. Source data are provided with
this paper.'
date_created: 2026-01-08T07:57:17Z
date_published: 2026-01-29T00:00:00Z
date_updated: 2026-07-27T10:36:28Z
day: '29'
ddc:
- '570'
department:
- _id: JaBr
doi: 10.1038/s41586-025-09852-9
external_id:
pmid:
- '41501459'
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creator: dernst
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intvolume: ' 649'
language:
- iso: eng
month: '01'
oa: 1
oa_version: Published Version
page: 1312-1321
pmid: 1
publication: Nature
publication_identifier:
eissn:
- 1476-4687
issn:
- 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: RNA-triggered Cas12a3 cleaves tRNA tails to execute bacterial immunity
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 649
year: '2026'
...