tRNA-derived second messengers confer bacterial immunity
- 1Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel
Abstract
Bacterial small-molecule messengers that function in diverse immune signaling pathways have been thought to derive strictly from biosynthesis using nucleotide and cofactor substrates. Here we report a nuclease-driven immune signaling pathway in which tRNA cleavage generates a specific small molecule that triggers cell death in response to RNA-guided transcript recognition in prokaryotes. We identify a class of type VI-B CRISPR systems in which the RNA-guided nuclease Cas13 and its accessory transmembrane protein, 2TM{beta}, are co-encoded in an operon and are jointly required for bacteriophage defense. Upon target RNA recognition, Cas13 activates 2TM{beta} by producing mono- and dinucleotide messengers bearing 2',3'-cyclic uridine phosphate ends by tRNA cleavage. Activated 2TM{beta} destroys infected cells by forming a multimeric complex that disrupts cell membranes to mediate cell death. These findings demonstrate RNA-programmed tRNA cleavage for second-messenger biogenesis, revealing a new logic for prokaryotic immune signaling.
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BibTeX
@misc{valentinalvarado2026trnaderived,
title = {{tRNA-derived second messengers confer bacterial immunity}},
author = {L. E. Valentin-Alvarado and P. H. Yoon and S. C. Lopez and Y. Shulgina and C. Langeberg and E. Armbruster and M. M. Ur-Rehman and K. Loi and C. Taveneau and I. Esain-Garcia and M. Koka and Z. T. Zhang and D. Kashin and F. Schwede and G. Burgio and M. R. OConnell and E. E. Doherty and J. H. D. Cate and G. J. Knott and J. A. Doudna},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756102},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756102v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - tRNA-derived second messengers confer bacterial immunity
AU - L. E. Valentin-Alvarado
AU - P. H. Yoon
AU - S. C. Lopez
AU - Y. Shulgina
AU - C. Langeberg
AU - E. Armbruster
AU - M. M. Ur-Rehman
AU - K. Loi
AU - C. Taveneau
AU - I. Esain-Garcia
AU - M. Koka
AU - Z. T. Zhang
AU - D. Kashin
AU - F. Schwede
AU - G. Burgio
AU - M. R. OConnell
AU - E. E. Doherty
AU - J. H. D. Cate
AU - G. J. Knott
AU - J. A. Doudna
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756102
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756102v1
AB - Bacterial small-molecule messengers that function in diverse immune signaling pathways have been thought to derive strictly from biosynthesis using nucleotide and cofactor substrates. Here we report a nuclease-driven immune signaling pathway in which tRNA cleavage generates a specific small molecule that triggers cell death in response to RNA-guided transcript recognition in prokaryotes. We identify a class of type VI-B CRISPR systems in which the RNA-guided nuclease Cas13 and its accessory transmembrane protein, 2TM{beta}, are co-encoded in an operon and are jointly required for bacteriophage defense. Upon target RNA recognition, Cas13 activates 2TM{beta} by producing mono- and dinucleotide messengers bearing 2',3'-cyclic uridine phosphate ends by tRNA cleavage. Activated 2TM{beta} destroys infected cells by forming a multimeric complex that disrupts cell membranes to mediate cell death. These findings demonstrate RNA-programmed tRNA cleavage for second-messenger biogenesis, revealing a new logic for prokaryotic immune signaling.
ER -