Base-modified nucleotides mediate immune signaling in bacteria

Zeng, Z.; Hu, Z.; Zhao, R.; Rao, J.; Mestre, M.; Liu, Y.; Liu, S.; Feng, H.; Chen, Y.; He, H.; Chen, N.; Zheng, J.; Peng, D.; Luo, M.; She, Q.; Pinilla-Redondo, R.; Han, W.

doi:10.1101/2024.12.20.629578

bioRxiv · 10.1101/2024.12.20.629578

Base-modified nucleotides mediate immune signaling in bacteria

Zeng, Z.·Hu, Z.·Zhao, R.·Rao, J.·Mestre, M.·Liu, Y.·Liu, S.·Feng, H.·Chen, Y.·He, H.·Chen, N.·Zheng, J.·Peng, D.·Luo, M.·She, Q.·Pinilla-Redondo, R.·Han, W.

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Abstract

Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. While cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. Here, we reveal a bacterial anti-phage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine 5-triphosphate (dITP) as immune messengers. The dITP signal activates downstream effector to mediate cellular NAD+ depletion, resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular dAMP, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based anti-phage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.

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Zeng, Z., Hu, Z., Zhao, R., Rao, J., Mestre, M., Liu, Y., Liu, S., Feng, H., Chen, Y., He, H., Chen, N., Zheng, J., Peng, D., Luo, M., She, Q., Pinilla-Redondo, R., Han, W.. 2024-12-20. Base-modified nucleotides mediate immune signaling in bacteria. https://doi.org/10.1101/2024.12.20.629578

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