Base-modified nucleotides mediate immune signaling in bacteria
Zhifeng Zeng, Zeyu Hu, Ruiliang Zhao, Jikai Rao, Mario Rodríguez Mestre, Yanqiu Liu, Shunhang Liu, Hao Feng, Yu Chen, Huan He, Nuo Chen, Jinshui Zheng, Donghai Peng, Min Luo, Qunxin She, Rafael Pinilla‐Redondo, Wenyuan Han
Abstract
Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. Whereas cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. In this study, we reveal a bacterial antiphage 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 triphosphates (dITPs) as immune messengers. The dITP signal activates a downstream effector to mediate depletion of cellular nicotinamide adenine dinucleotide (oxidized form), resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular deoxyadenosine monophosphate, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based antiphage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.