Base-modified nucleotides mediate immune signaling in bacteria

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.