Rao1 Raw sequence reads
Coupling pathogen sensing with effector activation is a fundamental principle of cellular immunity. While cyclic (oligo) nucleotides have emerged as key immune signaling molecules across all domains of life, the existence of other immune messengers remains largely unexplored. Here, we reveal a family of bacterial anti-phage defense systems that mediate immune signaling through nucleobase modification . Immunity is triggered by phage nucleotide kinases, which initiate a cascade reaction involving an adenosine deaminase within the anti-phage system and lead to the synthesis of deoxyinosine 5'-triphosphate (dITP) messengers. These dITP signals are recognized by a HAM1 subunit within the immune effector complex, which activates a SIR2 subunit to deplete cellular NAD+, resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete bacterial dAMP , the precursor of dITP messengers. Our findings uncover an anti-phage signaling pathway that relies on nucleobase modification, establishing noncanonical nucleotides as a new type of immune secondary messengers in bacteria.