The widespread prokaryotic immune systems, in particular restriction–modification, CRISPR–Cas and defensive toxin–antitoxin systems, are absent in eukaryotes, whereas relatively rare ones, such as Arg...

Many bacterial defense systems restrict phage infection by breaking the molecule NAD+ to its constituents, adenosine diphosphate ribose (ADPR) and nicotinamide (Nam). To counter NAD+ depletion-mediated defense, phages evolved NAD+ reconstitution pathway 1 (NARP1), which uses ADPR and Nam to rebuild NAD+. Here we report a bacterial defense system called aRES, involving RES-domain proteins that degrade NAD+ into Nam and ADPR-1″-phosphate (ADPR-1P). This molecule cannot serve as a substrate for NARP1, so that NAD+ depletion by aRES defends against phages even if they encode NARP1. We further discover that some phages evolved an extended NARP1 pathway capable of overcoming aRES defense. In these phages, the NARP1 operon also includes a specialized phosphatase, which dephosphorylates ADPR-1P to form ADPR, a substrate from which NARP1 then reconstitutes NAD+. Other phages encode inhibitors that directly bind aRES proteins and physically block their active sites. Our study describes new layers in the NAD+-centric arms race between bacteria and phages and highlights the centrality of the NAD+ pool in cellular battles between viruses and their hosts. ### Competing Interest Statement The authors have declared no competing interest. European Research Council, ERC-AdG GA 101018520 Israel Science Foundation, MAPATS grant 2720/22 Deutsche Forschungsgemeinschaft, SPP 2330, grant 464312965 Minerva Foundation with funding from the Federal German Ministry for Education and Research research grant from Magnus Konow in honor of his mother Olga Konow Rappaport Ministry of Aliyah and Immigrant Absorption, https://ror.org/05aycsg86 Clore Scholars Program

Recognition of foreign molecules inside cells is critical for immunity in all domains of life. Proteins of the STAND NTPase superfamily, including eukaryotic nucleotide-binding oligomerization domain ...

Across all domains of life, immune systems rely on nucleotide-based signaling molecules to activate defense responses. In a recent Cell Host & Microbe study, Doherty, Nomburg, and colleagues identify ...

Oligonucleotides play fundamental roles in immune system activation across the tree of life. Viral proteins, 2H phosphodiesterases (PDEs), evade immunity by degrading these signals. Doherty and Nombur...

Across all domains of life, immune systems rely on nucleotide-based signaling molecules to activate defense responses. In a recent Cell Host & Microbe study, Doherty, Nomburg, and colleagues identify ...

Toll/interleukin-1 receptor (TIR) domains are important for immune signaling across humans, plants and bacteria. These domains were recently found to produce immune signaling molecules in plant immuni...

Defense-associated reverse transcriptases (DRTs) employ diverse and distinctive mechanisms of cDNA synthesis to protect bacteria against viral infection. However, much of DRT family diversity remains ...

VAD is a Viral AlphaFold Database of protein monomers and homodimers from viruses infecting hosts across the tree of life.

Cyclic dinucleotides (CDNs) and other short oligonucleotides play fundamental roles in immune system activation in organisms ranging from bacteria to humans. In response, viruses use phosphodiesterase...