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

Rhinoviruses are the most frequent cause of common colds and also a major cause of respiratory distress in high-risk groups. Using single-cell sequencing of rhinovirus-infected nasal epithelial organo...

A library of 400 phage protein-coding genes is used to find a trove of antiphage systems, revealing systems that target tail fibre and major capsid proteins.

Bacteria must distinguish phage attack from normal homeostatic processes, yet the danger signals that trigger many defence systems remain unknown. Here, we show that a PUA-Calcineurin-CE-HAD module from Escherichia coli ECOR28 confers broad anti-phage protection by binding Dam-methylated deoxyadenosine monophosphate (m6-dAMP) generated during phage-induced chromosome degradation. Ligand binding converts a preassembled PUA-Calcineurin-CE hexamer loaded with six HAD phosphatases into a polymerising filament. The filament acts as a high-flux dNTP sink through a two-enzyme cascade: HAD first dephosphorylates dATP to dADP, and Calcineurin-CE then converts dADP to dAMP. dNTP collapse halts phage replication and enforces abortive infection. Multiple mobile-element DNA mimic proteins block filament assembly, revealing a direct phage counter-defence. More broadly, our findings extend a conserved, cross-kingdom paradigm of immune filament assembly to nucleotide-depletion antiviral defence and suggest modified-nucleotide sensing by related PUA-Calcineurin-CE modules as a widespread, underappreciated bacterial strategy. ### Competing Interest Statement The authors have declared no competing interest. NIHR Southampton Biomedical Research Centre, https://ror.org/01qqpzg67, Postdoctoral Bridging Fellowship F.L.N. is supported by a Wessex Health Partners (WHP) and National Institute for Health and Care Research Wessex Experimental Medicine Network (NIHR WEMN), Seed fund National Institutes of Health, GM145888, U24 GM129539) Maloris Foundation Memorial Sloan Kettering Cancer Center, P30-CA008748 Simons Foundation, SF349247 New York State Assembly

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...

Nature Structural & Molecular Biology - Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that...

Key actors of mammalian immunity originated from bacterial antiphage systems. The full extent of immune system conservation between bacteria and eukaryotes is unknown. Here, we show that the silent in...

Protein-protein interactions (PPIs) drive virtually all biological processes, yet most PPIs have not been identified and even more remain structurally unresolved. We developed a two-step computational...

Inflammasomes are multiprotein signaling platforms that activate inflammatory caspases to induce pyroptosis. In humans, canonical inflammasomes activate CASP1, which cleaves the pore-forming protein g...

We discover and study reverse transcriptases

Bacteria are frequently attacked by viruses, known as phages, and rely on diverse defence systems like restriction endonucleases and CRISPR-Cas to survive. While phages can evade these defences by cov...

The cryo-EM structure of the retron Eco8 system reveals an autoinhibited 4:4:4 complex of RT, msDNA, and OLD nuclease. Phage SSB binding to msdDNA unleashes non-specific nuclease activity to restrict ...

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