Although plants, animals and fungi all use NOD-like receptors (NLRs) to sense pathogen-associated molecular patterns (PAMPs) and respond to infection, it was unclear if prokaryotes use this defence strategy. Here, Gao et al. show that intracellular NLR-like Avs proteins in bacteria and archaea detect conserved phage PAMPs. They describe four main Avs families that respond to two structurally conserved viral proteins; the phage terminase (in the case of Avs1–Avs3) and phage portal (for Avs4). Sensing of phage PAMPs triggered the tetramerization of Avs proteins and activation of their N-terminal effector domains. For example, some Avs proteins contained N-terminal DNA endonucleases that could degrade both phage and host DNA to disrupt the infection cycle. Genes expressed early in the phage life cycle were found to encode Avs inhibitors, suggesting phages have evolved mechanisms to counter these defences. Importantly, this study shows that all domains of life use pattern-recognition receptors to mount defence responses to pathogens.

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