Defense mechanism of a bacterial retron supramolecular assembly

Retrons are a class of multigene antiphage defense system typically consisting of a retron reverse transcriptase, a non-coding RNA, and a cognate effector. Although the triggers for several retron systems have been discovered recently, the full picture of how retron systems sense invading phages and mediate defense remains to be elucidated. Here, we focus on the retron Ec86 defense system and report its modes of activation and action. We identified a phage-encoded DNA cytosine methyltransferase (Dcm) as the trigger of the Ec86 system and show that Ec86 senses msDNA methylation and becomes activated. We further determined the structure of a tripartite retron Ec86 supramolecular assembly, which is primed for activation by Dcm, and demonstrated that the activated system confers defense through depletion of nucleoside derivatives. These findings emphasize the role of retrons being a second line of defense and highlight an emerging theme of anti-phage defense through supramolecular complex assemblies.