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Carabias A, Camara-Wilpert S, Mestre MR, Lopéz-Méndez B, Hendriks IA, Zhao R, Pape T, Fuglsang A, Luk SH, Nielsen ML, Pinilla-Redondo R, Montoya G
Mol. Cell - (-) - [2024-05-18; online 2024-05-18]
Retrons are toxin-antitoxin systems protecting bacteria against bacteriophages via abortive infection. The Retron-Eco1 antitoxin is formed by a reverse transcriptase (RT) and a non-coding RNA (ncRNA)/multi-copy single-stranded DNA (msDNA) hybrid that neutralizes an uncharacterized toxic effector. Yet, the molecular mechanisms underlying phage defense remain unknown. Here, we show that the N-glycosidase effector, which belongs to the STIR superfamily, hydrolyzes NAD+ during infection. Cryoelectron microscopy (cryo-EM) analysis shows that the msDNA stabilizes a filament that cages the effector in a low-activity state in which ADPr, a NAD+ hydrolysis product, is covalently linked to the catalytic E106 residue. Mutations shortening the msDNA induce filament disassembly and the effector's toxicity, underscoring the msDNA role in immunity. Furthermore, we discovered a phage-encoded Retron-Eco1 inhibitor (U56) that binds ADPr, highlighting the intricate interplay between retron systems and phage evolution. Our work outlines the structural basis of Retron-Eco1 defense, uncovering ADPr's pivotal role in immunity.
PubMed 38788717
DOI 10.1016/j.molcel.2024.05.001
Crossref 10.1016/j.molcel.2024.05.001
pii: S1097-2765(24)00394-0