Structural basis of Retron–Eco8-mediated antiphage defense

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Abstract
Retrons represent a novel class of bacterial defense systems that employ reverse transcriptase (RT), noncoding RNA, and effector proteins to counteract phage infections. In this study, we elucidate the molecular mechanism of a retron system, Retron–Eco8. Biochemical experiments reveal that the Retron–Eco8 holocomplex, rather than the effector alone, exhibits double-stranded DNA cleavage activity, triggering abortive infection and therefore effectively halting phage propagation. Cryo-electron microscopy (cryo-EM) analysis reveals a supramolecular assembly comprising four RT subunits, four multicopy single-stranded DNA molecules, and four overcoming lysogenization defect (OLD) nucleases—a configuration critical for antiphage defense. Notably, we examine the activation of Retron–Eco8 by diverse single-stranded DNA-binding (SSB) proteins, and phylogenetic analysis of these SSB proteins elucidates the phage resistance specificity. Collectively, our findings delineate the structural architecture of the Retron–Eco8 defense complex and provide mechanistic insights into retron-mediated bacterial immunity.
Funding Information
  • National Key Research and Development Program of China (2025YFC3408400)
  • National Natural Science Foundation of China (32270761)
  • Sichuan Science and Technology Program (25QNJJ4988)
  • Sichuan Science and Technology Program (2024NSFTD0029)
  • Sichuan Foundation for Distinguished Young Scholars (25NSFJQ0249)
  • National Key Research and Development Program of China (2025YFC3408400)

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