Structural biology of retron-mediated immunity against phage
Abstract Retrons recently emerged as widespread anti-phage systems in which a dedicated reverse transcriptase (RT) produces multicopy single-stranded DNA (msDNA) that regulates associated effector proteins. Once regarded as peculiar retroelements of unknown function, retrons are now understood to operate as modular defense platforms in which the RT–msDNA module maintains nucleases, hydrolases or other effector domains in an inactive state until a phage-trigger perturbs the complex. Current biochemical and cryo-EM structural studies across different retron types have begun to define a unifying mechanism for retron-mediated immunity. Despite substantial variation in architecture and effector types, these studies converge on a common principle: msDNA acts as a structural and functional hub that scaffolds multimeric assemblies, occludes catalytic sites or stabilizes inactive effector conformations. Phage infection is sensed through perturbation of the msDNA, including cleavage, modification or binding by phage-encoded factors, thereby activating the effector to trigger an immune response. Here, we discuss recent structural and mechanistic advances of retron immune systems. We detail how distinct retron types deploy different effectors and phage-factor-sensing strategies while preserving a shared msDNA-centered regulatory paradigm. We further place retrons in the broader landscape of bacterial defense, comparing their regulatory logic with that of toxin–antitoxin modules and other immune systems.