Structure and Activation Mechanism of a Lamassu Phage Defence System

Summary Lamassu is a diverse family of defence systems that protect bacteria, including pandemic strains of Vibrio cholerae , against phage infection. They target essential cellular processes, aborting infection and preventing phage propagation by terminating the infected host. The mechanisms by which Lamassu efectors are activated when needed and otherwise suppressed are unknown. Here, we present structures of a Lamassu defence system from Salmonella enterica . We show that an oligomerization domain of the nuclease efector, LmuA, is sequestered by two tightly-folded SMC-like LmuB protomers and LmuC. Upon activation, liberated LmuA proteins assemble into a cyclic homo-tetramer, in which two of four nuclease domains are brought into proximity to create an active site capable of cleaving DNA. We propose tetramer formation is likely a one-way switch that establishes a threshold to limit potential spontaneous activation and cell death. Our findings reveal a mechanism of cellular defence, involving liberation and oligomerization of immune efectors, and shed light on how Lamassu systems balance potent immune responses with self-preservation.