Structure and Activation Mechanism of a Lamassu Phage and Plasmid Defence System

Lamassu is a diverse family of defence systems that protect bacteria, including seventh-pandemic strains of Vibrio cholerae, against both plasmids and phage infection. During phage infection, Lamassu targets essential cellular processes, thereby halting phage propagation by terminating the infected host. The mechanisms by which Lamassu effectors 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 effector subunit, LmuA, is sequestered by two tightly-folded SMC-like LmuB protomers and LmuC. Upon activation, liberated LmuA assembles into homo-tetramers, 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 effectors, and shed light on how Lamassu systems balance potent immune responses with self-preservation.