Legionella effector protein SidG disrupts host cytoskeleton via targeting Arp2/3 complex.

Legionella pneumophila is a facultative intracellular bacterial pathogen capable of surviving and replicating within host cells, including macrophages and protozoans. It employs the Dot/Icm type IV secretion system (T4SS) to inject over 330 effector proteins into host cells, manipulating various cellular processes to facilitate infection. Characterizing the functions of these effectors is crucial to deciphering the pathogenesis of L. pneumophila. In this study, we identified SidG as an effector containing a Cys-His-Asp triad, whose functional state is strictly gated by its interaction with the cellular GTPase Rac1, particularly via its C-terminal domain. Rac1-activated SidG then utilizes an acidic (A) domain to target the Arp2/3 complex, the key regulator of actin nucleation. Importantly, SidG disrupts cytoskeletal architecture via both Rac1- and Arp2/3-dependent mechanisms. During L. pneumophila infection, SidG is crucial to promote efficient bacterial invasion of host cells in a Cys-His-Asp motif-dependent manner. Together, our study elucidates a sophisticated pathogenic mechanism where a bacterial effector co-opts a host GTPase to allosterically regulate its function towards the Arp2/3 complex, thereby facilitating bacterial entry into host cells.