Structural basis for membrane targeting and secretion of legionella SidE ubiquitin ligases

SidE family effectors from Legionella pneumophila catalyze serine ubiquitination of host proteins via phospho-ribose (PR) linkages, disrupting host compartments, facilitating the formation of Legionella-containing vacuoles (LCVs) and blocking xenophagy. Upon infection, SidE proteins are injected into the cytosol and recruited to host membranes. Here we present structural and functional insights into a previously uncharacterized C-terminal domain (CTD) of SidE effectors. The crystal structure reveals a banana-shape resembling eukaryotic BAR-domain dimers, with an amphipathic helix and electropositive patch mediating membrane association. Membrane targeting to ER and Golgi confers substrate specificity for PR-ubiquitination. We further show that the CTD binds the IcmS-IcmW-DotL complex, acting as a secretion signal for the Type IV secretion system. Our findings establish membrane localization and secretion as critical determinants of SidE effector function during Legionella infection.