Fig. 1: Phosphoribose-polyubiquitin chain building on LCV by Sdc and SidEs prevents autophagic clearance of Legionella pneumophila.

a In general, intracellular bacteria such as Legionella are recognized by host-autophagic adaptor molecules, such as p62. The interaction between p62 and ubiquitin on the bacteria is required for guiding the pathogen to the autophagosome. Following fusion of the autophagosome and lysosome, the bacteria are cleared from the cytosol. b Legionella pneumophila avoids host-autophagic clearance through the cooperative action of the Sdc and SidE effector families. Upon internalization, Legionella resides within the Legionella-containing vacuole (LCV). The bacterial effectors Sdc and SidEs are translocated into the host cell, where they work together to modify the ubiquitin landscape on the LCV surface. Sdc catalyzes conventional polyubiquitination on host substrates, while SidEs perform phosphoribosyl-linked serine ubiquitination (PR-ubiquitination). Furthermore, SidEs modify the polyubiquitin chains assembled by Sdc by adding PR moieties to the Arg42 residue of ubiquitin. This coordinated action of Sdc and SidEs generates a unique ubiquitin code on the LCV, consisting of mixed ubiquitin chains with both conventional and PR linkages, as well as PR-modified ubiquitins within the polyubiquitin chains. The modification of the polyubiquitin chains by SidEs prevents recognition by ubiquitin-binding autophagy adaptors like p62, thereby allowing L. pneumophila to evade autophagic clearance via xenophagy. As a result, the LCV matures into an ER-derived replicative niche, promoting bacterial survival and growth.