Subversion of the host endocytic pathway by Legionella pneumophila–mediated ubiquitination of Rab5

Legionella pneumophila is an intracellular bacterial pathogen that modulates membrane trafficking to survive and proliferate within host cells. After phagocytosis, the L. pneumophila–containing vacuole evades the endocytic pathway by excluding the host GTPase Rab5, a crucial regulator of phagosomal maturation. In this study, we show that the evolutionarily conserved lysine residue K134 of Rab5 undergoes ubiquitination during infection. This modification depends on Lpg2525, an F-box protein from L. pneumophila that acts as a component of the SKP–Cullin–F-box complex. We further demonstrate that Rab5 ubiquitination facilitates the recruitment of RabGAP-5, a Rab5-specific GAP, leading to Rab5 inactivation and subsequent release from the bacterial vacuole. Importantly, the K134 Rab5 mutant limits L. pneumophila replication within host cells. These findings reveal that Lpg2525-mediated Rab5 ubiquitination is a key survival strategy employed by L. pneumophila in infected host cells.