VipD of Legionella pneumophila targets activated Rab5 and Rab22 to interfere with endosomal trafficking in macrophages.

[legionellosis]

Upon phagocytosis , Legionella pneumophila translocates numerous effector proteins into host cells to perturb cellular metabolism and immunity , ultimately establishing intracellular survival and growth . VipD of L . pneumophila belongs to a family of bacterial effectors that contain the N-terminal lipase domain and the C-terminal domain with an unknown function . We report the crystal structure of VipD and show that its C-terminal domain robustly interferes with endosomal trafficking through tight and selective interactions with Rab 5 and Rab 22 . This domain , which is not significantly similar to any known protein structure , potently interacts with the GTP-bound active form of the two Rabs by recognizing a hydrophobic triad conserved in Rabs . These interactions prevent Rab 5 and Rab 22 from binding to downstream effectors Rabaptin-5 , Rabenosyn-5 and EEA 1 , consequently blocking endosomal trafficking and subsequent lysosomal degradation of endocytic materials in macrophage cells . Together , this work reveals endosomal trafficking as a target of L . pneumophila and delineates the underlying molecular mechanism .