Abstract
In mammalian cells, autophagy plays crucial roles in restricting further spread of invading bacterial pathogens. Previous studies have established that the Salmonella virulence factors SseF and SseG are required for intracellular bacterial survival and replication. However, the underlying mechanism by which these two effectors facilitate bacterial infection remains elusive. Here, we report that SseF and SseG secreted by Salmonella Typhimurium (S. Typhimurium) inhibit autophagy in host cells and thereby establish a replicative niche for the bacteria in the cytosol. Mechanistically, SseF and SseG impaired autophagy initiation by directly interacting with the small GTPase Rab1A in the host cell. This interaction abolished Rab1A activation by disrupting the interaction with its guanine nucleotide exchange factor (GEF), the TRAPPIII (transport protein particle III) complex. This disruption of Rab1A signaling blocked the recruitment and activation of Unc-51-like autophagy-activating kinase 1 (ULK1) and decreased phosphatidylinositol 3-phosphate biogenesis, which ultimately impeded autophagosome formation. Furthermore, SseF- or SseG-deficient bacterial strains exhibited reduced survival and growth in both mammalian cell lines and mouse infection models, and Rab1A depletion could rescue these defects. These results reveal that virulence factor-dependent inactivation of the small GTPase Rab1A represents a previously unrecognized strategy of S Typhimurium to evade autophagy and the host defense system.
Highlights
In mammalian cells, autophagy plays crucial roles in restricting further spread of invading bacterial pathogens
We report that the Salmonella SPI2T3SS effectors, SseF and SseG, facilitate intracellular pathogen replication by attenuating autophagy, and this function is mediated by the inactivation of Rab1A, a small GTPase that plays essential roles in Golgi homeostasis and autophagy initiation
The formation of Atg16 punctum, an indicator of early autophagic structures, was significantly impaired (Fig. 1F). These results demonstrate that SseF and SseG interrupt the initiation of autophagy
Summary
Autophagy plays crucial roles in restricting further spread of invading bacterial pathogens. The molecular targets for most of the SPI2-T3SS effector proteins remain largely unexplored, and mutational analyses indicated that the intracellular replication of Salmonella requires a subset of these proteins, including SifA, SseF, SseG, PipB2, and SopD2 [5, 6] These effectors share a common subcellular localization after SPI2-T3SS– dependent translocation and can be found in close association with the membrane of SCV [7]. We report that the Salmonella SPI2T3SS effectors, SseF and SseG, facilitate intracellular pathogen replication by attenuating autophagy, and this function is mediated by the inactivation of Rab1A, a small GTPase that plays essential roles in Golgi homeostasis and autophagy initiation. Our findings provide mechanistic insights into the schemes adopted by Salmonella to manipulate host functions and to enable bacterial infection
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