Abstract
Salmonella Typhimurium drives uptake into non-phagocytic host cells by injecting effector proteins that reorganize the actin cytoskeleton. The host actin regulator N-WASP has been implicated in bacterial entry, but its precise role is not clear. We demonstrate that Cdc42-dependent N-WASP activation, instigated by the Cdc42-activating effector SopE2, strongly impedes Salmonella uptake into host cells. This inhibitory pathway is predominant later in invasion, with the ubiquitin ligase activity of the effector SopA specifically interfering with negative Cdc42-N-WASP signaling at early stages. The cell therefore transitions from being susceptible to invasion, into a state almost completely recalcitrant to bacterial uptake, providing a mechanism to limit the number of internalized Salmonella. Our work raises the possibility that Cdc42-N-WASP, known to be activated by numerous bacterial and viral species during infection and commonly assumed to promote pathogen uptake, is used to limit the entry of multiple pathogens.