A Salmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization

A central feature of Salmonella pathogenicity is the bacterium's ability to enter into non-phagocytic cells. Bacterial internalization is the conseque nce of cellular responses characterized by Cdc42- and Rac-dependent actin c ytoskeleton rearrangements. These responses are triggered by the co-ordinat ed function of bacterial proteins delivered into the host cell by a special ized protein secretion system termed type III. We report here that SopB, a Salmonella inositol polyphosphatase delivered to the host cell by this secr etion system, mediates actin cytoskeleton rearrangements and bacterial entr y in a Cdc42-dependent manner. SopB exhibits overlapping functions with two other effectors of bacterial entry, the Rho family GTPase exchange factors SopE and SopE2. Thus, Salmonella strains deficient in any one of these pro teins can enter into cells at high efficiency, whereas a strain lacking all three effectors is completely defective for entry. Consistent with an impo rtant role for inositol phosphate metabolism in Salmonella-induced cellular responses, a catalytically defective mutant of SopB failed to stimulate ac tin cytoskeleton rearrangements and bacterial entry. Furthermore, bacterial infection of intestinal cells resulted in a marked increase in Ins(1,4,5,6 )P-4, a consumption of InsP(5) and the activation of phospholipase C. In ag reement with the in vivo findings, purified SopB specifically dephosphoryla ted InsP(5) to Ins(1,4,5,6)P-4 in vitro. Surprisingly, the inositol phospha te fluxes induced by Salmonella were not caused exclusively by SopB. We sho w that the SopB-independent inositol phosphate fluxes are the consequence o f the SopE-dependent activation of an endogenous inositol phosphatase. The ability of Salmonella to stimulate Rho GTPases signalling and inositol phos phate metabolism through alternative mechanisms is an example of the remark able ability of this bacterial pathogen to manipulate host cellular functio ns.