Activation of Akt/protein kinase B in epithelial cells by the Salmonella typhimurium effector SigD

The serine-threonine kinase Akt is a protooncogene involved in the regulati on of cell proliferation and survival. Activation of Abt is initiated by bi nding to the phospholipid products of phosphoinositide 3-kinase at the inne r leaflet of the plasma membranes followed by phosphorylation at Ser(473) a nd Thr(308). We have found that Akt is activated by Salmonella enterica ser ovar Typhimurium in epithelial cells. A bacterial effector protein, SigD, w hich is translocated into host cells via the specialized type III secretion system, is essential for Akt activation. In HeLa cells, wild type S. typhi murium induced translocation of Akt to membrane ruffles and phosphorylation at residues Thr(308) and Ser(473) and increased kinase activity. In contra st, infection with a SigD deletion mutant did not induce phosphorylation or activity although Akt was translocated to membrane ruffles. Complementatio n of the SigD deletion strain with a mutant containing a single Cys to Ser mutation (C462S), did not restore the Akt activation phenotype, This residu e has previously been shown to be essential for inositol phosphatase activi ty of the SigD homologue, SopB, Our data indicate a novel mechanism of Akt activation in which the endogenous cellular pathway does not convert membra ne-associated Akt into its active form. SigD is also the first bacterial ef fector to be identified as an activator of Akt.