Signal transduction by bacterial Ser/Thr kinases

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Reversible phosphorylation controlled by protein kinases and protein phosphatases is a central regulatory mechanism that allows cells to adapt to environmental changes. In bacteria, phosphorylation is accomplished primarily by two-component regulatory systems that phosphorylate histidine and aspartate residues. In the last decade, phosphorylation of bacterial proteins on serine, threonine and tyrosine residues by eukaryotic-like protein kinases has also been found to play a major role in signaling. Little is known about the mechanism of action and signaling pathways controlled by eukaryotic-like protein kinases in bacteria. We identified in the genomes of Salmonella enterica serovar Typhi (S. Typhi), the etiologic agent of typhoid fever, a cluster of genes that is not present in other Salmonella serovars for which the genome has been sequenced. This gene cluster consists of three open reading frames encoding proteins with homology to Ser/Thr protein kinases (prkX and prkY) and protein phosphatase 2C (prpZ). These three genes of opposing functions appear to control a signaling pathway specific to S. Typhi. We showed that deletion of the three genes affects the long-term survival of S. Typhi in macrophages, indicating that these genes are involved in virulence. Here, we propose to better characterize this signaling pathway by examining the enzymatic activities of the three proteins as well as their regulation by covalent modification and identifying the physiological substrate(s) that is(are) reversibly phosphorylated by the three proteins. The proposed research has the potential to provide the first detailed picture of an "eukaryotic-like" phosphorylation cascade that could be involved in the long-term persistence of S. Typhi during infection.