FIGURE 12.

Model depicting the up-/down-regulation of pro-/anti-apoptotic cascades in both the cytoplasmic and nuclear compartments of the Detroit 562 human pharyngeal cells upon SP-STP treatment. GAS responds to the external environment. Hence the genes expression repertoire in GAS varies according to the constantly changing environments within the host. As a result, the gene expression profiles of the GAS population not in contact with the host cells (floating/non adherent GAS) versus the GAS population in contact with the host cells (adherent GAS) versus those that are found within the host cells (invaded GAS) are quite different. We found that the GAS found exclusively within the host cells is highly virulent as many virulence and virulence-regulating genes are up-regulated. Among them, eukaryote-like Ser/Thr phosphatase (SP-STP) is the focus of this study, which has been reported previously as a secretory protein. SP-STP, by virtue of its eukaryote-type nature and its overexpression within the cytoplasm of pharyngeal cells upon GAS invasion, becomes a promiscuous protein exploited by GAS to hijack host signal transduction cascades both extrinsically, i.e. when it is secreted from the adherent GAS, and intrinsically, when it is secreted in large amounts by the intracellular invaded GAS. We demonstrate that the final destination of SP-STP whether from outside or inside is the host cell nucleus. The Ser/thr phosphatase activity of SP-STP directly or indirectly activates expression of several pro-apoptotic genes and suppresses anti-apoptotic genes. The cumulative effects of these processes culminate in mitochondrial malfunctioning, changes in histone phosphorylation status, chromatin fragmentation, and condensation. Ultimately these changes result in apoptosis and proliferation inhibition of pharyngeal cells. SP-STP thus significantly contributes to the GAS-mediated apoptosis.