Group A Streptococcus (GAS)
infection is associated with a variety of human diseases. Previous studies indicate GAS
infection leads to RAW264.7 cell death, but the mechanism is unclear. Here, analyzing the timing of
reactive oxygen species (ROS) production and using mitochondrial ROS scavenger, we found the wild type GAS-induced RAW264.7 cell death was associated with mitochondrial ROS. The wild type GAS
infection could activate
glycogen synthase kinase-3β (GSK-3β). Inhibition of GSK-3β activity by
lithium chloride or decreasing GSK-3β expression by lentivirus-mediated
short hairpin RNA for GSK-3β could not only decrease the wild type GAS-induced mitochondrial ROS generation, mitochondria damage and cell death, but also reduced GAS intracellular replication.
Streptolysin S (SLS), a GAS toxin, played the important role on GAS-induced macrophage death. Compared to the wild type GAS with its isogenic sagB mutant (SLS mutant)-infected macrophages, we found sagB mutant
infection caused less mitochondrial ROS generation and cell death than those of the wild type GAS-infected ones. Furthermore, the sagB mutant, but not the wild type or the sagB-complementary mutant, could induce GSK-3β degradation via a
proteasome-dependent pathway. These results suggest that a new mechanism of SLS-induced macrophage death was through inhibiting GSK-3β degradation and further enhancing mitochondrial damage.