Role for caspase-2 during pore-forming toxin-mediated apoptosis

Pore-forming toxins (PFT) form the largest family of secreted toxins from pathogenic bacteria. Staphylococcus aureus produces different hemolysins, and α-hemolysin is one of the well-studied PFTs for which the X-ray structure of the pore is available. These toxins form heptameric pores of 1–2 nm in size in cell membranes, leading to various outcomes, including apoptotic cell death, in the host cells. As epithelial cells and keratinocytes are the major sites of pathogen entry, we have set out to investigate the molecular machinery driving cell death mediated by α-hemolysin in these cell types. To our surprise, we have detected an initiator caspase role for caspase-2 during PFT-mediated apoptosis, and further investigations revealed that caspase-2 is activated in a PIDDosome-independent manner under these conditions. Caspases are effector proteases of the apoptotic cascade and broadly divided into two major classes depending on the structure and chronology of their activation as initiator and effector caspases. Despite being the first mammalian caspases to be cloned and highly conserved, the physiological role of this caspase remains unclear. Caspase-2-deficient mice develop normally, with mild defects, and emerging evidence suggests a role for this caspase in regulating DNA damage response, cell cycle regulation and tumor suppression. Like other initiator caspases, caspase-2 is activated by dimerization mediated through the CARD domains, and initial studies revealed that caspase-2 is recruited to a high molecular weight complex distinct from the apoptosome in cell lysates upon transfer from 4°C to 37°C. During genotoxic stress, caspase-2 has been shown to be recruited to a Role for caspase-2 during pore-forming toxin-mediated apoptosis