Uncovering the molecular machinery driving caspase-2 activation

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Apoptosis is a form of programmed cell death characterized by unique morphological and biochemical features including activation of proteases called caspases, which are classified into initiator and effector caspases. Initiator caspases are recruited to multimeric protein complexes for their dimerization and activation. Caspase-2 is a unique member of the caspase family as it exhibits features of both initiator and effector caspases. Despite being the first cloned mammalian caspase the role of caspase-2 remained enigmatic and the unique apoptotic stimuli that activate caspase-2 as an initiator caspase remained unknown. We have uncovered that caspase-2 is activated as an initiator caspase during Pore forming toxins (PFTs)-mediated apoptosis. PFTs (for instance alpha-hemolysin and aerolysin) are major bacterial virulence factors secreted by pathogenic bacteria and they elicit cytotoxic effects primarily by forming pores on the host cell membranes. We have sown that caspase-2 is required for mediating both alpha-hemolysin and aerolysin-mediated apoptosis in human epithelial cells. Caspase-2 is activated in a PIDDosome independent manner and by employing high-resolution gel filtration chromatography, we have identified that caspase-2 is recruited to a novel high molecular weight complex (Castosome) in PFT-treated cells. Recruitment of caspase-2 to this high molecular weight complex and its activation are dependent on PFT-induced potassium efflux thus revealing a crucial role for potassium ions in regulating caspase-2 activation. We aim to decipher the components of castosome complex and further elucidate mechanisms behind caspase-2 activation. These results will enable us to design rational therapeutic drugs to combat several bacterial infections and cancer.