Executioner caspases (Caspase-3, -6, -7)

Executioner caspases, primarily caspase-3, -6, and -7, are cysteine aspartyl proteases that serve as the primary effectors in the apoptosis cascade, activated by upstream initiator caspases such as caspase-8 or caspase-9. They function as heterotetramers with large and small subunits, cleaving over 600 cellular substrates including poly(ADP-ribose) polymerase (PARP), lamins, and cytoskeletal proteins to dismantle the cell in a controlled manner, resulting in DNA fragmentation, membrane blebbing, and apoptotic body formation without inflammation. These caspases are produced as inactive procaspases and require proteolytic cleavage for activation, enabling a feedback amplification loop during apoptosis. Beyond apoptosis, they have non-canonical roles in inflammation, development, and tissue homeostasis, with dysregulation implicated in diseases like cancer (where inhibition may enhance tumorigenesis) and neurodegeneration (via excessive neuronal death). Caspase-3 is the most promiscuous and dominant executioner, while caspase-7 shows substrate specificity differences. Therapeutic targeting remains challenging due to their essential developmental roles, as evidenced by knockout mouse phenotypes showing brain hyperplasia and perinatal lethality for caspase-3 and -9 deficiencies. No approved drugs directly target executioner caspases, but their activity is monitored via DEVD peptide substrates in research.

Other names

Effector caspasesApoptotic caspasesDownstream caspases