Caspases

Caspases are a family of cysteine proteases that cleave substrates after aspartate residues, playing central roles in programmed cell death and inflammation. They are synthesized as inactive zymogens (procaspases) and must be proteolytically activated to become functional enzymes. Once active, they initiate or execute proteolysis that dismantles cells or processes cytokines.

Caspases are commonly divided into initiator caspases (such as caspase-2, -8, -9 and -10), executioner caspases (caspase-3, -6, -7), and inflammatory caspases (caspase-1, -4, -5 in humans; caspase-11 in mice). Initiators respond to death signals and activate executioners, which then cleave multiple substrates leading to apoptosis. Inflammatory caspases process pro-inflammatory cytokines like IL-1β and IL-18 and can induce pyroptosis.

Activation and pathways: In the intrinsic (mitochondrial) pathway, cytochrome c release leads to apoptosome formation with Apaf-1 and procaspase-9, activating caspase-9 which then activates executioners. The extrinsic pathway involves death receptors and the DISC, activating caspase-8 or -10. Caspase-8 can activate downstream executioners or, in some contexts, cleave Bid to amplify mitochondrial signaling. Inflammation involves inflammasomes that activate caspase-1; noncanonical caspases respond to intracellular LPS.

Regulation and impact: Caspase activity is tightly regulated by inhibitor of apoptosis proteins (IAPs) and other regulators; dysregulation is linked to cancer, neurodegeneration, and inflammatory diseases. Caspases are also essential for normal development and immune function.