caspase9

Caspase-9 is a cysteine protease that functions as an initiator caspase in the intrinsic, or mitochondrial, pathway of apoptosis. It is encoded by the CASP9 gene and is widely expressed in human tissues.

In response to cellular stress and the release of cytochrome c from mitochondria, cytochrome c binds to APAF1 to form the apoptosome. Procaspase-9 is recruited to the apoptosome through CARD–CARD interactions, leading to dimerization and proteolytic activation. The activated caspase-9 then cleaves and activates downstream executioner caspases such as caspase-3 and caspase-7, amplifying the apoptotic cascade and driving cellular disassembly.

Caspase-9 activity is tightly regulated. Inhibitors of apoptosis proteins (IAPs), notably XIAP, can bind to and inhibit active caspase-9, preventing apoptosis. Smac/DIABLO released from mitochondria can antagonize IAPs to promote caspase-9 activation. Other regulatory factors influence apoptosome formation and caspase-9 activation in response to stress.

Beyond its role in programmed cell death, caspase-9 participates in diverse cellular processes linked to development, stress responses, and tissue homeostasis. Dysregulation of caspase-9–dependent apoptosis has been observed in cancer, ischemic injury, and neurodegenerative diseases, making the caspase-9 axis a target of therapeutic research.

Structurally, caspase-9 contains an N-terminal caspase activation and recruitment domain (CARD) that mediates assembly with the apoptosome, and a catalytic domain with the active-site cysteine that performs substrate cleavage. The protein is activated by autoproteolysis within the apoptosome, enabling downstream caspase activation.