Procaspase8

Procaspase-8 is the inactive zymogen form of caspase-8, encoded by the CASP8 gene in humans. It functions as an initiator caspase in the extrinsic pathway of apoptosis, becoming activated in response to death receptor signaling.

The protein features an N-terminal prodomain containing two death effector domains (DEDs) that mediate recruitment to adaptor proteins such as FADD at death-inducing signaling complexes (DISC). The catalytic domain comprises large (p18) and small (p10) subunits that arise after proteolytic processing.

Activation occurs when death receptors—such as Fas (CD95), TRAIL receptors, or TNFR1—are engaged, bringing procaspase-8 molecules into close proximity. Dimerization triggers autocatalytic cleavage, producing active caspase-8, which then cleaves and activates downstream executioner caspases-3 and -7 and cleaves BID to tBID, thereby linking the extrinsic pathway to mitochondrial apoptosis.

Caspase-8 activity also modulates cell fate by inhibiting necroptosis: it cleaves RIPK1 and RIPK3, blocking the necroptotic pathway in many contexts. The outcome is influenced by regulatory proteins such as cFLIP, which can modulate DISC assembly and caspase-8 activation, affecting the balance between apoptosis and necroptosis.

In humans, CASP8 expression is widespread, and multiple isoforms can arise from alternative splicing. Dysregulation of CASP8 signaling has been associated with cancer, immune dysregulation, and susceptibility to infections. Due to its central role in programmed cell death, procaspase-8 and caspase-8 remain subjects of ongoing biomedical research, including therapeutic strategies that aim to modulate apoptosis or necroptosis.