caspasa8

Caspase-8, encoded by the CASP8 gene in humans, is a cysteine protease and an initiator member of the caspase family. It has also been known by several alternative names in different species, including FLICE, MACH, and Mch6. Caspase-8 plays a central role in the extrinsic pathway of apoptosis, helping to transmit death receptor signals into a cell’s programmed death program.

Structure and activation: Caspase-8 contains two amino-terminal death effector domains (DEDs) that recruit it to death-inducing signaling complexes, and a C-terminal catalytic domain. It is produced as an inactive zymogen and becomes activated through proteolytic processing after recruitment to signaling complexes. The active enzyme consists of subunits derived from the zymogen, including mature forms such as p18, following initial cleavage to p43/p41 intermediates.

Mechanism of action: Activation occurs when death receptors such as Fas (CD95), TNF receptor 1, or TRAIL receptors engage their ligands and recruit the adaptor protein FADD, forming the DISC (death-inducing signaling complex). Pro-caspase-8 is cleaved within the DISC to generate active caspase-8, which then cleaves and activates downstream effector caspases-3 and -7, driving apoptosis. Caspase-8 can also cleave Bid, linking the extrinsic pathway to the mitochondrial (intrinsic) apoptotic pathway and amplifying cell death.

Additional roles and regulation: Beyond initiating apoptosis, caspase-8 participates in immune signaling and can regulate cell death decisions by inhibiting necroptosis in certain contexts, via cleavage of RIPK1 and RIPK3. This positions caspase-8 as a molecular switch between apoptosis and necroptosis, depending on cellular context and molecular environment.

Clinical and evolutionary notes: In model organisms, loss of caspase-8 can cause embryonic lethality due to unrestrained necroptosis, with viability rescued by disabling RIPK3. In humans, pathogenic variants in CASP8 have been associated with immune dysregulation and altered cancer susceptibility in some studies, reflecting its broad role in cell fate and host defense.