CASPASE8

Caspase-8, encoded by the CASP8 gene, is a cysteine-aspartic protease belonging to the caspase family. It functions primarily as an initiator caspase in the extrinsic pathway of apoptosis and participates in other cellular processes related to immune signaling and inflammation.

Caspase-8 is synthesized as an inactive zymogen called procaspase-8, roughly 55 kDa in size, and contains an N-terminal death effector domain (DED) along with a catalytic domain. Upon activation, procaspase-8 is processed into an active heterotetramer composed of large and small subunits (p18 and p10), enabling proteolytic activity.

Activation occurs at the death-inducing signaling complex (DISC) formed after engagement of death receptors such as FAS (CD95), TRAIL receptors DR4/DR5, or TNFR1. Adaptors like FADD recruit procaspase-8 to the DISC, promoting dimerization and autoproteolysis to generate active caspase-8. The active enzyme cleaves and activates downstream effector caspases such as caspase-3 and caspase-7, and it also cleaves Bid to truncated Bid (tBid), linking the extrinsic pathway to mitochondrial amplification of apoptosis.

Regulation of caspase-8 activity involves c-FLIP, which has isoforms that can either inhibit or promote activation by forming heterodimers with procaspase-8. Caspase-8 also plays a critical role in suppressing necroptosis by cleaving RIPK1 and RIPK3; when caspase-8 activity is compromised, necroptotic signaling can proceed via RIPK1/RIPK3 and MLKL.

Clinically, CASP8 mutations or dysregulation have been associated with human immunological and inflammatory disorders and may influence cancer susceptibility. In mice, loss of caspase-8 causes embryonic lethality due to unrestrained necroptosis, a phenotype that can be rescued by deleting RIPK3, underscoring its role as a regulator of cell death pathways.