Caspase‐8 in Apoptosis: The Beginning of “The End”?

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Abstract
Caspase‐8 is a member of the cysteine proteases, which are implicated in apoptosis and cytokine processing. Like all caspases, caspase‐8 is synthesized as an inactive single polypeptide chain zymogen procaspase and is activated by proteolytic cleavage, through either autoactivation after recruitment into a multimeric complex or trans‐cleavage by other caspases. Thus, ligand binding‐induced trimerization of death receptors results in recruitment of the receptor‐specific adapter protein Fas‐associated death domain (FADD), which then recruits caspase‐8. Activated caspase‐8 is known to propagate the apoptotic signal either by directly cleaving and activating downstream caspases or by cleaving the BH3 Bcl2‐interacting protein, which leads to the release of cytochrome c from mitochondria, triggering activation of caspase‐9 in a complex with dATP and Apaf‐1. Activated caspase‐9 then activates further “downstream caspases, ” including caspase‐8. Knockout data indicate that caspase‐8 is required for killing induced by the death receptors Fas, tumor necrosis factor receptor 1, and death receptor 3. Moreover, caspase‐8‐/‐ mice die in utero as a result of defective development of heart muscle and display fewer hematopoietic progenitor cells, suggesting that the FADD/caspase‐8 pathway is absolutely required for growth and development of specific cell types.

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