Caspase-8 in Apoptosis: The Beginning of "The End"?

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.

Altered Chondrocyte Apoptosis Status in Developmental Hip Dysplasia in Rabbits

“…Caspase-8 is an initiator caspase to cleave inactive pro-forms of effector caspases, thereby activating them to trigger apoptosis (22). It is activated in response to agents or insults inducing the release of cytochrome from the inner mitochondrial membrane (23), playing a crucial role in generating cell apoptosis downstream pathway (24). Caspase-3 is required for cell deaths and distinct apoptotic processes (25).…”

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

“…We proceeded to determine the levels of some of the other components of the ''death ligand'' apoptotic pathway by Western blot, specifically caspase-8, an initiator caspase of the Fas signaling pathway 48,49 and c-FLIP isoforms. Both large and small c-FLIP can form inactive heterodimers with caspase-8 (FLICE), and thus act as apoptosis inhibitors early in the pathway.…”

Estrogen-induced dimerization and activation of ERα-fused caspase-8: Artificial reversal of the estrogenic hormone effect in carcinogenesis

“…By associating with the adaptor molecules such as Fas-associating protein with death domain (FADD), activated receptors recruit procaspase-8 to the receptor complex, where it undergoes autocatalytic activation. 6,17 In contrast to the physiological machinery, artificial approaches of initiator caspase activation have been developed. [8][9][10][11][12] In principle, the target caspase is fused to a heterologous domain which dimerizes either spontaneously or upon induction by a small dimeric ligand.…”

“…Consequently, the active caspase-8 initiates a protease cascade and causes the activation of another group of caspases, effector caspases, ultimately leading to the irreversible cleavage of target proteins and apoptotic cell death. 3,6,7 An "induced proximity model" of caspase activation has been established by different researchers since 1998, which demonstrated that caspase-8 could be activated after an inducible dimerization driven by a heterologous domain fused to the zymogen. [8][9][10][11][12] Breast cancers are among the most threatening malignancies and are responsible for about 20% of women's deaths worldwide.…”

“…3,5 Caspase-8 (FLICE/MACH/Mch5) represents a group of initiator caspases, which are characterized by a long prodomain and the activation of which are normally achieved by homotypic proteolysis in response to upstream proapoptotic signals. 6 Caspase-8 plays a crucial role in CD95/ Fas-mediated apoptosis. The binding of the trivalent Fas ligand (FasL) to Fas causes the aggregation of Fas cytoplasmic death domains (DD) and increases its affinity for the DD of an adaptor protein, the Fas-associated death domain protein (FADD).…”