Activation of initiator caspases by the DISC

Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)

Both caspases-8 and -10 are synthesized as inactive single-chain pro-caspases with an N-terminal pro-domain containing two tandems of DEDs, and a C-terminal catalytic domain consisting of a large subunit (p18/α with the protease active-site cysteine) and one small subunit (p10/β; 36). When recruited to FADD at the DISC, pro-caspases-8/10 can form chains through their DEDs (37–38), leading to proximity-driven dimerization, sequential cleavage steps, and caspase activation (39–40). Structural and biochemical analyses indicate that dimerization of caspase-8 triggers caspase-8 activation by inducing a conformational change in the linker region between the large and small subunits (41–43), which leads to activation and further processing of the linker region between the large and small subunits. Subsequently, the pro-domain is cleaved from the large subunit, leading to the formation of active the 2 2 heterotetramer (Figure 30.3; 44). Mature caspase-8 is released from the DISC to cleave executioner caspases (e.g. caspases-3, -6, -7). Cleavage is sufficient for activation of these pre-dimerized executioner caspases. Executioner caspases snip specific target proteins to cause cell death.

Mature active capase-8 is not stable enough to activate its downstream targets for long (45), but apparently can be stabilized by polyubiquitination (46; Figure 30.4). In this model, the small catalytic subunit p10 of caspase-8 is polyubiquitinated with K63-linked chains by ubiquitin E3 ligase cullin3 (CUL3) at the DISC. The ubiquitin-binding protein p62 serves to relocalize polyubiquitinated caspase-8 to ubiquitin-rich foci within the cytosol, where caspase-8 remains active in its dimeric form. Later studies by the same group showed that during caspase-8 activation, its large catalytic subunit p18 can be conjugated to K48-ubiquitin chains by TRAF2. This modification leads to rapid proteosome degradation of caspase-8, setting a shutoff timer for extrinsic apoptosis (47).


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