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Caspase-8 Acts in a Non-enzymatic Role as a Scaffold for Assembly of a Pro-inflammatory “FADDosome” Complex upon TRAIL Stimulation

Author:
Henry, Conor M., Martin, Seamus J.
Source:
Molecular cell 2017 v.65 no.4 pp. 715-729.e5
ISSN:
1097-2765
Subject:
apoptosis, caspase-8, chemokines, inflammation, mutants, transcription factor NF-kappa B
Abstract:
TRAIL is a potent inducer of apoptosis and has been studied almost exclusively in this context. However, TRAIL can also induce NFκB-dependent expression of multiple pro-inflammatory cytokines and chemokines. Surprisingly, whereas inhibition of caspase activity blocked TRAIL-induced apoptosis, but not cytokine production, knock down or deletion of caspase-8 suppressed both outcomes, suggesting that caspase-8 participates in TRAIL-induced inflammatory signaling in a scaffold role. Consistent with this, introduction of a catalytically inactive caspase-8 mutant into CASP-8 null cells restored TRAIL-induced cytokine production, but not cell death. Furthermore, affinity precipitation of the native TRAIL receptor complex revealed that pro-caspase-8 was required for recruitment of RIPK1, via FADD, to promote NFκB activation and pro-inflammatory cytokine production downstream. Thus, caspase-8 can serve in two distinct roles in response to TRAIL receptor engagement, as a scaffold for assembly of a Caspase-8-FADD-RIPK1 “FADDosome” complex, leading to NFκB-dependent inflammation, or as a protease that promotes apoptosis.
Agid:
5640551