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

• Published in: Molecular cell 2017-02, Vol.65 (4), p.715-729.e5
• Main Authors: Henry, Conor M., Martin, Seamus J.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-8; cell death; Chemotaxis - drug effects; cytokines; Cytokines - metabolism; death receptors; Dose-Response Relationship, Drug; FADDosome; Fas-Associated Death Domain Protein - genetics; Fas-Associated Death Domain Protein - metabolism; Female; HCT116 Cells; HEK293 Cells; HeLa Cells; HT29 Cells; Humans; Inflammation; Inflammation Mediators - metabolism; Mice; Multiprotein Complexes; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; NF-kappa B - metabolism; NF-κB; Phagocytes - drug effects; Phagocytes - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; RIPK1; RNA Interference; Signal Transduction - drug effects; Time Factors; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL; Transfection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.01.022

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. [Display omitted] •TRAIL induces NFκB-dependent expression of pro-inflammatory cytokines and chemokines•Caspase-8 is required for TRAIL-induced inflammatory signaling in a scaffold role•Caspase-8 recruits RIPK1 to the TRAIL receptor complex to promote inflammation•A TRAIL-induced Caspase-8-FADD-RIPK1 “FADDosome” complex initiates inflammation TRAIL receptor engagement induces apoptosis and NFκB-dependent expression of multiple pro-inflammatory mediators. Here, Henry and Martin show that caspase-8 participates in a non-enzymatic role in TRAIL-induced inflammatory signaling by serving as a scaffold for assembly of a Caspase-8-FADD-RIPK1 “FADDosome” complex that leads to NFκB-dependent inflammation.