title: Caspase-8 Acts in a Non-enzymatic Role as a Scaffold for Assembly of a Pro-inflammatory "FADDosome" Complex upon TRAIL Stimulation.
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.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Conor M
authors.initials: CM
authors.lastname: Henry
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland. Electronic address: martinsj@tcd.ie.
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D018836:Inflammation Mediators; D046912:Multiprotein Complexes; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Caspase-8; FADDosome; Inflammation; NF-κB; RIPK1; TRAIL; apoptosis; cell death; cytokines; death receptors