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.
Keywords:
Caspase-8; FADDosome; Inflammation; NF-κB; RIPK1; TRAIL; apoptosis; cell death; cytokines; death receptors.
Copyright © 2017 Elsevier Inc. All rights reserved.
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Apoptosis / drug effects*
-
Caspase 8 / genetics
-
Caspase 8 / metabolism*
-
Chemotaxis / drug effects
-
Cytokines / metabolism
-
Dose-Response Relationship, Drug
-
Fas-Associated Death Domain Protein / genetics
-
Fas-Associated Death Domain Protein / metabolism*
-
Female
-
HCT116 Cells
-
HEK293 Cells
-
HT29 Cells
-
HeLa Cells
-
Humans
-
Inflammation Mediators / metabolism*
-
Mice
-
Multiprotein Complexes
-
NF-kappa B / metabolism
-
Neoplasms / drug therapy*
-
Neoplasms / enzymology
-
Neoplasms / genetics
-
Neoplasms / pathology
-
Phagocytes / drug effects
-
Phagocytes / metabolism
-
RNA Interference
-
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
-
Signal Transduction / drug effects
-
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
-
Time Factors
-
Transfection
Substances
-
Antineoplastic Agents
-
Cytokines
-
FADD protein, human
-
Fas-Associated Death Domain Protein
-
Inflammation Mediators
-
Multiprotein Complexes
-
NF-kappa B
-
Receptors, TNF-Related Apoptosis-Inducing Ligand
-
TNF-Related Apoptosis-Inducing Ligand
-
TNFSF10 protein, human
-
RIPK1 protein, human
-
Receptor-Interacting Protein Serine-Threonine Kinases
-
CASP8 protein, human
-
Caspase 8