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

Mol Cell. 2017 Feb 16;65(4):715-729.e5. doi: 10.1016/j.molcel.2017.01.022.

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.

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