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.

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

“…Moreover, (4) a different complex, the PIDDosome (Tinel and Tschopp, 2004), is activated by ATM and executes apoptosis in response to DNA damage (Ando et al., 2012). Finally, (5) it was demonstrated recently that a structural (rather than enzymatic) function of these signaling complex is central for the production of chemotactic cytokines (Hartwig et al., 2017, Henry and Martin, 2017). Although not providing a direct proof of their regulatory function, the downregulation of LUBAC components and IAPs occurring in temporal association with the formation of the complex discovered here is remarkable.…”

Caspase‐8: regulating life and death

“…Because apoptotic CD95 signaling depends on FADD-caspase-8 it is assumed that it is the loss of FADD-caspase-8-induced apoptosis, permitted by RIPK3 or MLKL ablation, that is responsible for ALPS. Alternatively, since T cells from the non-cleavable caspase-8 mutant mouse do not show functional defects and splenomegaly of the mouse was not reported (71, 78), the scaffolding functions of caspase-8, important for antigen and death receptor-induced gene expression (described below) (79, 80), could be required for proper T cell functioning and simultaneously hints to a role for necroptosis in ALPS. However, whereas ripk3 D161N / D161N mice are asympomatic, co-ablation of caspase-8 induces development of ALPS in ripk3 D161N / D161N animals, suggesting that it is the balance between apoptosis and necroptosis that keeps the T cells from developing their ALPS phenotype.…”

“…The DISC rapidly forms on activated CD95 and TRAILR and initiates death, but a subsequent secondary complex, dubbed the FADDosome (80), was shown to form (Figure 4). This complex does not contain the receptor and ligand, but consists of FADD-caspase-8 in association with RIPK1, cIAP1/2, TRAF2 and NEMO, that can function to activate the NF-κB, JNK and p38 pathways (79, 80, 116, 117).…”

“…The DISC rapidly forms on activated CD95 and TRAILR and initiates death, but a subsequent secondary complex, dubbed the FADDosome (80), was shown to form (Figure 4). This complex does not contain the receptor and ligand, but consists of FADD-caspase-8 in association with RIPK1, cIAP1/2, TRAF2 and NEMO, that can function to activate the NF-κB, JNK and p38 pathways (79, 80, 116, 117). The interaction between FADD and caspase-8 is integral, since TRAIL-induced cytokine expression is abrogated in cells lacking FADD or caspase-8, or cells that express a caspase-8 mutant that is unable to bind FADD (80, 117).…”

“…This complex does not contain the receptor and ligand, but consists of FADD-caspase-8 in association with RIPK1, cIAP1/2, TRAF2 and NEMO, that can function to activate the NF-κB, JNK and p38 pathways (79, 80, 116, 117). The interaction between FADD and caspase-8 is integral, since TRAIL-induced cytokine expression is abrogated in cells lacking FADD or caspase-8, or cells that express a caspase-8 mutant that is unable to bind FADD (80, 117). ERK and p38 activation depend on the catalytic activity of caspase-8 at least to some extend, but this activity is totally dispensable for NF-κB activation (80, 117).…”