Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis

Abstract

Caspase-8 has two opposing biological functions - it promotes cell death by triggering the extrinsic pathway of apoptosis, but also has a survival activity, as it is required for embryonic development1, T lymphocyte activation2, and resistance to necrosis induced by Tumor Necrosis Factor-α (TNF) and related family ligands3,4. Here we show that development of caspase-8-deficient mice is completely rescued by ablation of Receptor Interacting Protein Kinase-3 (RIPK3). Adult animals lacking both caspase-8 and RIPK3 display a progressive lymphoaccumulative disease resembling that seen with defects in CD95 or CD95-ligand, and resist the lethal effects of CD95 ligation in vivo. We have found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-Like Inhibitory Protein Long (FLIPL), and this complex is required for the protective function.

RIP kinases: key decision makers in cell death and innate immunity

“…61 Interestingly, RIP3 and its catalytic activity facilitate a switch between TNF-induced apoptosis and necrosis, 60 with embryonic fibroblasts from RIP3-deficient mice being resistant to TNF-induced necrosis 61 and RIP3 kinase dead knock-in mice displaying developmental lethality due to RIP1-and caspase 8-driven apoptosis. 63 RIP3 deficiency also rescues the prenatal lethality of caspase 8 knockout mice with double knockouts lacking both caspase 8 and RIP3 surviving and reaching maturity, 64,65 indicating that RIP3 mediates lethality in the absence of caspase 8. This is consistent with the ability of caspase 8 to cleave RIP3 resulting in loss of the kinase domain of RIP3 and abrogation of its ability to trigger caspaseindependent cell death.…”

“…66 Caspase 8 has also been shown to repress necrosis by processing CYLD. 67 Interestingly, caspase 8 appears to act in a proteolytically active complex with FADD and cFLIP to block RIP1-and RIP3-mediated necrosis, 65,68 with c-FLIP- 69 and FADD-70,71 deficient cells being highly sensitive to death by necrosis. This is consistent with the developmental lethality, due to cardiac failure, in FADDdeficient embryos, 72 with RIP1 deficiency rescuing the embryonic lethality associated with FADD deficiency.…”

Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis

“…[5][6][7] Physiological function of necroptosis has been illustrated in host defense, [8][9][10][11] inflammation, [12][13][14][15][16] tissue injury, 10,17,18 and development. [19][20][21] Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis.…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…Although cFLIP L suppresses the ability of caspase-8 to induce cell death, binding of cFLIP L to caspase-8 actually promotes localised activation of caspase-8. This cFLIP L -caspase-8 heteromer cleaves RIPK1 and prevents RIPK1-RIPK3 association (Micheau et al, 2002;Oberst et al, 2011). cFLIP L therefore, inhibits necroptosis as well as apoptosis.…”

“…Additionally, RIP3-and caspase-8-double knockout mice exhibit enlarged spleens and lymph nodes and an abnormal accumulation of T cells in secondary lymphoid tissues (Kaiser et al, 2011;Oberst et al, 2011). A marked increase in T-cell numbers was also observed in RIP1-and FADD-double knockout chimaeras (Zhang et al, 2011), suggesting that a hyper-proliferative disorder can occur when components of necroptosis signalling are altered.…”