Caspase-8: regulating life and death

Abstract

Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Although excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediated activation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in the development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

Keywords: apoptosis; caspase-8; development; hematopoiesis; inflammation; necroptosis.

Figure 1. cFLIP regulates death receptor-mediated apoptosis

Ligated CD95 or TRAILR recruits FADD via homotypic DD interactions. FADD then recruits caspase-8 via DED interactions, forming the DISC. When cFLIP levels are low, caspase-8 homodimerizes and activates itself by autoproteolytic cleavage, resulting in the release of activated caspase-8 and the initiation of apoptosis. cFLIP_S blocks apoptosis by abrogating caspase-8 filament formation. cFLIP_L blocks apoptosis by inhibiting the full maturation and release of caspase-8.

Figure 2. Regulation of TNFR1-mediated cell death

TNFR1 ligation leads to the recruitment of TRADD, TRAF2, cIAP1/2 and RIPK1 (complex I). RIPK1 ubiquitylation by cIAP1/2 mediates activation of NF-κB and the production of pro-inflammatory and pro-survival gene expression. RIPK1 is deubiquitylated by CYLD and leaves complex I to recruit FADD via homotypic DD interactions and RIPK3 through homotypic RHIM domain interactions, thereby forming the ripoptosome. Homodimerization and activation of caspase-8 on FADD induces apoptosis, whereas RIPK3 ameloid formation and MLKL activation engages necroptosis. One of the expressed pro-survival genes, cFLIP_L, heterodimerizes with caspase-8, resulting in inhibition of caspase-8 activation and apoptosis. Caspase-8 retains its catalytic activity and is able to cleave RIPK1 and RIPK3 in the apoptosome, thereby blocking necroptosis.

Figure 3. Regulation of signal II-mediated cell death

Ligation of signal II receptors induces pro-inflammatory and pro-survival gene expression and activates RIPK3 to engage necroptosis. RIPK1 links the inhibitory FADD-caspase-8-cFLIP_L complex to RIPK3 via homotypic RHIM domain interactions between RIPK1 and RIPK3 and homotypic DD interactions between RIPK1 and FADD. When cFLIP_L levels are low, RIPK3 induces necroptosis, but when MLKL is absent or blocked RIPK3 induces caspase-8 mediated necroptosis. When cFLIP_L levels are high, the caspase-8-cFLIP_L heterodimer blocks both apoptosis and necroptosis.

Figure 4. Caspase-8 regulates apoptosis, gene expression and necroptosis following CD95 and TRAILR ligation

Ligation of CD95 or TRAILR induces the rapid association of FADD-caspase-8 with the intracellular domain of the receptor, forming the DISC. This can lead to caspase-8 homodimerization, activation and dissociation from the DISC to initiate apoptosis. The FADD-caspase-8 complex can also dissociate from the ligated receptor and recruit RIPK1. The additional association of TRADD, TRAF2 and cIAP1/2 leads to the formation of a complex similar to complex I in TNFR1 signaling and results in gene expression. Recruitment of RIPK1 and RIPK3 to the dissociated FADD-caspase-8 complex results in RIPK3 and MLKL activation and necroptosis.