It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival

Abstract

Caspase 8 can initiate apoptosis, but it also has non-apoptotic roles; for example, it is required for embryonic development and immune cell proliferation. Recent work has indicated that the requirement for caspase 8 in development and immune cell proliferation is defined by suppression of receptor-interacting protein kinase 3 (RIPK3), a kinase that triggers an alternative form of cell death called programmed necrosis. Interestingly, these recent findings can be reconciled with earlier work on the non-apoptotic roles of caspase 8.

Fig. 1

Activation of caspase-8 by homo- and heterodimerization. This Figure depicts activation of caspase-8 at the receptor-associated DISC; however, similar homo- and heterodimerization events take place in the RIPK1-associated complex depicted in Fig. 2. A) Inactive caspase-8 zymogens are present in the cytosol of most healthy cells. These are composed of a prodomain (light blue), and one large and one small subunit (green and dark blue, respectively). B) Ligation of cell surface receptors such as CD95 leads to recruitment of the adapter FADD, which in turn recruits monomeric caspase-8 zymogens present in the cytosol via interactions with the caspase-8 prodomain. C) When FLIP levels are low, this recruitment leads to homodimerization, which is followed by cleavage of the interdomain linker regions. These cleavage events stabilize the homodimer and allow formation of the proteolytic active sites, symbolized by stars. D) The fully active caspase-8 homodimer can then transduce the pro-apoptotic signal by activating downstream caspases, or by cleaving and activating the Bcl-2 family member Bid. E) When FLIP levels are high (e.g. following NF-kB activation by the TNF-R1-associated complex I; see Box 2), caspase-8 preferentially recruits and homodimerizes with FLIP. The caspase-8-FLIP heterodimeric complex is catalytically active, and importantly FLIP can activate caspase-8 in the absence of interdomain cleavage events. The activity of the caspase-8-FLIP complex does not trigger apoptosis, and is responsible for the suppression of RIPK1-RIPK3 signaling. However, the key substrate(s) of this complex, as well as how FLIP limits caspase-8 activation in vivo, remain to be elucidated.

Fig. 2

Recruitment of caspase-8 and FLIP to a RIPK1-containing complex determines cell fate. This Figure depicts the formation of the RIPK1 containing, RIPK3 activating complex II following TNFR1 ligation; however, recent evidence indicates that a similar complex can be induced by TLR-3 or -4 ligation or genotoxic stress^, . TNFR1 ligation initially triggers NF-kB activation and transcriptional upregulation of FLIP (see Box 2). RIPK1 is then deubiquitinated and translocates to the cytosol, where it can recruit FADD, caspase-8, and/or FLIP in a manner analogous to that depicted in Fig. 1. RIPK1 can also recruit and activate RIPK3 in this complex, a process that is controlled by FADD, caspase-8 and FLIP. A) When both caspase-8 and FLIP are present, these proteins are recruited to the RIPK1-containing complex. The caspase-8-FLIP heterodimer limits RIPK1-RIPK3 signaling, but does not trigger apoptosis. Importantly, the mechanism by which suppression of RIPK1-RIPK3 signaling by the caspase-8-FLIP complex is carried out remains controversial^, . B) When FLIP levels are low (for example, if NF-kB signaling is prevented), caspase-8 activation is unchecked, leading to apoptosis^, . FLIP is required not only to limit caspase-8 activation, but also to for suppression of RIPK signaling, so reduced FLIP levels can also sensitize cells to RIPK3-dependnent necrosis if apoptosis is prevented. C) When caspase-8 (or FADD) is absent, apoptotic activation of caspase-8 is prevented, but RIPK signaling proceeds unchecked. The result is sensitization to RIPK3-dependent programmed necrosis.