RIPK1 Blocks Early Postnatal Lethality Mediated by Caspase-8 and RIPK3

Abstract

SUMMARY Receptor interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of RIPK1 causes postnatal lethality, which was not prevented by deletion of RIPK3, caspase-8 or FADD. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1−/− mice suggests that RIPK3 activation is inhibited by RIPK1 post-birth. While TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1−/− tnfr1−/− mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.

TAK1 control of cell death

“…Interestingly, even though RIPK1 was believed to be an essential mediator of RIPK3 activation, necroptosis can still be engaged with Ripk1 deletion. 80,81 Thus, necroptosis may be mediated through not only TAK1-RIPK1-RIPK3 complex but also through alternative complexes lacking either TAK1 or RIPK1. In summary, despite the fact that Tak1 deletion leads to hypersensitivity to TNFa-induced cell death (apoptosis), activation of TAK1 is also associated with TNFa-induced cell death (necroptosis).…”

“…Two lines of evidence support the idea that necroptosis inhibits apoptosis: (1) inhibition of RIPK3 by expressing a kinase-dead version of RIPK3 is reported to cause apoptotic cell death in vivo, which results in blood vessel abnormalities similar to endothelial-specific deletion of Tak1; 37,97 (2) deletion of Ripk1 primarily induces apoptotic cell death and tissue injury in vivo, although necroptosis is also induced. 80,81 Thus, inhibition and/or deletion of any part of the necroptotic protein kinase cascade (TAK1, RIPK1 or RIPK3) activates apoptotic cell death in vivo. Based on these, we propose that apoptosis and necroptosis are reciprocally regulated ( Figure 4).…”

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

“…63,76,77 In addition, during development the physiological role of RIP1 in regulating RIP3-driven necroptosis appears to be highly dependent on the stage of development with RIP1 being required for TNF-induced necroptosis at E10.5 78 but inhibiting necroptosis and associated inflammation at later stages of development. 78,79 Although RIP3-driven necroptosis contributes to the perinatal defects associated with RIP1 deficiency, it is not the sole underlying mechanism. 63 This is supported by recent studies demonstrating an important role for RIP1 in protecting against TNF-and caspase 8-driven apoptosis.…”

“…63 This is supported by recent studies demonstrating an important role for RIP1 in protecting against TNF-and caspase 8-driven apoptosis. 76,79 Under conditions of TNF stimulation, or during virus infection, that trigger RIP1-dependent necrosis, RIP3 promotes necrosis-specific phosphorylation of RIP1, thus forming a pro-necrotic necrosome complex. 62 Phosphorylation-induced activation of the necrosome is dependent on prior de-ubiquitination of RIP1 by CYLD, a step that is proposed to take place in the necrosome itself and not in Complex I.…”

“…RIP1 recruits caspase 8 to the RIG-1 complex resulting in RIP1 cleavage and termination of RIG-I signalling RIP kinases and innate immunity F Humphries et al necroptosis, 78 a recent report has indicated that RIP1 blocks TLR3-, TRIF-and IFN-driven necroptosis before birth. 79 TLRs that do not employ TRIF can also induce necroptosis in an indirect manner by inducing TNF to trigger necrosis via TNFR-1 as described above. 109 In addition, some of these pathways have been associated with cell apoptosis.…”