| TNFR1 signaling,apart from its pleiotropic functions in inflammation,plays a role in embryogenesis as deficiency of varieties of its downstream molecules leads to embryonic lethality in mice.Caspase-8 non-cleavable RIPK1 mutations occur naturally in humans and the corresponding D325A mutation in murine RIPK1 leads to death at early mid-gestation.We show that the defects in Ripk1D325A/D325A embryos occur at E10.5,earlier than that caused by Casp8 knockout.By analyzing a series of genetically mutated mice,we found that the lethality caused by RIPK1 D325A is mediated by a mechanism different from that triggered by Casp8 deletion.The former is initiated by apoptosis which requires a scaffold function of RIPK3 and enzymatically active caspase-8 while the latter is triggered by RIPK3-dependent necroptosis,although both types of demise are initiated by TNFR1.Unexpectedly,caspase-1 and caspase-11 are downstream of activated caspase-8 and only concurrent depletion of Caspl and Caspl1 blocks the E10.5 lethality.Moreover,caspase-3 is an executioner of apoptosis at E10.5 in Ripk1D325A/D325A mice.Hence,an unexpected death pathway of TNFR1 controls RIPK1 D325A mutation-induced lethality at E10.5. |
