Open AccessA unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5
Author(s) -
Yingying Zhang,
Kai Huang,
Yuxia Zhang,
Tao Han,
Lang Li,
Chenchen Ruan,
Ye-hsuan Sun,
Wei Shi,
Weiping Han,
Shuodong Wu,
Jing Song,
Jun Li,
Jiahuai Han
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001304
Subject(s) - ripk1 , necroptosis , biology , microbiology and biotechnology , embryonic stem cell , caspase 8 , programmed cell death , caspase , tumor necrosis factor receptor 1 , apoptosis , embryo , mutant , mutation , knockout mouse , zebrafish , genetics , receptor , gene , tumor necrosis factor receptor
Tumor necrosis factor receptor-1 (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 noncleavable receptor interacting serine/threonine kinase 1 (RIPK1) mutations occur naturally in humans, and the corresponding D325A mutation in murine RIPK1 leads to death at early midgestation. It is known that both the demise of Ripk1 D325A/D325A embryos and the death of Casp8 −/− mice are initiated by TNFR1, but they are mediated by apoptosis and necroptosis, respectively. Here, we show that the defects in Ripk1 D325A/D325A embryos occur at embryonic day 10.5 (E10.5), earlier than that caused by Casp8 knockout. By analyzing a series of genetically mutated mice, we elucidated a mechanism that leads to the lethality of Ripk1 D325A/D325A embryos and compared it with that underlies Casp8 deletion-mediated lethality. We revealed that the apoptosis in Ripk1 D325A/D325A embryos requires a scaffold function of RIPK3 and enzymatically active caspase-8. Unexpectedly, caspase-1 and caspase-11 are downstream of activated caspase-8, and concurrent depletion of Casp1 and Casp11 postpones the E10.5 lethality to embryonic day 13.5 (E13.5). Moreover, caspase-3 is an executioner of apoptosis at E10.5 in Ripk1 D325A/D325A mice as its deletion extends life of Ripk1 D325A/D325A mice to embryonic day 11.5 (E11.5). Hence, an unexpected death pathway of TNFR1 controls RIPK1 D325A mutation-induced lethality at E10.5.