A unique death pathway keeps RIPK1 D325A mutant mice in check at embryonic day 10.5.

Abstract

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 Ripk1D325A/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 Ripk1D325A/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 Ripk1D325A/D325A embryos and compared it with that underlies Casp8 deletion-mediated lethality. We revealed that the apoptosis in Ripk1D325A/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 Ripk1D325A/D325A mice as its deletion extends life of Ripk1D325A/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.

• Authors: Yingying Zhang, Kai Huang, Yuxia Zhang, Tao Han, Lang Li, Chenchen Ruan, Ye-Hsuan Sun, Wenke Shi, Wei Han, Su-Qin Wu, Jing Song, Jun Liu, Jiahuai Han
• Journal: PLoS biology (PLoS Biol) Vol. 19 Issue 8 Pg. e3001304 (08 2021) ISSN: 1545-7885 [Electronic] United States
• PMID: 34437534 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Tumor Necrosis Factor, Type I
• Tnfrsf1a protein, mouse
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• Ripk3 protein, mouse
• Casp8 protein, mouse
• Caspase 8
• Caspases

Topics

• Animals
• Caspase 8 (physiology)
• Caspases (metabolism)
• Cell Death
• Embryonic Development
• Mice
• Primary Cell Culture
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism, physiology)
• Receptors, Tumor Necrosis Factor, Type I (metabolism)