Caspase-8 Blocks Receptor-Interacting Protein Kinase-1 Kinase-Independent Necroptosis during Embryogenesis.

ImmunoHorizons 2022 Jul 20

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Caspase-8 (Casp8) suppresses receptor-interacting protein kinase-3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis, demonstrated by the genetic evidence that deletion of Ripk3 or Mlkl prevented embryonic lethality of Casp8-deficient mice. However, the detailed mechanisms by which Casp8 deficiency triggers necroptosis during embryonic development remain unclear. In this article, we show that Casp8 deletion caused formation of the RIPK1-RIPK3 necrosome in the yolk sac, leading to vascularization defects, prevented by MLKL and RIPK3 deficiency, or RIPK3 RHIM mutant (RIPK3 V448P), but not by the RIPK1 kinase-dead mutant (RIPK1 K45A). In addition, Ripk1K45A/K45ACasp8 -/- mice died on embryonic day 14.5, which was delayed to embryonic day 17.5 by ablation of one allele in Ripk1 and was completely rescued by ablation of Mlkl Our results revealed an in vivo role of RIPK3 RHIM and RIPK1K45A scaffold-mediated necroptosis in Casp8 deficiency embryonic development and suggested that the Casp8-deficient yolk sac might be implicated in identifying novel regulators as an in vivo necroptotic model. Copyright © 2022 The Authors.

Citation

Haiwei Zhang, Xiaoxia Wu, Ming Li, Xiaoming Li, Lingxia Wang, Jianling Liu, Yangjing Ou, Xuanhui Wu, Mingyan Xing, Fang Li, Xiaoming Zhao, Han Liu, Connor Jones, Jiangshan Deng, Qun Xie, Yue Zhang, Yan Luo, Yuwu Zhao, Haibing Zhang. Caspase-8 Blocks Receptor-Interacting Protein Kinase-1 Kinase-Independent Necroptosis during Embryogenesis. ImmunoHorizons. 2022 Jul 20;6(7):465-475