Cell Reports
Volume 19, Issue 4, 25 April 2017, Pages 798-808
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Article
RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice

https://doi.org/10.1016/j.celrep.2017.04.011Get rights and content
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Highlights

  • Generation of Ripk3Δ/Δ mice by altering the RIPK3 kinase domain

  • Ripk3Δ/Δ mice were protected against necroptosis in vitro and in vivo

  • Fadd−/−Ripk3Δ/Δ mice developed normally during embryogenesis but die at P1

  • The postnatal death of Fadd−/−Ripk3Δ/Δ mice was caused by excessive inflammation

Summary

RIPK3 mediates cell death and regulates inflammatory responses. Although genetic studies have suggested that RIPK3-MLKL-mediated necroptosis leads to embryonic lethality in Fadd or Caspase-8-deficient mice, the exact mechanisms are not fully understood. Here, we generated Ripk3 mutant mice by altering the RIPK3 kinase domain (Ripk3Δ/Δ mice), thus abolishing its kinase activity. Ripk3Δ/Δ cells were resistant to necroptosis stimulation in vitro, and Ripk3Δ/Δ mice were protected from necroptotic diseases. Although the Ripk3Δ/Δ mutation rescued embryonic lethality in Fadd−/− embryos, Fadd−/− Ripk3Δ/Δ mice died within 1 day after birth due to massive inflammation. These results indicate that Ripk3 ablation rescues embryonic lethality in Fadd-deficient mice by suppressing two RIPK3-mediating processes: necroptosis during embryogenesis and inflammation during postnatal development in Fadd−/− mice.

Keywords

RIPK3
Fadd
kinase activity
necroptosis
embryogenesis
inflammation
cell death

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