Abstract
RIP1 is an essential regulator of TNF-induced signaling complexes mediating NF-κB activation, apoptosis and necroptosis. Loss of Rip1 rescues the embryonic lethality of Fadd or Caspase-8-deficient mice, even though the double knockout mice die shortly after birth like Rip1-deficient mice. Recent studies demonstrated that mice expressing RIP1 kinase-dead mutants developed normally and resisted necroptotic stimuli in vitro and in vivo. However, the impact of RIP1 kinase activity on Fadd−/− embryonic development remains unknown. Here, we engineered two RIP1 kinase inactive mutant mouse lines, a Rip1K45A/K45A mouse line as previously reported and a novel Rip1Δ/Δ mouse line with an altered P-loop in the kinase domain. While RIP1K45A could not rescue the embryonic lethality of Fadd-deficient mice at E11.5, RIP1Δ rescued lethality of Fadd−/− mice at E11.5 and Fadd−/−Rip1Δ/Δ mice eventually died at E16.5 due to excessive death of fetal liver cells and unregulated inflammation. Under necropotosis-inducing conditions, comparing to Rip1K45A/K45A cells, Rip1Δ/Δcells displayed reduced phosphorylation and oligomerization of RIP3 and MLKL, which lead to increased cell viability. Thus, our study provides genetic evidence that different kinase inactive mutations have distinct impacts on the embryogenesis of Fadd-deficient mice, which might attribute to their extents of protection on necroptosis signaling.
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Acknowledgements
We thank Dr Xiaodong Wang (National Institute of Biological Sciences, Beijing, China) for providing Ripk3−/− mice and Dr. Jianke Zhang (Thomas Jefferson University, Philadelphia, PA, USA) for providing Fadd+/− mice. We also thank Dr Yu Sun (David Geffen School of Medicine, UCLA, USA) for insightful discussions and critical reading of the manuscript. This work was supported by grants from the National Natural Science Foundation of China (31571426) and the Ministry of Science and Technology of the People’s Republic of China (2016YFC1304900, 2016YFA0500100). HBZ was supported by Thousand Young Talents Program of the Chinese government.
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Liu, Y., Fan, C., Zhang, Y. et al. RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice. Cell Death Differ 24, 1459–1469 (2017). https://doi.org/10.1038/cdd.2017.78
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DOI: https://doi.org/10.1038/cdd.2017.78
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