Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis

Xixi Zhang, Haiwei Zhang, Chengxian Xu, Xiaoming Li, Ming Li, Xiaoxia Wu, Wenjuan Pu, Bin Zhou, Haikun Wang, Dali Li, Qiurong Ding, Hao Ying, Hui Wang and Haibing Zhang ()
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Xixi Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Haiwei Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Chengxian Xu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiaoming Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ming Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiaoxia Wu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Wenjuan Pu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Bin Zhou: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Haikun Wang: Chinese Academy of Sciences
Dali Li: East China Normal University (ECNU)
Qiurong Ding: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hao Ying: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hui Wang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Haibing Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract The ubiquitination status of RIPK1 is considered to be critical for cell fate determination. However, the in vivo role for RIPK1 ubiquitination remains undefined. Here we show that mice expressing RIPK1K376R which is defective in RIPK1 ubiquitination die during embryogenesis. This lethality is fully rescued by concomitant deletion of Fadd and Ripk3 or Mlkl. Mechanistically, cells expressing RIPK1K376R are more susceptible to TNF-α induced apoptosis and necroptosis with more complex II formation and increased RIPK1 activation, which is consistent with the observation that Ripk1K376R/K376R lethality is effectively prevented by treatment of RIPK1 kinase inhibitor and is rescued by deletion of Tnfr1. However, Tnfr1−/− Ripk1K376R/K376R mice display systemic inflammation and die within 2 weeks. Significantly, this lethal inflammation is rescued by deletion of Ripk3. Taken together, these findings reveal a critical role of Lys376-mediated ubiquitination of RIPK1 in suppressing RIPK1 kinase activity–dependent lethal pathways during embryogenesis and RIPK3-dependent inflammation postnatally.

Date: 2019
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DOI: 10.1038/s41467-019-11839-w

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