Volume 12 Issue 11
Nov.  2021
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Xiang Li, Chuan-Qi Zhong, Rui Wu, Xiaozheng Xu, Zhang-Hua Yang, Shaowei Cai, Xiurong Wu, Xin Chen, Zhiyong Yin, Qingzu He, Dianjie Li, Fei Xu, Yihua Yan, Hong Qi, Changchuan Xie, Jianwei Shuai, Jiahuai Han. RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes[J]. Protein&Cell, 2021, 12(11): 858-875. doi: 10.1007/s13238-020-00810-x
Citation: Xiang Li, Chuan-Qi Zhong, Rui Wu, Xiaozheng Xu, Zhang-Hua Yang, Shaowei Cai, Xiurong Wu, Xin Chen, Zhiyong Yin, Qingzu He, Dianjie Li, Fei Xu, Yihua Yan, Hong Qi, Changchuan Xie, Jianwei Shuai, Jiahuai Han. RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes[J]. Protein&Cell, 2021, 12(11): 858-875. doi: 10.1007/s13238-020-00810-x

RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes

doi: 10.1007/s13238-020-00810-x

We thank Dr. Zhuobin Xu and Dr. Yuwei Yu for help in using high performance computer. This work was supported by the National Natural Science Foundation of China (Grants No. 81788101, 11675134, 11704318, 81630042 and 31420103910), the China Postdoctoral Science Foundation (Grant No. 2016M602071), and the 111 Project (Grant Nos. B16029 and B12001).

  • Received Date: 2020-05-04
  • Rev Recd Date: 2020-11-12
  • Publish Date: 2021-11-12
  • There remains a significant gap in our quantitative understanding of crosstalk between apoptosis and necroptosis pathways. By employing the SWATH-MS technique, we quantified absolute amounts of up to thousands of proteins in dynamic assembling/de-assembling of TNF signaling complexes. Combining SWATH-MS-based network modeling and experimental validation, we found that when RIP1 level is below~1000 molecules/cell (mpc), the cell solely undergoes TRADD-dependent apoptosis. When RIP1 is above~1000 mpc, pro-caspase-8 and RIP3 are recruited to necrosome respectively with linear and nonlinear dependence on RIP1 amount, which well explains the co-occurrence of apoptosis and necroptosis and the paradoxical observations that RIP1 is required for necroptosis but its increase down-regulates necroptosis. Higher amount of RIP1 (>~46,000 mpc) suppresses apoptosis, leading to necroptosis alone. The relation between RIP1 level and occurrence of necroptosis or total cell death is biphasic. Our study provides a resource for encoding the complexity of TNF signaling and a quantitative picture how distinct dynamic interplay among proteins function as basis sets in signaling complexes, enabling RIP1 to play diverse roles in governing cell fate decisions.
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