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

• 作者: 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
• 来源期刊: 蛋白质与细胞
• 年，卷（期）: 2021,（11）
• 所属期刊栏目: RESEARCH ARTICLES
• 页码范围: 858-876
• 页数: 19页
• 语种: 英文

摘要

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 obser-vations 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 com-plexity 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.