Journal Article

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

Wu, Xiurong, Qi, Hong, Xu, Xiaozheng, Yin, Zhiyong, He, Qingzu, Zhong, Chuan-Qi, Yang, Zhang-Hua, Cai, Shaowei, Li, Dianjie, Xie, Changchuan, Chen, Xin, Wu, Rui, Yan, Yihua, Han, Jiahuai, Li, Xiang, Shuai, Jianwei, Xu, Fei

2021

Overview

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/deassembling 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 TRADDdependent 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.

• Publisher: Higher Education Press,Springer Nature B.V
• Subject: Animals / Apoptosis / Biochemistry / Biomedical and Life Sciences / Caspase 8 - genetics / Caspase 8 - metabolism / Caspase-8 / Cell Biology / Cell death / Cell fate / Developmental Biology / GTPase-Activating Proteins - genetics / GTPase-Activating Proteins - metabolism / HEK293 Cells / Human Genetics / Humans / Life Sciences / Mice / Mice, Knockout / Necroptosis / necrosome / network modeling / protein complexes quantification / Protein Science / Receptor-Interacting Protein Serine-Threonine Kinases - genetics / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Research Article / RIP1 / Stem Cells / SWATH-MS / Tumor necrosis factor