RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes. Issue 11 (2nd January 2021)

• Record Type: Journal Article
• Authors: Li, Xiang; Zhong, Chuan-Qi; Wu, Rui; Xu, Xiaozheng; Yang, Zhang-Hua; Cai, Shaowei; Wu, Xiurong; Chen, Xin; Yin, Zhiyong; He, Qingzu; Li, Dianjie; Xu, Fei; Yan, Yihua; Qi, Hong; Xie, Changchuan; Shuai, Jianwei; Han, Jiahuai
• Is Part Of: Protein & cell. Volume 12:Issue 11(2021)
• Page Start: 858
• Page End: 876
• Publication Date: 2021-01-02
• Subjects: necrosome -- protein complexes quantification -- RIP1 -- SWATH-MS -- network modeling; Proteins -- Periodicals; Cells -- Periodicals; Cytology -- Periodicals; 572.6
• DOI: 10.1007/s13238-020-00810-x
• Languages: English
• ISSNs: 1674-800X

Abstract

Abstract: 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.