1.RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes.
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
Protein & Cell 2021;12(11):858-876
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.
Animals
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Apoptosis
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Caspase 8/metabolism*
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GTPase-Activating Proteins/metabolism*
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HEK293 Cells
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Humans
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Mice
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Mice, Knockout
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Necroptosis
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Receptor-Interacting Protein Serine-Threonine Kinases/metabolism*
Result Analysis
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