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RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes
Protein & Cell ; (12): 858-876, 2021.
Article in En | WPRIM | ID: wpr-922480
Responsible library: WPRO
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.
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Full text: 1 Index: WPRIM Main subject: Apoptosis / Mice, Knockout / GTPase-Activating Proteins / Caspase 8 / Receptor-Interacting Protein Serine-Threonine Kinases / HEK293 Cells / Necroptosis Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Protein & Cell Year: 2021 Type: Article
Full text: 1 Index: WPRIM Main subject: Apoptosis / Mice, Knockout / GTPase-Activating Proteins / Caspase 8 / Receptor-Interacting Protein Serine-Threonine Kinases / HEK293 Cells / Necroptosis Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Protein & Cell Year: 2021 Type: Article