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RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes.
- Source :
-
Protein & cell [Protein Cell] 2021 Nov; Vol. 12 (11), pp. 858-876. Date of Electronic Publication: 2021 Jan 02. - Publication Year :
- 2021
-
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.<br /> (© 2021. The Author(s).)
- Subjects :
- Animals
Caspase 8 genetics
GTPase-Activating Proteins genetics
HEK293 Cells
Humans
Mice
Mice, Knockout
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Apoptosis
Caspase 8 metabolism
GTPase-Activating Proteins metabolism
Necroptosis
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1674-8018
- Volume :
- 12
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Protein & cell
- Publication Type :
- Academic Journal
- Accession number :
- 33389663
- Full Text :
- https://doi.org/10.1007/s13238-020-00810-x