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RIPK1- and RIPK3-induced cell death mode is determined by target availability
W D Cook1, D M Moujalled2, T J Ralph1
1La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3086, Australia.
Cell Death and Differentiation
|June 7, 2014
Summary
Receptor-interacting protein kinases (RIPK1 and RIPK3) trigger cell death. Their activation mode, independent of death ligands, depends on downstream protein availability, not a simple switch.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 are key regulators of programmed cell death.
- Understanding RIPK-triggered cell death independent of death receptor signaling is crucial for disease research.
Purpose of the Study:
- To investigate the signaling requirements for RIPK1 and RIPK3-induced cell death in the absence of death receptor ligands.
- To elucidate the mechanisms by which RIPK1 and RIPK3 activate distinct cell death pathways.
Main Methods:
- Engineered inducible versions of RIPK1 and RIPK3 activated by dimerization with coumermycin.
- Studied cell death mechanisms in the absence of TNF or other death ligands.
- Assessed the roles of FADD, caspase 8, and MLKL in RIPK-mediated cell death.
Main Results:
- RIPK1 dimerization induced cell death via caspase- or RIPK3-dependent pathways.
- RIPK3 dimerization triggered MLKL-dependent death and also FADD, caspase 8, and RIPK1-mediated death.
- RIPK3 kinase activity was essential for MLKL-dependent but not caspase 8-dependent death.
Conclusions:
- The mode of RIPK-induced cell death is determined by the availability of downstream signaling molecules like FADD, caspase 8, and MLKL.
- RIPK-mediated cell death does not operate via a simple switch but is modulated by the levels of signaling and effector proteins.
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