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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
PubMed

Insights

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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