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RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts

Douglas R Green1, Andrew Oberst, Christopher P Dillon

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. douglas.green@stjude.org

Molecular Cell
|October 11, 2011
PubMed

Insights

Caspase-8, FADD, and FLIP are crucial for apoptosis and development. New evidence suggests uncontrolled RIPK1 and RIPK3 signaling causes cell death in their absence.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Death Pathways

Background:

  • Caspase-8, FADD, and FLIP regulate apoptosis via death receptors.
  • These proteins are also vital for embryonic development and immune cell function.
  • Their roles extend beyond apoptosis, suggesting involvement in nonapoptotic processes.

Purpose of the Study:

  • To review current evidence on the nonapoptotic roles of Caspase-8, FADD, and FLIP.
  • To investigate the link between these proteins and RIPK1/RIPK3 signaling.
  • To elucidate the mechanism by which Caspase-8, FADD, and FLIP control RIPK activation.

Main Methods:

  • Genetic analysis of caspase-8-, FADD-, and FLIP-deficient models.
  • Biochemical assays to study protein interactions and signaling pathways.
  • Review and reinterpretation of existing literature.

Main Results:

  • Unregulated signaling by RIPK1 and RIPK3 is identified as the cause of lethality in deficient models.
  • RIPKs mediate a nonapoptotic cell death resembling necrosis.
  • The precise mechanism of RIPK inhibition by Caspase-8, FADD, and FLIP remains unclear.

Conclusions:

  • Caspase-8, FADD, and FLIP are essential regulators preventing RIPK-driven cell death.
  • Further research is needed to understand the upstream signals triggering RIPK activation.
  • This review consolidates evidence and proposes future research directions.

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