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A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins

T Miyazaki1, J C Reed

  • 1The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.

Nature Immunology
|May 29, 2001
PubMed

Insights

Tumor necrosis factor (TNF) family receptors initiate apoptosis by recruiting caspases. This study reveals GTP-binding protein DAP3 is crucial for TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death by linking TRAIL receptors to FADD and pro-caspase-8.

Area of Science:

  • Molecular Biology
  • Cell Death Pathways
  • Signal Transduction

Background:

  • Apoptosis-inducing tumor necrosis factor (TNF) family receptors initiate programmed cell death.
  • These receptors recruit intracellular adapter proteins to activate caspase proteases.

Purpose of the Study:

  • To investigate the role of the GTP-binding protein DAP3 in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.
  • To elucidate the molecular mechanism by which DAP3 mediates TRAIL receptor signaling.

Main Methods:

  • Direct binding assays to determine DAP3 interaction with TRAIL receptors.
  • Co-immunoprecipitation to assess DAP3 association with FADD and caspases.
  • In vitro reconstituted system to evaluate GTP-dependent activation of pro-caspase-8.

Main Results:

  • DAP3 directly binds to the death domain of TRAIL receptors (DR4 and DR5) with high affinity.
  • DAP3 associates with Fas-associated death domain (FADD) and bridges it to TRAIL receptors.
  • GTP-dependent binding of DAP3 to FADD is required for pro-caspase-8 activation in vitro.

Conclusions:

  • DAP3 is an essential component of the TRAIL-induced apoptosis signaling complex.
  • The GTP-binding activity of DAP3 is critical for its function in linking TRAIL receptors to the caspase cascade.
  • GTP-binding proteins represent potential therapeutic targets for modulating TRAIL-induced apoptosis.

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