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BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane

Z T Schug1, F Gonzalvez, R H Houtkooper

  • 1Laboratory of Apoptosis and Tumour Metabolism, Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.

Cell Death and Differentiation
|November 13, 2010
PubMed

Insights

Active caspase-8 targets BID on mitochondria during extrinsic apoptosis, initiating cytochrome c release and cell death. This mitochondrial targeting is crucial for apoptosis execution.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Caspase-8 localizes to the mitochondrial outer membrane during extrinsic apoptosis.
  • Mitochondrial caspase-8 enrichment is vital for its activation and subsequent apoptosis.
  • The precise function of active caspase-8 at the mitochondria remains unclear.

Purpose of the Study:

  • To elucidate the role of active caspase-8 on the mitochondrial membrane during extrinsic apoptosis.
  • To identify interacting partners of caspase-8 at the mitochondria.
  • To determine the necessity of mitochondrial caspase-8 activity for apoptosis.

Main Methods:

  • Mitochondrial isolation and biochemical fractionation.
  • Co-immunoprecipitation assays to identify protein complexes.
  • Western blotting to detect protein cleavage and localization.
  • Analysis of apoptosis markers, including cytochrome c release.

Main Results:

  • A native complex of caspase-8 and BID was identified on the mitochondrial membrane.
  • Death receptor activation (Fas, TRAIL) induced BID cleavage (tBID formation) within this mitochondrial complex.
  • tBID translocated to other mitochondria-associated complexes containing BCL-2 family members (BAK, BCL-X(L)).
  • Mitochondrial caspase-8 specifically targets BID on the mitochondrial surface, which is essential for cytochrome c release.

Conclusions:

  • Caspase-8 stabilizes on mitochondria to specifically cleave BID.
  • BID cleavage on mitochondria is a critical step for caspase-8-mediated cytochrome c release and apoptosis.
  • This study reveals a targeted mechanism for caspase-8 action at the mitochondria during extrinsic apoptosis.

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