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

Cell Death Differ. 2011 Mar;18(3):538-48. doi: 10.1038/cdd.2010.135. Epub 2010 Nov 12.

Abstract

Caspase-8 stably inserts into the mitochondrial outer membrane during extrinsic apoptosis. Inhibition of caspase-8 enrichment on the mitochondria impairs caspase-8 activation and prevents apoptosis. However, the function of active caspase-8 on the mitochondrial membrane remains unknown. In this study, we have identified a native complex containing caspase-8 and BID on the mitochondrial membrane, and showed that death receptor activation by Fas or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced the cleavage of BID (tBID formation) within this complex. tBID then shifted to separate mitochondria-associated complexes that contained other BCL-2 family members, such as BAK and BCL-X(L). We report that cells stabilize active caspase-8 on the mitochondria in order to specifically target mitochondria-associated BID, and that BID cleavage on the mitochondria is essential for caspase-8-induced cytochrome c release. Our findings indicate that during extrinsic apoptosis, caspase-8 can specifically target BID where it is mostly needed, on the surface of mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BH3 Interacting Domain Death Agonist Protein / metabolism*
  • Caspase 8 / metabolism*
  • Cell Death / drug effects
  • Cytochromes c / metabolism
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / metabolism
  • Models, Biological
  • Molecular Weight
  • Mutant Proteins / metabolism
  • Peptide Elongation Factor Tu / metabolism
  • Point Mutation / genetics
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • fas Receptor / metabolism

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • FAS protein, human
  • Mitochondrial Proteins
  • Mutant Proteins
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TUFM protein, human
  • fas Receptor
  • Green Fluorescent Proteins
  • Cytochromes c
  • CASP8 protein, human
  • Caspase 8
  • Peptide Elongation Factor Tu