Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling

Cell. 2009 May 15;137(4):721-35. doi: 10.1016/j.cell.2009.03.015. Epub 2009 May 7.


Cell-surface death receptors such as DR4 and DR5 trigger apoptosis through a death-inducing signaling complex (DISC) that recruits the apical protease caspase-8. Apoptosis commitment requires efficient activation and autocatalytic release of caspase-8 into the cytoplasm to engage executioner caspases. While DISC recruitment initiates caspase-8 stimulation, full activation of the protease depends on further molecular aggregation events that are not fully understood. Here, we show that death receptor ligation induces polyubiquitination of caspase-8, through a previously unknown interaction of the DISC with a cullin3 (CUL3)-based E3 ligase. CUL3-mediated caspase-8 polyubiquitination required the RING box protein RBX1, whereas the deubiquitinase A20 reversed this modification. The ubiquitin-binding protein p62/sequestosome-1 promoted aggregation of CUL3-modified caspase-8 within p62-dependent foci, leading to full activation and processing of the enzyme and driving commitment to cell death. These results identify a mechanism that positively controls apoptosis signaling by polyubiquitination and aggregation of a key initiator caspase.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis
  • Carrier Proteins / metabolism
  • Caspase 8 / metabolism*
  • Cell Line, Tumor
  • Cullin Proteins / metabolism*
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Protein Transport
  • Sequestosome-1 Protein
  • Ubiquitin / metabolism
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • CUL3 protein, human
  • Carrier Proteins
  • Cullin Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • RBX1 protein, human
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • Caspase 8