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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
08:47

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

Zhaoyu Jin1, Yun Li, Robert Pitti

  • 1Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Cell
|May 12, 2009
PubMed

Insights

Death receptor activation triggers caspase-8 polyubiquitination and aggregation, enhancing apoptosis. This process involves a CUL3 E3 ligase and p62, leading to cell death commitment.

Area of Science:

  • Cell biology
  • Molecular biology
  • Biochemistry

Background:

  • Cell-surface death receptors (DR4, DR5) initiate apoptosis via DISC formation.
  • Apoptosis commitment depends on caspase-8 activation and release, but full activation mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms controlling caspase-8 activation and apoptosis commitment.

Main Methods:

  • Investigated caspase-8 polyubiquitination and aggregation following death receptor ligation.
  • Utilized techniques to identify interacting E3 ligases and deubiquitinases.
  • Examined the role of p62 in caspase-8 aggregation and activation.

Main Results:

  • Discovered that death receptor ligation induces caspase-8 polyubiquitination via a novel CUL3-based E3 ligase interaction with the DISC.
  • RBX1 was essential for CUL3-mediated polyubiquitination, while A20 reversed it.
  • p62 promoted aggregation of polyubiquitinated caspase-8, driving its full activation and commitment to cell death.

Conclusions:

  • Identified a novel polyubiquitination and aggregation-dependent mechanism for positive control of apoptosis signaling.
  • Caspase-8 polyubiquitination and subsequent aggregation are critical for efficient apoptosis initiation.

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