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TRAF2 Sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer.

Apoptotic caspase activation mechanisms are well defined, yet inactivation modes remain unclear. The death receptors (DRs), DR4, DR5, and Fas, transduce cell-extrinsic apoptotic signals by recruiting caspase-8 into a death-inducing signaling complex (DISC). At the DISC, Cullin3-dependent polyubiquitination on the small catalytic subunit of caspase-8 augments stimulation. Here we report that tumor necrosis factor receptor-associated factor 2 (TRAF2) interacts with caspase-8 at the DISC, downstream of Cullin3. TRAF2 directly mediates RING-dependent, K48-linked polyubiquitination on the large catalytic domain of caspase-8. This modification destines activated caspase-8 molecules to rapid proteasomal degradation upon autoprocessing and cytoplasmic translocation. TRAF2 depletion lowers the signal threshold for DR-mediated apoptosis, altering cell life versus death decisions in vitro and in vivo. Thus, TRAF2 sets a critical barrier for cell-extrinsic apoptosis commitment by tagging activated caspase-8 with a K48-ubiquitin shutoff timer. These results may have important implications for caspase regulation mechanisms.

Pubmed ID: 23142077

Authors

  • Gonzalvez F
  • Lawrence D
  • Yang B
  • Yee S
  • Pitti R
  • Marsters S
  • Pham VC
  • Stephan JP
  • Lill J
  • Ashkenazi A

Journal

Molecular cell

Publication Data

December 28, 2012

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Caspase 8
  • Catalytic Domain
  • Cell Survival
  • Cullin Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Enzyme Activation
  • HCT116 Cells
  • Humans
  • Leupeptins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Peptide Mapping
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors
  • Protein Processing, Post-Translational
  • Proteolysis
  • TNF Receptor-Associated Factor 2
  • Ubiquitination