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 RIS Download
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