title: TRAF2 Sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Gonzalvez
authors.forename: David
authors.initials: D
authors.lastname: Lawrence
authors.forename: Becky
authors.initials: B
authors.lastname: Yang
authors.forename: Sharon
authors.initials: S
authors.lastname: Yee
authors.forename: Robert
authors.initials: R
authors.lastname: Pitti
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Pham
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.forename: Jennie
authors.initials: J
authors.lastname: Lill
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism*; D020134:Catalytic Domain; D002470:Cell Survival; D044842:Cullin Proteins / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004789:Enzyme Activation; D045325:HCT116 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D007976:Leupeptins; D061988:Proteasome Inhibitors; D047992:TNF Receptor-Associated Factor 2; C505530:CASP8 protein, human; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde