TRAF2 Must Bind to Cellular Inhibitors of Apoptosis for Tumor Necrosis Factor (TNF) to Efficiently Activate NF-kappa B and to Prevent TNF-induced Apoptosis
- Author(s)
- Vince, JE; Pantaki, D; Feltham, R; Mace, PD; Cordier, SM; Schmukle, AC; Davidson, AJ; Callus, BA; Wong, WWL; Gentle, IE; Carter, H; Lee, EF; Walczak, H; Day, CL; Vaux, DL; Silke, J;
- Details
- Publication Year 2009-12-18,Volume 284,Issue #51,Page 35906-35915
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Publication Type
- Journal Article
- Abstract
- Tumor necrosis factor (TNF) receptor-associated factor-2 (TRAF2) binds to cIAP1 and cIAP2 (cIAP1/2) and recruits them to the cytoplasmic domain of several members of the TNF receptor (TNFR) superfamily, including the TNF-TNFR1 ligand-receptor complex. Here, we define a cIAP1/2-interacting motif (CIM) within the TRAF-N domain of TRAF2, and we use TRAF2 CIM mutants to determine the role of TRAF2 and cIAP1/2 individually, and the TRAF2-cIAP1/2 interaction, in TNFR1-dependent signaling. We show that both the TRAF2 RING domain and the TRAF2 CIM are required to regulate NF-kappa B-inducing kinase stability and suppress constitutive noncanonical NF-kappa B activation. Conversely, following TNFR1 stimulation, cells bearing a CIM-mutated TRAF2 showed reduced canonical NF-kappa B activation and TNF-induced RIPK1 ubiquitylation. Remarkably, the RING domain of TRAF2 was dispensable for these functions. However, like the TRAF2 CIM, the RING domain of TRAF2 was required for protection against TNF-induced apoptosis. These results show that TRAF2 has anti-apoptotic signaling roles in addition to promoting NF-kappa B signaling and that efficient activation of NF-kappa B by TNFR1 requires the recruitment of cIAP1/2 by TRAF2.
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- RECEPTOR-ASSOCIATED FACTOR-2; ALPHA-DEPENDENT APOPTOSIS; SIGNALING COMPLEX; MULTIPLE-MYELOMA; STRUCTURAL BASIS; UBIQUITINATION; PROTEIN; CIAP1; DEGRADATION; SURVIVAL
- Publisher's Version
- https://doi.org/10.1074/jbc.M109.072256
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- Refer to copyright notice on published article.
Creation Date: 2009-12-18 12:00:00