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
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
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2009-12-18 12:00:00
Last Modified: 0001-01-01 12:00:00
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