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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.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2009 Dec 18; Vol. 284 (51), pp. 35906-15. - Publication Year :
- 2009
-
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-kappaB-inducing kinase stability and suppress constitutive noncanonical NF-kappaB activation. Conversely, following TNFR1 stimulation, cells bearing a CIM-mutated TRAF2 showed reduced canonical NF-kappaB 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-kappaB signaling and that efficient activation of NF-kappaB by TNFR1 requires the recruitment of cIAP1/2 by TRAF2.
- Subjects :
- Amino Acid Motifs physiology
Animals
Cell Line
Inhibitor of Apoptosis Proteins genetics
Mice
Mice, Knockout
NF-kappa B genetics
Protein Binding physiology
Protein Structure, Tertiary physiology
Receptors, Tumor Necrosis Factor, Type I genetics
TNF Receptor-Associated Factor 2 genetics
Apoptosis physiology
Inhibitor of Apoptosis Proteins metabolism
NF-kappa B metabolism
Receptors, Tumor Necrosis Factor, Type I metabolism
TNF Receptor-Associated Factor 2 metabolism
Tumor Necrosis Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 284
- Issue :
- 51
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19815541
- Full Text :
- https://doi.org/10.1074/jbc.M109.072256