TRAF2 Must Bind to Cellular Inhibitors of Apoptosis for Tumor Necrosis Factor (TNF) to Efficiently Activate NF-κB and to Prevent TNF-induced Apoptosis
Copyright policy )TRAF2 Must Bind to Cellular Inhibitors of Apoptosis for Tumor Necrosis Factor (TNF) to Efficiently Activate NF-κB and to Prevent TNF-induced Apoptosis
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.
- Imperial College London United Kingdom
- Imperial College Healthcare NHS Trust United Kingdom
- La Trobe University Australia
- Hammersmith Hospital United Kingdom
- University of Zurich Switzerland
1303 Biochemistry, Amino Acid Motifs, Proliferation and Death, 610 Medicine & health, Apoptosis, 10263 Institute of Experimental Immunology, Cell Line, Inhibitor of Apoptosis Proteins, 1307 Cell Biology, Mice, 0601 (four-digit-FOR), 1312 Molecular Biology, Animals, Mice, Knockout, NF-kappa B, 600, TNF Receptor-Associated Factor 2, Protein Structure, Tertiary, 060103 Cell Development, Receptors, Tumor Necrosis Factor, Type I, Tumor Necrosis Factors, 570 Life sciences; biology, Protein Binding
1303 Biochemistry, Amino Acid Motifs, Proliferation and Death, 610 Medicine & health, Apoptosis, 10263 Institute of Experimental Immunology, Cell Line, Inhibitor of Apoptosis Proteins, 1307 Cell Biology, Mice, 0601 (four-digit-FOR), 1312 Molecular Biology, Animals, Mice, Knockout, NF-kappa B, 600, TNF Receptor-Associated Factor 2, Protein Structure, Tertiary, 060103 Cell Development, Receptors, Tumor Necrosis Factor, Type I, Tumor Necrosis Factors, 570 Life sciences; biology, Protein Binding
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