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.
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.
Vince
James E
JE
Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, Victoria 3086, Australia.
Pantaki
Delara
D
Feltham
Rebecca
R
Mace
Peter D
PD
Cordier
Stephanie M
SM
Schmukle
Anna C
AC
Davidson
Angelina J
AJ
Callus
Bernard A
BA
Wong
Wendy Wei-Lynn
WW
Gentle
Ian E
IE
Carter
Holly
H
Lee
Erinna F
EF
Walczak
Henning
H
Day
Catherine L
CL
Vaux
David L
DL
Silke
John
J
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; C506236:Tnfrsf1a protein, mouse; D048069:Tumor Necrosis Factors