title: 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.
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.
authors.affiliation: Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, Victoria 3086, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.forename: Delara
authors.initials: D
authors.lastname: Pantaki
authors.forename: Rebecca
authors.initials: R
authors.lastname: Feltham
authors.forename: Peter D
authors.initials: PD
authors.lastname: Mace
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cordier
authors.forename: Anna C
authors.initials: AC
authors.lastname: Schmukle
authors.forename: Angelina J
authors.initials: AJ
authors.lastname: Davidson
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Callus
authors.forename: Wendy Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.forename: Ian E
authors.initials: IE
authors.lastname: Gentle
authors.forename: Holly
authors.initials: H
authors.lastname: Carter
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Day
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: 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*
chemical_list: 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