title: TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2.
abstract: Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins. Among the signalling components that associate with TNF receptors are members of the TNF-R-associated factor (TRAF) family. TRAF2 is required for TNF-alpha-mediated activation of c-Jun N-terminal kinase (JNK), contributes to activation of NF-kappaB, and mediates anti-apoptotic signals,. TNF-RI and TNF-RII signalling complexes also contain the anti-apoptotic ('inhibitor of apoptosis') molecules c-IAP1 and c-IAP2 (refs 5, 6), which also have RING domain-dependent ubiquitin protein ligase (E3) activity. The function of IAPs in TNF-R signalling is unknown. Here we show that binding of TNF-alpha to TNF-RII induces ubiquitination and proteasomal degradation of TRAF2. Although c-IAP1 bound TRAF2 and TRAF1 in vitro, it ubiquitinated only TRAF2. Expression of wild-type c-IAP1, but not an E3-defective mutant, resulted in TRAF2 ubiquitination and degradation. Moreover, E3-defective c-IAP1 prevented TNF-alpha-induced TRAF2 degradation and inhibited apoptosis. These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Yili
authors.initials: Y
authors.lastname: Yang
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019169:Jurkat Cells; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D015703:Antigens, CD; D051034:Inhibitor of Apoptosis Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex