title: Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses.
abstract: Tumor necrosis factor receptor 1 (TNFR1) and Toll-like receptors (TLRs) regulate immune and inflammatory responses. Here we show that the TNFR1-associated death domain protein (TRADD) is critical in TNFR1, TLR3 and TLR4 signaling. TRADD deficiency abrogated TNF-induced apoptosis, prevented recruitment of the ubiquitin ligase TRAF2 and ubiquitination of the adaptor RIP1 in the TNFR1 signaling complex, and considerably inhibited but did not completely abolish activation of the transcription factor NF-kappaB and mitogen-activated protein kinases 'downstream' of TNFR1. TRIF-dependent cytokine production induced by the synthetic double-stranded RNA poly(I:C) and lipopolysaccharide was lower in TRADD-deficient mice than in wild-type mice. Moreover, TRADD deficiency inhibited poly(I:C)-mediated RIP1 ubiquitination and activation of NF-kappaB and mitogen-activated protein kinase signaling in fibroblasts but not in bone marrow macrophages. Thus, TRADD is an essential component of TNFR1 signaling and has a critical but apparently cell type-specific function in TRIF-dependent TLR responses.
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ermolaeva
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Michallet
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Papadopoulou
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.forename: Ksanthi
authors.initials: K
authors.lastname: Kranidioti
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
mesh_terms: D000818:Animals; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053199:TNF Receptor-Associated Death Domain Protein / Q000172:deficiency* / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D025801:Ubiquitin; D020928:Mitogen-Activated Protein Kinases