Article abstract
Nature Immunology 9, 1037 - 1046 (2008)
Published online: 20 July 2008 | doi:10.1038/ni.1638
Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses
Maria A Ermolaeva1,2, Marie-Cécile Michallet3, Nikoletta Papadopoulou1, Olaf Utermöhlen4, Ksanthi Kranidioti5, George Kollias5, Jürg Tschopp3 & Manolis Pasparakis1,2
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-
B 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-B 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.
- Institute for Genetics, Centre for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
- European Molecular Biology Laboratory Mouse Biology Unit, 00016 Monterotondo, Italy.
- Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
- Institute for Medical Microbiology, Immunology and Hygiene, Medical Center of the University of Cologne, 50935 Cologne, Germany.
- Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari 16672, Greece.
Correspondence to: Manolis Pasparakis1,2 e-mail: pasparakis@uni-koeln.de
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