The viral oncoprotein LMP1 exploits TRADD for signaling by masking its apoptotic activity

• Published in: PLoS biology Vol. 6; no. 1; p. e8
• Main Authors: Schneider, Frank, Neugebauer, Julia, Griese, Janine, Liefold, Nicola, Kutz, Helmut, Briseño, Cinthia, Kieser, Arnd
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2008; Public Library of Science (PLoS)
• Subjects: Adapter proteins; Amino acids; Apoptosis; B-Lymphocytes - metabolism; Binding Sites; Cell Biology; Cells, Cultured; Enzyme Activation; Epstein-Barr virus; Flow cytometry; Genetics and Genomics; Herpes viruses; Humans; I-kappa B Kinase - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Lymphocytes; Molecular Sequence Data; NF-kappa B - metabolism; Oncogene Proteins - metabolism; Phosphorylation; Protein Binding; Signal Transduction; TNF Receptor-Associated Death Domain Protein - deficiency; TNF Receptor-Associated Death Domain Protein - genetics; TNF Receptor-Associated Death Domain Protein - metabolism; Viral infections; Viral Matrix Proteins - metabolism; Virology; Viral Matrix Proteins; Signal Transduction; Humans; Cells, Cultured; B-Lymphocytes; Molecular Sequence Data; Oncogene Proteins; I-kappa B Kinase; NF-kappa B; JNK Mitogen-Activated Protein Kinases; Protein Binding; TNF Receptor-Associated Death Domain Protein; Enzyme Activation; Binding Sites; Apoptosis
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0060008

The tumor necrosis factor (TNF)-receptor 1-associated death domain protein (TRADD) mediates induction of apoptosis as well as activation of NF-kappaB by cellular TNF-receptor 1 (TNFR1). TRADD is also recruited by the latent membrane protein 1 (LMP1) oncoprotein of Epstein-Barr virus, but its role in LMP1 signaling has remained enigmatic. In human B lymphocytes, we have generated, to our knowledge, the first genetic knockout of TRADD to investigate TRADD's role in LMP1 signal transduction. Our data from TRADD-deficient cells demonstrate that TRADD is a critical signaling mediator of LMP1 that is required for LMP1 to recruit and activate I-kappaB kinase beta (IKKbeta). However, in contrast to TNFR1, LMP1-induced TRADD signaling does not induce apoptosis. Searching for the molecular basis for this observation, we characterized the 16 C-terminal amino acids of LMP1 as an autonomous and unique virus-derived TRADD-binding domain. Replacing the death domain of TNFR1 by LMP1's TRADD-binding domain converts TNFR1 into a nonapoptotic receptor that activates NF-kappaB through a TRAF6-dependent pathway, like LMP1 but unlike wild-type TNFR1. Thus, the unique interaction of LMP1 with TRADD encodes the transforming phenotype of viral TRADD signaling and masks TRADD's pro-apoptotic function.