The viral oncoprotein LMP1 exploits TRADD for signaling by masking its apoptotic activity.
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.
Schneider
Frank
F
Department of Gene Vectors, GSF-National Research Center for Environment and Health, Munich, Germany.
Neugebauer
Julia
J
Griese
Janine
J
Liefold
Nicola
N
Kutz
Helmut
H
Briseño
Cinthia
C
Kieser
Arnd
A
D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*
D016328:NF-kappa B; D015513:Oncogene Proteins; D053199:TNF Receptor-Associated Death Domain Protein; D014763:Viral Matrix Proteins; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases