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Schneider, F. ; Neugebauer, J. ; Griese, J. ; Liefold, N. ; Kutz, H. ; Briseño, C. ; Kieser, A.

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

PLoS Biol. 6, 86-98:e8 (2008)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords EPSTEIN-BARR-VIRUS; NF-KAPPA-B; LATENT MEMBRANE-PROTEIN; TUMOR-NECROSIS-FACTOR; LYMPHOCYTE GROWTH TRANSFORMATION; TERMINAL KINASE PATHWAY; INFECTION MEMBRANE-PROTEIN-1; LIPID RAFTS; CELL-DEATH; RAT-1 FIBROBLASTS
ISSN (print) / ISBN 1544-9173
e-ISSN 1545-7885
Journal PLoS Biology
Quellenangaben Volume: 6, Issue: 1, Pages: 86-98, Article Number: e8 Supplement: ,
Publisher Public Library of Science (PLoS)
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)