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The viral oncoprotein LMP1 exploits TRADD for signaling by masking its apoptotic activity.
PLoS Biol. 6, 86-98:e8 (2008)
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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13.501
1.810
35
36
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Publication type
Article: Journal article
Document type
Scientific Article
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
Language
english
Publication Year
2008
HGF-reported in Year
0
ISSN (print) / ISBN
1544-9173
e-ISSN
1545-7885
Journal
PLoS Biology
Quellenangaben
Volume: 6,
Issue: 1,
Pages: 86-98,
Article Number: e8
Publisher
Public Library of Science (PLoS)
Reviewing status
Peer reviewed
Institute(s)
Research Unit Gene Vector (AGV)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Immune Response and Infection
PSP Element(s)
G-501500-001
PubMed ID
18198944
WOS ID
000254928300010
Scopus ID
38949176077
Erfassungsdatum
2008-03-10