LMP1 Subverts "TRADDitional" Signals

Epstein-Barr virus (EBV) is a DNA tumor virus that infects and transforms B lymphocytes. The viral oncoprotein latent membrane protein 1 (LMP1) promotes the proliferation of infected B lymphocytes and is critical for cellular transformation by EBV. LMP1 recruits the tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1)-associated death domain protein (TRADD), which seems counterintuitive given that the major role of TRADD as a TNFR1 adaptor protein is to promote the apoptosis of cells in response to TNF-α. TRADD also leads to the activation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK) and the transcription factor nuclear factor κB (NF-κB). LMP1 contains two cytoplasmic C-terminal activating regions (CTARs) that are important for triggering canonical and noncanonical NF-κB signaling and the activation of JNK. To try to understand the role of TRADD in LMP1 signaling, Schneider et al . first had to generate human B lymphocytes that were deficient in TRADD. Western blotting analyses showed that, whereas TRADD was necessary for both TNF-α- and LMP1-induced NF-κB activation, it was dispensable for LMP-1-mediated JNK activation. Coimmunoprecipitation studies demonstrated that TRADD mediated the interaction between the LMP1 CTAR2 domain and inhibitor of NF-κB kinase β, which is necessary for NF-κB activation. The authors then showed that amino acid residues 371 to 386 of LMP1 contained the TRADD-binding domain. When this domain was substituted for the death domain of TNFR1 in mouse embryonic fibroblasts, reporter assays showed that the TNFR1-LMP1 chimera activated NF-κB similarly to wild-type TNFR1 but that the chimeric receptor no longer induced apoptosis. This study shows that EBV, through LMP1, alters the functional properties of TRADD to promote cellular transformation. F. Schneider, J. Neugebauer, J. Griese, N. Liefold, H. Kutz, C. Briseño, A. Kieser, The viral oncoprotein LMP1 exploits TRADD for signaling by masking its apoptotic activity. PLoS Biol . 6 , e8 (2008). [PubMed]