Epstein-Barr virus-driven B cell lymphoma mediated by a unique LMP1-TRAF6 complex

Abstract The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) drives viral B cell transformation and oncogenesis. LMP1's transforming activity depends on its cytoplasmic C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 interaction with LMP1 and its critical role for LMP1 signaling has remained elusive. Here we demonstrate that TRAF6 interacts directly with a novel viral TRAF6 binding motif within CTAR2. Structural modeling supported by NMR and functional studies provides insight into the molecular architecture of the LMP1-TRAF6 complex and reveals substantial differences to CD40-TRAF6 interaction. The direct recruitment of TRAF6 to LMP1 is essential for NF-κB activation and survival of LMP1-driven B cell lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with proliferation of EBV-transformed B cells. We identify LMP1-TRAF6 as critical virus-host interface and validate this interaction as novel therapeutic target against EBV.