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


  • F. Giehler
  • M.S. Ostertag
  • T. Sommermann
  • D. Weidl
  • K.R. Sterz
  • H. Kutz
  • A. Moosmann
  • S.M. Feller
  • A. Geerlof
  • B. Biesinger
  • G.M. Popowicz
  • J. Kirchmair
  • A. Kieser


  • Nature Communications


  • Nat Commun 15 (1): 414


  • Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1's transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 recruitment to LMP1 and its role in LMP1 signalling remains elusive. Here we demonstrate that TRAF6 interacts directly with a viral TRAF6 binding motif within CTAR2. Functional and NMR studies supported by molecular modeling provide insight into the architecture of the LMP1-TRAF6 complex, which differs from that of CD40-TRAF6. The direct recruitment of TRAF6 to LMP1 is essential for NF-κB activation by CTAR2 and the survival of LMP1-driven lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with the survival of EBV-transformed B cells. In this work, we identify LMP1-TRAF6 as a critical virus-host interface and validate this interaction as a potential therapeutic target in EBV-associated cancer.