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

  • Nat Commun. 2024 Jan 10;15(1):414. doi: 10.1038/s41467-023-44455-w.
Fabian Giehler  1  2  3 ,  Michael S Ostertag  4 ,  Thomas Sommermann  5 ,  Daniel Weidl  6 ,  Kai R Sterz  2 ,  Helmut Kutz  2 ,  Andreas Moosmann  2  3  7 ,  Stephan M Feller  8 ,  Arie Geerlof  4 ,  Brigitte Biesinger  6 ,  Grzegorz M Popowicz  4 ,  Johannes Kirchmair  9  10 ,  Arnd Kieser  11  12  13
Affiliations
  • 1. Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental Health, 85764, Neuherberg, Germany.
  • 2. Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health, 81377, Munich, Germany.
  • 3. German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
  • 4. Institute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental Health, 85764, Neuherberg, Germany.
  • 5. Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany.
  • 6. Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.
  • 7. Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
  • 8. Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, 06120, Halle, Germany.
  • 9. Universität Hamburg, Department of Informatics, Center for Bioinformatics (ZBH), 20146, Hamburg, Germany.
  • 10. Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, 1090, Vienna, Austria.
  • 11. Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental Health, 85764, Neuherberg, Germany. [email protected].
  • 12. Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health, 81377, Munich, Germany. [email protected].
  • 13. German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. [email protected].
PMID: 38195569 DOI: 10.1038/s41467-023-44455-w
Abstract

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.

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