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

Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair and Arnd Kieser ()
Additional contact information
Fabian Giehler: Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental Health
Michael S. Ostertag: Institute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental Health
Thomas Sommermann: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine
Daniel Weidl: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Kai R. Sterz: Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health
Helmut Kutz: Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health
Andreas Moosmann: Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health
Stephan M. Feller: Martin-Luther-University Halle-Wittenberg
Arie Geerlof: Institute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental Health
Brigitte Biesinger: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Grzegorz M. Popowicz: Institute of Structural Biology, Helmholtz Center Munich - German Research Center for Environmental Health
Johannes Kirchmair: Universität Hamburg, Department of Informatics, Center for Bioinformatics (ZBH)
Arnd Kieser: Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental Health

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44455-w

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