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

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  • Fabian Giehler

    (Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental Health
    Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health
    German Center for Infection Research (DZIF), Partner Site Munich)

  • 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
    German Center for Infection Research (DZIF), Partner Site Munich
    University Hospital, Ludwig-Maximilians-University Munich)

  • 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)
    University of Vienna)

  • Arnd Kieser

    (Research Unit Signaling and Translation, Helmholtz Center Munich - German Research Center for Environmental Health
    Research Unit Gene Vectors, Helmholtz Center Munich - German Research Center for Environmental Health
    German Center for Infection Research (DZIF), Partner Site Munich)

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.

Suggested Citation

  • 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 &, 2024. "Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44455-w
    DOI: 10.1038/s41467-023-44455-w
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    References listed on IDEAS

    as
    1. Young Chul Park & Vicki Burkitt & Anthony R. Villa & Liang Tong & Hao Wu, 1999. "Structural basis for self-association and receptor recognition of human TRAF2," Nature, Nature, vol. 398(6727), pages 533-538, April.
    2. Stefanie Voigt & Kai R. Sterz & Fabian Giehler & Anne-Wiebe Mohr & Joanna B. Wilson & Andreas Moosmann & Arnd Kieser, 2020. "A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Hong Ye & Joseph R. Arron & Betty Lamothe & Maurizio Cirilli & Takashi Kobayashi & Nirupama K. Shevde & Deena Segal & Oki K. Dzivenu & Masha Vologodskaia & Mijung Yim & Khoi Du & Sujay Singh & J. Wesl, 2002. "Distinct molecular mechanism for initiating TRAF6 signalling," Nature, Nature, vol. 418(6896), pages 443-447, July.
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