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

Giehler F, Ostertag MS, Sommermann T, Weidl D, Sterz KR, Kutz H, Moosmann A, Feller SM, Geerlof A, Biesinger B, Popowicz GM, Kirchmair J, Kieser A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 15

Article Number: 414

Journal Issue: 1

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.

Authors with CRIS profile

Daniel Weidl Institute of Clinical and Molecular Virology Brigitte Biesinger-Zwosta Institute of Clinical and Molecular Virology

Involved external institutions

Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universität Hamburg (UHH) DE Germany (DE) Martin-Luther-Universität Halle-Wittenberg (MLU) DE Germany (DE)

How to cite

APA:

Giehler, F., Ostertag, M.S., Sommermann, T., Weidl, D., Sterz, K.R., Kutz, H.,... Kieser, A. (2024). Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex. Nature Communications, 15(1). https://dx.doi.org/10.1038/s41467-023-44455-w

MLA:

Giehler, Fabian, et al. "Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex." Nature Communications 15.1 (2024).

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