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

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Item Type:

Article

Title:

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

Creators Name:

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

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.

Keywords:

B-Cell Lymphoma, Epstein-Barr Virus Infections, Human Herpesvirus 4, NF-kappa B, Neoplastic Cell Transformation, TNF Receptor-Associated Factor 6, Viral Cell Transformation, Animals, Mice

Source:

Nature Communications

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Volume:

Number:

Page Range:

414

Date:

10 January 2024