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

• Published in: Nature communications Vol. 15; no. 1; p. 414
• Main Authors: Giehler, Fabian, Ostertag, Michael S., Sommermann, Thomas, Weidl, Daniel, Sterz, Kai R., Kutz, Helmut, Moosmann, Andreas, Feller, Stephan M., Geerlof, Arie, Biesinger, Brigitte, Popowicz, Grzegorz M., Kirchmair, Johannes, Kieser, Arnd
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-01-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 13/95; 42/109; 42/41; 631/326/596/2557; 631/535; 631/67/1858; 631/67/1990/291; 631/80/86; 96; 96/106; 96/63; B-cell lymphoma; CD40 antigen; Cell Transformation, Neoplastic; Cell Transformation, Viral; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Herpesvirus 4, Human; Humanities and Social Sciences; Humans; Latent membrane protein 1; Lymphocytes B; Lymphoma; Lymphoma, B-Cell; Membrane proteins; Molecular modelling; multidisciplinary; NF-kappa B; NF-κB protein; NMR; Nuclear magnetic resonance; Peptides; Proteins; Science; Science (multidisciplinary); Survival; Therapeutic targets; TNF Receptor-Associated Factor 6; TRAF6 protein; Tumor necrosis factor receptors; Tumorigenesis; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44455-w

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.
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.