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

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Item Type:

Preprint

Title:

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

Creators Name:

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

Abstract:

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) drives viral B cell transformation andoncogenesis. LMP1's transforming activity depends on its cytoplasmic C-terminal activation region 2(CTAR2), which induces NF-?B and JNK by engaging TNF receptor-associated factor 6 (TRAF6). Themechanism of TRAF6 interaction with LMP1 and its critical role for LMP1 signaling has remained elusive.Here we demonstrate that TRAF6 interacts directly with a novel viral TRAF6 binding motif within CTAR2.Structural modeling supported by NMR and functional studies provides insight into the moleculararchitecture of the LMP1-TRAF6 complex and reveals substantial differences to CD40-TRAF6 interaction.The direct recruitment of TRAF6 to LMP1 is essential for NF-?B activation and survival of LMP1-driven Bcell lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with proliferationof EBV-transformed B cells. We identify LMP1-TRAF6 as critical virus-host interface and validate thisinteraction as novel therapeutic target against EBV.

Keywords:

Epstein-Barr Virus (EBV), Latent Membrane Protein 1 (LMP1), B Cell Lymphoma, TRAF6, Protein-Protein Interaction, NF-kB, Transformation, in silico Structure, NMR Spectroscopy, Therapeutic Target, Animals, Mice

Source:

Research Square

Publisher:

Research Square

Article Number:

rs.3.rs-1295699/v1

Date:

4 February 2022

Official Publication:

https://doi.org/10.21203/rs.3.rs-1295699/v1

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