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  Rewiring of B cell receptor signaling by Epstein–Barr virus LMP2A

Fish, K., Comoglio, F., Shaffer, A. L., Jia, Y., Pan, K. T., Scheich, S., et al. (2020). Rewiring of B cell receptor signaling by Epstein–Barr virus LMP2A. Proceedings of the National Academy of Sciences of the USA, 117(42), 26318-26327. doi:10.1073/pnas.2007946117.

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Fish, K., Author
Comoglio, F., Author
Shaffer, A. L., Author
Jia, Y., Author
Pan, K. T.1, Author              
Scheich, S., Author
Oellerich, A., Author
Doebele, C., Author
Ikeda, M., Author
Schaller, S. J., Author
Nguyen, H., Author
Muppidi, J., Author
Wright, G. W., Author
Urlaub, H.2, Author              
Serve, H., Author
Staudtd, L. M., Author
Longnecker, R., Author
Oellerich, T., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              
2Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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 Abstract: Epstein–Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis remains elusive. By comparing LMP2A and BCR signaling in primary human B cells using phosphoproteomics and transcriptome profiling, we identified molecular mechanisms through which LMP2A affects B cell biology. Consistent with the literature, we found that LMP2A mimics a subset of BCR signaling events, including tyrosine phosphorylation of the kinase SYK, the calcium initiation complex consisting of BLNK, BTK, and PLCγ2, and its downstream transcription factor NFAT. However, the majority of LMP2A-induced signaling events markedly differed from those induced by BCR stimulation. These included differential phosphorylation of kinases, phosphatases, adaptor proteins, transcription factors such as nuclear factor κB (NF-κB) and TCF3, as well as widespread changes in the transcriptional output of LMP2A-expressing B cells. LMP2A affected apoptosis and cell-cycle checkpoints by dysregulating the expression of apoptosis regulators such as BCl-xL and the tumor suppressor retinoblastoma-associated protein 1 (RB1). LMP2A cooperated with MYC and mutant cyclin D3, two oncogenic drivers of Burkitt lymphoma, to promote proliferation and survival of primary human B cells by counteracting MYC-induced apoptosis and by inhibiting RB1 function, thereby promoting cell-cycle progression. Our results indicate that LMP2A is not a pure BCR mimic but rather rewires intracellular signaling in EBV-infected B cells that optimizes cell survival and proliferation, setting the stage for oncogenic transformation.

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Language(s): eng - English
 Dates: 2020-10-052020-10-20
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1073/pnas.2007946117
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Title: Proceedings of the National Academy of Sciences of the USA
Source Genre: Journal
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Pages: - Volume / Issue: 117 (42) Sequence Number: - Start / End Page: 26318 - 26327 Identifier: -