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

Kamonwan Fish, Federico Comoglio, Arthur L. Shaffer, Yanlong Ji, Kuan Ting Pan, Sebastian Scheich, Angelika Oellerich, Carmen Doebele, Masato Ikeda, Samantha J. Schaller, Hang Nguyen, Jagan Muppidi, George W. Wright, Henning Urlaub, Hubert Serve, Louis M. Staudt, Richard Longnecker, Thomas Oellerich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 PLCλ2, 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 LMP2Aexpressing 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 MYCinduced 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 EBVinfected B cells that optimizes cell survival and proliferation, setting the stage for oncogenic transformation.

Original languageEnglish (US)
Pages (from-to)26318-26327
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number42
DOIs
StatePublished - Oct 20 2020

Keywords

  • B cell receptor
  • Epstein-Barr virus
  • Lymphoma
  • Signal transduction

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Rewiring of B cell receptor signaling by Epstein-Barr virus LMP2A'. Together they form a unique fingerprint.

Cite this