Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal
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RESEARCH
Open Access
Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal Niklas Engels1*, Gökhan Yigit1, Christoph H Emmerich1, Dirk Czesnik2, Detlev Schild2 and Jürgen Wienands1*
Abstract Background: The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is expressed during different latency stages of EBV-infected B cells in which it triggers activation of cytoplasmic protein tyrosine kinases. Early studies revealed that an immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic N-terminus of LMP2A can trigger a transient increase of the cytosolic Ca2+ concentration similar to that observed in antigenactivated B cells when expressed as a chimeric transmembrane receptor. Even so, LMP2A was subsequently ascribed an inhibitory rather than an activating function because its expression seemed to partially inhibit B cell antigen receptor (BCR) signaling in EBV-transformed B cell lines. However, the analysis of LMP2A signaling has been hampered by the lack of cellular model systems in which LMP2A can be studied without the influence of other EBV-encoded factors. Results: We have reanalyzed LMP2A signaling using B cells in which LMP2A is expressed in an inducible manner in the absence of any other EBV signaling protein. This allowed us for the first time to monitor LMP2A signaling in statu nascendi as it occurs during the EBV life cycle in vivo. We show that mere expression of LMP2A not only stimulated protein tyrosine kinases but also induced phospholipase C-g2-mediated Ca2+ oscillations followed by activation of the extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase pathway and induction of the lytic EBV gene bzlf1. Furthermore, expression of the constitutively phosphorylated LMP2A ITAM modulated rather than inhibited BCR-induced Ca2+ mobilization. Conclusion: Our data establish that LMP2A expression has a function beyond the putative inhibition of the BCR by generating a ligand-independent cellular activation signal that may provide a molecular switch for different EBV life cycle stages and most probably contributes to EBV-associated lymphoproliferative disorders. Keywords: B Cells, Epstein-Barr virus, LMP2A, B cell antigen receptor, ITAM, tyrosine phosphorylation, Ca2+, latency, lytic replication
Background A common feature of herpes viruses is their ability to maintain latent infections during which no virus particles are produced. The oncogenic Epstein-Barr virus (EBV) establishes such a latent infection in human B cells [1]. At least four different types of EBV latency have been described based on the expression patterns of EBV genes including those encoding latent membrane * Correspondence: [email protected]; [email protected] 1 Institute of Cellular and Molecular Immunology, Georg-August-University Göttingen, Humboldtallee 34, Göttingen 37073, Germany Full list of author information is available at the end of the article
protein (LMP) 1 and 2A [2]. The lipid raft-resident LMP2A contains 12 tran
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