Latent Membrane Protein 2A, a Viral B Cell Receptor Homologue, Induces CD5+ B-1 Cell Development

Abstract

The latent membrane protein 2A (LMP2A) of EBV plays a key role in regulating viral latency and EBV pathogenesis by functionally mimicking a constitutively active B cell Ag receptor. When expressed as a B cell-specific transgene in mice, LMP2A drives B cell development, resulting in the bypass of normal developmental checkpoints. In this study, we have demonstrated that expression of LMP2A in transgenic mice results in B cell development that exclusively favors B-1 cells. This switch to B-1 cell development occurs at the pre-B-cell stage of normal B cell development in the bone marrow, a B cell stage much earlier than appreciated for B-1 commitment. This finding indicates that all pre-B cells have the capacity to assume a B-1 cell phenotype if they encounter the appropriate signal during normal development. Furthermore, these studies offer insight into EBV latency and pathogenesis in the human host.

Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

“…The enhancement of survival seen in LMP2A-expressing cells results in altered B cell development phenotypes in some transgenic mouse models (24,27,33,34). We chose to use the Tg6 E LMP2A transgenic line used for the experiments in this article because it has normal B cell development that is indistinguishable from wild-type mice (27,33).…”

The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

“…The expression of LMP2A interferes with BCR signaling and function. It has been demonstrated that low LMP2A expression does not inhibit Ig rearrangement, BCR expression or normal B-cell differentiation into follicular and marginal zone B cells, while high LMP2A expression inhibits BCR expression and results in exclusive B-1 differentiation in the bone marrow and peripheral lymphoid organs [49,86,87]. Most of the phosphotyrosine activity in latently infected B-cells is associated with LMP2A patches, and these clustered membrane patches mimic the activated BCR [70,82,88,89].…”

“…Several studies involving microsequence and mutation analysis and structural approaches showed that the HECT-domain containing the Nedd4 ubiquitin protein ligase family, which contains WW domains, participates in WW-PY interaction [54,55]. The ubiquitin protein ligase family includes AIP4/Itchy, WWP2, Nedd4 and KIAA0439/Nedd4-2 [49,56,57]. Microarray analysis has identified a number of LMP2A-mediated transcriptional changes in the genes encoding ubiquitination [58].…”

“…The LMP2A N-terminal proline-rich motifs are conserved among different EBV clinical isolates and EBV-related herpes virus papio [46,47]. These proline-rich regions contain a consensus sequence that is required to interact with SH3 and WW domains, interactions which in turn yield various biological effects [48][49][50][51][52]. The SH3 domain consists of 50 to 70 amino acid sequences often present in eukaryotic signal transduction and cytoskeletal proteins.…”

Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A

“…Likewise, LMP2A is essential for growth transformation of germinal center (GC)-derived BCR − B cells (13). Depending on its B-cell expression level in murine models, constitutive LMP2A expression alters B-cell development or augments the differentiation and activation of antigen-driven B cells (9,10,(14)(15)(16).…”