Abstract
MicroRNAs (miRNAs) are post-transcriptional regulatory RNAs that can modulate cell signaling and play key roles in cell state transitions. Epstein-Barr virus (EBV) expresses >40 viral miRNAs that manipulate both viral and cellular gene expression patterns and contribute to reprogramming of the host environment during infection. Here, we identified a subset of EBV miRNAs that desensitize cells to B cell receptor (BCR) stimuli, and attenuate the downstream activation of NF-kappaB or AP1-dependent transcription. Bioinformatics and pathway analysis of Ago PAR-CLIP datasets identified multiple EBV miRNA targets related to BCR signal transduction, including GRB2, SOS1, MALT1, RAC1, and INPP5D, which we validated in reporter assays. BCR signaling is critical for B cell activation, proliferation, and differentiation, and for EBV, is linked to reactivation. In functional assays, we demonstrate that EBV miR-BHRF1-2-5p contributes to the growth of latently infected B cells through GRB2 regulation. We further determined that activities of EBV miR-BHRF1-2-5p, EBV miR-BART2-5p, and a cellular miRNA, miR-17-5p, directly regulate virus reactivation triggered by BCR engagement. Our findings provide mechanistic insight into some of the key miRNA interactions impacting the proliferation of latently infected B cells and importantly, governing the latent to lytic switch.
Highlights
Epstein Barr virus (EBV) is a human gamma-herpesvirus that infects >90% of adults worldwide
In addition to IL1R1, we recently reported that the EBV BHRF1-2 miRNAs target other IL-1 signaling components such as SOS1, a Ras GDP/GTP exchange factor, and PLCG1, encoding phospholipase C gamma 1 that contributes to receptor-mediated tyrosine kinase signal transduction [11]
As BJAB cells are not infected with EBV, these results further show that desensitization to B cell receptor (BCR) stimuli occurs through viral miRNA actions on the host cell, presumably through the partial inhibition or complete silencing of cellular targets
Summary
Epstein Barr virus (EBV) is a human gamma-herpesvirus that infects >90% of adults worldwide. Following EBV transmission through the oral cavity and subsequent infection of naïve B cells, EBV co-opts multiple aspects of normal B cell activation that induces cell proliferation, initiates differentiation programs, and can drive infected B cells through germinal center (GC) reactions to establish latency in the memory B cell compartment [3,4,5]. Periodic virus reactivation can occur throughout life-long infection of the host and is thought to help maintain the pool of latently infected cells [5,6]. EBV has both latent and lytic replication phases, and key to the success of long-term persistence is the ability to navigate between these phases
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