Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation

Yan Chen, Devin Fachko, Nikita S. Ivanov, Camille M. Skinner, Rebecca Skalsky

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e1007535
JournalPLoS Pathogens
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2019

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MicroRNAs
Human Herpesvirus 4
Signal Transduction
B-Lymphocytes
Viral Genes
NF-kappa B
Computational Biology
Cell Differentiation
Cell Proliferation
RNA
Viruses
Gene Expression
Growth
Infection

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation. / Chen, Yan; Fachko, Devin; Ivanov, Nikita S.; Skinner, Camille M.; Skalsky, Rebecca.

In: PLoS Pathogens, Vol. 15, No. 1, 01.01.2019, p. e1007535.

Research output: Contribution to journalArticle

Chen, Yan ; Fachko, Devin ; Ivanov, Nikita S. ; Skinner, Camille M. ; Skalsky, Rebecca. / Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation. In: PLoS Pathogens. 2019 ; Vol. 15, No. 1. pp. e1007535.
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