1. Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation
- Author
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Chen, Yan, Fachko, Devin, Ivanov, Nikita S, Skinner, Camille M, and Skalsky, Rebecca L
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Rare Diseases ,Hematology ,Biotechnology ,Genetics ,Infectious Diseases ,Cancer ,Aetiology ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Infection ,B-Lymphocytes ,Cell Line ,Epstein-Barr Virus Infections ,GRB2 Adaptor Protein ,Gene Expression Regulation ,Viral ,HEK293 Cells ,Herpesvirus 4 ,Human ,Humans ,MicroRNAs ,NF-kappa B ,Receptors ,Antigen ,B-Cell ,Signal Transduction ,Viral Proteins ,Virus Latency ,Microbiology ,Medical Microbiology ,Virology ,Medical microbiology - 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.
- Published
- 2019