Epstein-Barr Virus Latent Membrane Protein 1 Induces Cellular MicroRNA miR-146a, a Modulator of Lymphocyte Signaling Pathways

Tulane University Health Sciences Center, 1430 Tulane Ave., SL79, New Orleans, LA 70112, USA.
Journal of Virology (Impact Factor: 4.44). 03/2008; 82(4):1946-58. DOI: 10.1128/JVI.02136-07
Source: PubMed


The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a functional homologue of the tumor necrosis factor receptor family and contributes substantially to the oncogenic potential of EBV through activation of nuclear factor kappaB (NF-kappaB). MicroRNAs (miRNAs) are a class of small RNA molecules that are involved in the regulation of cellular processes such as growth, development, and apoptosis and have recently been linked to cancer phenotypes. Through miRNA microarray analysis, we demonstrate that LMP1 dysregulates the expression of several cellular miRNAs, including the most highly regulated of these, miR-146a. Quantitative reverse transcription-PCR analysis confirmed induced expression of miR-146a by LMP1. Analysis of miR-146a expression in EBV latency type III and type I cell lines revealed substantial expression of miR-146a in type III (which express LMP1) but not in type I cell lines. Reporter studies demonstrated that LMP1 induces miR-146a predominantly through two NF-kappaB binding sites in the miR-146a promoter and identified a role for an Oct-1 site in conferring basal and induced expression. Array analysis of cellular mRNAs expressed in Akata cells transduced with an miR-146a-expressing retrovirus identified genes that are directly or indirectly regulated by miR-146a, including a group of interferon-responsive genes that are inhibited by miR-146a. Since miR-146a is known to be induced by agents that activate the interferon response pathway (including LMP1), these results suggest that miR-146a functions in a negative feedback loop to modulate the intensity and/or duration of the interferon response.

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    • "The roles of microRNAs in the modulation of immune responses have been reported in various viral infections [23], [39], [40]. miR-146a have been reported to play important roles in the regulation of pro-inflammatory responses [36]. "
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    • "To add to this intriguing interplay between cellular miRNAs and viral pathogens, Huang and colleagues has demonstrated that HIV, an enveloped RNA virus of the Retreoviridae family utilise host cellular miR-28, miR-125b, miR-150, miR-223 and miR-382 to control viral protein synthesis in order to evade host immune system [47]. Epstein-Barr virus (EBV), a DNA virus of the Herpes family, for example induce the expression of miR-29b, miR-155 and miR-146a to mediate the down regulation of innate immune response and IFN signalling pathways to enhances its survival [46], [60], [61]. Lecellier and colleagues have shown that in primate foamy virus type 1 (PFV-1), overexpression of cellular miRNA miR-32 could induce an antiviral response to inhibit virus replication [37]. "
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    • "However, miR-146a expression can be highly induced in hematopoietic cells by a wide range of infectious and inflammatory stimuli, including Toll-like receptor (TLR) ligands, pro-inflammatory cytokines, T-cell receptor ligands, as well as numerous pathogens, implicating a role of miR-146a (Figure 1) in immune cell activation and stress-mediated hematopoiesis (So et al., 2013). The basal and inducible expression pattern of miR-146a is regulated by a combination of lineage-specific transcription factors, including PU.1 and c-ETS (Cameron et al., 2008; Curtale et al., 2010; Ghani et al., 2011), and activation-dependent transcription factors, most notably NF-κB and AP1 (Taganov et al., 2006; Ho et al., 2014). In non-hematopoietic cells, miR-146a can be upregulated by the transcription factor Snail in colorectal cancer stem cells (Hwang et al., 2014), and miR-146b is directly induced by transcription factor STAT3 in breast epithelial cancer cells (Xiang et al., 2014). "
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