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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Available from: Michelle R Lacey
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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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    ABSTRACT: Objectives Chikungunya virus causes chronic infection with manifestations of joint pain. Human synovial fibroblasts get infected with CHIKV and could lead to pro-inflammatory responses. MicroRNAs have potentials to regulate the gene expression of various anti-viral and pro-inflammatory genes. The study aims to investigate the role of miR-146a in modulation of inflammatory responses of human synovial fibroblasts by Chikungunya virus. Methods To study the role of miR-146a in CHIKV pathogenesis in human synovial cells and underlying inflammatory manifestations, we performed CHIKV infection in primary human synovial fibroblasts. Western blotting, real-time PCR, luciferase reporter assay, overexpression and knockdown of cellular miR-146a strategies have been employed to validate the role of miR-146a in regulation of pro-inflammatory NF-κB pathway. Results CHIKV infection induced the expression of cellular miR-146a, which resulted into down-regulation of TRAF6, IRAK1, IRAK2 and increased replication of CHIKV in human synovial fibroblasts. Exogenous expression of miR-146a in human synovial fibroblasts led to decreased expression of TRAF6, IRAK1, IRAK2 and decreased replication of CHIKV. Inhibition of cellular miR-146a by anti-miR-146a restored the expression levels of TRAF6, IRAK1 and IRAK2. Downregulation of TRAF6, IRAK1 and IRAK2 led to downstream decreased NF-κB activation through negative feedback loop. Conclusion This study demonstrated the mechanism of exploitation of cellular miR-146a by CHIKV in modulating the host antiviral immune response in primary human synovial fibroblasts.
    Full-text · Article · Aug 2014 · PLoS ONE
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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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    ABSTRACT: Hand, Foot and Mouth Disease (HFMD) is a self-limiting viral disease that mainly affects infants and children. In contrast with other HFMD causing enteroviruses, Enterovirus71 (EV71) has commonly been associated with severe clinical manifestation leading to death. Currently, due to a lack in understanding of EV71 pathogenesis, there is no antiviral therapeutics for the treatment of HFMD patients. Therefore the need to better understand the mechanism of EV71 pathogenesis is warranted. We have previously reported a human colorectal adenocarcinoma cell line (HT29) based model to study the pathogenesis of EV71. Using this system, we showed that knockdown of DGCR8, an essential cofactor for microRNAs biogenesis resulted in a reduction of EV71 replication. We also demonstrated that there are miRNAs changes during EV71 pathogenesis and EV71 utilise host miRNAs to attenuate antiviral pathways during infection. Together, data from this study provide critical information on the role of miRNAs during EV71 infection.
    Full-text · Article · Jul 2014 · PLoS ONE
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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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    ABSTRACT: Regulation of hematopoiesis is controlled by microRNAs (miRNAs). In this review, we focus on miR-146a, and its role in regulating normal and malignant hematopoiesis. miR-146a is a negative regulator of immune cell activation by repressing two targets, TRAF6 and IRAK1. Genetic deletion of miR-146a confirmed a role of miR-146a during innate immune signaling as well as for hematopoietic stem cell function. miR-146a is also implicated in the pathogenesis of human myelodysplastic syndromes (MDSs) as it is located within a commonly deleted region on chromosome 5, and miR-146a-deficient mice exhibit features of an MDS-like disease. With new insight into miR-146a through genetic and expression analyses, we highlight and discuss the recent advances in the understanding of miR-146a in physiological hematopoiesis during steady-state and inflammation, as well as in MDS.
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