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MicroRNA-155 Reinforces HIV Latency.

ABSTRACT: The presence of a small number of infected but transcriptionally dormant cells currently thwarts a cure for the more than 35 million individuals infected with HIV. Reactivation of these latently infected cells may result in three fates: 1) cell death due to a viral cytopathic effect, 2) cell death due to immune clearance, or 3) a retreat into latency. Uncovering the dynamics of HIV gene expression and silencing in the latent reservoir will be crucial for developing an HIV-1 cure. Here we identify and characterize an intracellular circuit involving TRIM32, an HIV activator, and miR-155, a microRNA that may promote a return to latency in these transiently activated reservoir cells. Notably, we demonstrate that TRIM32, an E3 ubiquitin ligase, promotes reactivation from latency by directly modifying I?B?, leading to a novel mechanism of NF-?B induction not involving I?B kinase activation.

SUBMITTER: Ruelas DS

PROVIDER: S-EPMC4447952 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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MicroRNA-155 Reinforces HIV Latency.

Ruelas Debbie S DS Chan Jonathan K JK Oh Eugene E Heidersbach Amy J AJ Hebbeler Andrew M AM Chavez Leonard L Verdin Eric E Rape Michael M Greene Warner C WC

The Journal of biological chemistry 20150414 22

The presence of a small number of infected but transcriptionally dormant cells currently thwarts a cure for the more than 35 million individuals infected with HIV. Reactivation of these latently infected cells may result in three fates: 1) cell death due to a viral cytopathic effect, 2) cell death due to immune clearance, or 3) a retreat into latency. Uncovering the dynamics of HIV gene expression and silencing in the latent reservoir will be crucial for developing an HIV-1 cure. Here we identif ...[more]

PMID: 25873391

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Project description:Skeletal myogenesis is a regulated process in which mononucleated cells, the myoblasts, undergo proliferation and differentiation. Upon differentiation, the cells align with each other, and subsequently fuse to form terminally differentiated multinucleated myotubes. Previous reports have identified the protein osteoglycin (Ogn) as an important component of the skeletal muscle secretome, which is expressed differentially during muscle development. However, the posttranscriptional regulation of Ogn by microRNAs during myogenesis is unknown. Bioinformatic analysis showed that miR-155 potentially targeted the Ogn transcript at the 3´-untranslated region (3´ UTR). In this study, we tested the hypothesis that miR-155 inhibits the expression of the Ogn to regulate skeletal myogenesis. C2C12 myoblast cells were cultured and miR-155 overexpression or Ogn knockdown was induced by transfection with miR-155 mimic, siRNA-Ogn, and negative controls with lipofectamine for 15 hours. Near confluence (80-90%), myoblasts were induced to differentiate myotubes in a differentiation medium. Luciferase assay was used to confirm the interaction between miR-155 and Ogn 3'UTR. RT-qPCR and Western blot analyses were used to confirm that the differential expression of miR-155 correlates with the differential expression of myogenic molecular markers (Myh2, MyoD, and MyoG) and inhibits Ogn protein and gene expression in myoblasts and myotubes. Myoblast migration and proliferation were assessed using Wound Healing and MTT assays. Our results show that miR-155 interacts with the 3'UTR Ogn region and decrease the levels of Ogn in myotubes. The overexpression of miR-155 increased MyoG expression, decreased myoblasts wound closure rate, and decreased Myh2 expression in myotubes. Moreover, Ogn knockdown reduced the expression levels of MyoD, MyoG, and Myh2 in myotubes. These results reveal a novel pathway in which miR-155 inhibits Ogn expression to regulate proliferation and differentiation of C2C12 myoblast cells.

Project description:Aims:Circulating microRNAs (miRNAs) have been identified as biomarkers for several diseases. Dysregulation of miRNA-126, microRNA-145, and microRNA-155 has been shown to be associated with atherosclerotic lesion formation. The aim of this study was to evaluate the association between atherosclerosis-related miRNAs and unfavorable atherosclerotic plaque characteristics. Methods and Results:Forty patients with stable coronary artery disease admitted for elective percutaneous coronary intervention (PCI) were enrolled in a prospective study. After PCI, intravascular ultrasound (IVUS), and iMAP-IVUS analysis were performed to assess the proportion of fibrotic, necrotic, lipidic, and calcific tissue within atherosclerotic plaques. Total RNA was isolated from plasma to evaluate the expression of circulating miRNA-126, miRNA-145, and miRNA-155. Plasma lipid and glucose metabolism-related variables were measured to determine any association with plaque characteristics or miRNA expression. Expression of miRNA-126 was negatively correlated with plaque fibrotic tissue (r=-0.28; P=0.044), while positively correlated with plaque necrotic tissue (r=0.31; P=0.029) and necrolipidic tissue (r=0.31; P=0.031). MiRNA-145 was positively correlated with plaque lipidic (r=0.32; P=0.023) and necrolipidic tissue (r=0.31; P=0.029). Patient age was associated with plaque fibrotic tissue (r=-0.41; P=0.005), necrotic tissue (r=0.33; P=0.022), and lipid content (r=0.33; P=0.022). High-density lipoprotein cholesterol was positively correlated with plaque necrotic (r=0.28; P=0.042) and calcific (r=0.28; P=0.044) tissue volume. Calcific tissue volume was positively correlated with C-peptide (r=0.34; P=0.033). After multivariate logistic regression analysis, both miRNA-126 and miRNA-145 expressions were associated with increased necrolipidic tissue content (?=0.34; P=0.050; and ?=0.35; P=0.037, respectively). Conclusions:Expressions of miRNA-126 and miRNA-145 were associated with increased plaque necrolipidic tissue content. Relevance for Patients:Although further research is needed to support the study data, miRNA-126 and miRNA-145 may serve as potential plaque vulnerability biomarkers in the future.

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MicroRNA-155 Reinforces HIV Latency.

Publications

MicroRNA-155 Reinforces HIV Latency.

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