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      Kaposi's Sarcoma Herpesvirus MicroRNAs Induce Metabolic Transformation of Infected Cells

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Altered cell metabolism is inherently connected with pathological conditions including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). KS tumour cells display features of lymphatic endothelial differentiation and in their vast majority are latently infected with KSHV, while a small number are lytically infected, producing virions. Latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, the metabolic properties of KSHV-infected cells closely resemble the metabolic hallmarks of cancer cells. However, how and why KSHV alters host cell metabolism remains poorly understood. Here, we investigated the effect of KSHV infection on the metabolic profile of primary dermal microvascular lymphatic endothelial cells (LEC) and the functional relevance of this effect. We found that the KSHV microRNAs within the oncogenic cluster collaborate to decrease mitochondria biogenesis and to induce aerobic glycolysis in infected cells. KSHV microRNAs expression decreases oxygen consumption, increase lactate secretion and glucose uptake, stabilize HIF1α and decreases mitochondria copy number. Importantly this metabolic shift is important for latency maintenance and provides a growth advantage. Mechanistically we show that KSHV alters host cell energy metabolism through microRNA-mediated down regulation of EGLN2 and HSPA9. Our data suggest that the KSHV microRNAs induce a metabolic transformation by concurrent regulation of two independent pathways; transcriptional reprograming via HIF1 activation and reduction of mitochondria biogenesis through down regulation of the mitochondrial import machinery. These findings implicate viral microRNAs in the regulation of the cellular metabolism and highlight new potential avenues to inhibit viral latency.

          Author Summary

          Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of this neoplasm. The discovery of KSHV and its oncogenic enigmas has enlightened many fields of tumor biology and viral oncogenesis. The metabolic properties of KS significantly differ from those of normal cells and resemble cancer cells in general, but the mechanisms employed by KSHV to alter host cell metabolism are poorly understood. Our work demonstrates that KSHV microRNAs can alter cell metabolism through coherent control of independent pathways, a key feature of microRNA-mediated control of cellular functions. This provides a fresh perspective for how microRNA-encoding pathogens shape a cell's metabolism to create an optimal environment for their survival and/or replication. Indeed, we show that, in the case of KSHV, viral microRNA-driven regulation of metabolism is important for viral latency. These findings will evoke new and exciting approaches to prevent KSHV from establishing latency and later on KS.

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          Most cited references 86

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          MicroRNAs: target recognition and regulatory functions.

           David Bartel (2009)
          MicroRNAs (miRNAs) are endogenous approximately 23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.
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            Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

            We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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              Targeting HIF-1 for cancer therapy.

              Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.
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                Author and article information

                Affiliations
                [1 ]UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom
                [2 ]Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom
                Duke University Medical Center, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: OY CB. Performed the experiments: OY. Analyzed the data: OY CB. Contributed reagents/materials/analysis tools: CB TE. Contributed to the writing of the manuscript: OY DL TE CB.

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                September 2014
                25 September 2014
                : 10
                : 9
                PPATHOGENS-D-14-00655
                10.1371/journal.ppat.1004400
                4177984
                25255370

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 15
                Funding
                This work was supported by grants from Cancer Research UK (C7893/A13100 and C7893/A12796) and Leukaemia & Lymphoma Research (10005). OY received an EMBO long-term fellowship (ALTF 1589–2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Biochemistry
                Metabolism
                Energy Metabolism
                RNA
                MicroRNAs
                Microbiology
                Virology
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology

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