title: Kaposi's sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells.
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.
authors.affiliation: UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom.
authors.forename: Ohad
authors.initials: O
authors.lastname: Yogev
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Lagos
authors.affiliation: UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom.
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
authors.affiliation: UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
mesh_terms: D000332:Aerobiosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D004734:Energy Metabolism; D015967:Gene Expression Regulation, Viral; D005947:Glucose / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014407:Tumor Cells, Cultured; D014771:Virion / Q000378:metabolism; D017735:Virus Latency
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D019344:Lactic Acid; D005947:Glucose