Yogev Ohad, Lagos Dimitris, Enver Tariq, Boshoff Chris
UCL Cancer Institute, Research Department of Cancer Biology, University College London, London, United Kingdom.
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, United Kingdom.
PLoS Pathog. 2014 Sep 25;10(9):e1004400. doi: 10.1371/journal.ppat.1004400. eCollection 2014 Sep.
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.
细胞代谢改变与包括癌症和病毒感染在内的病理状况有着内在联系。卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体。KS肿瘤细胞表现出淋巴管内皮分化的特征，并且绝大多数细胞潜伏感染KSHV，而少数细胞进行裂解感染，产生病毒粒子。潜伏感染的细胞仅表达一部分病毒基因，主要位于潜伏期相关区域，其中包括12种微小RNA。值得注意的是，KSHV感染细胞的代谢特性与癌细胞的代谢特征极为相似。然而，KSHV如何以及为何改变宿主细胞代谢仍知之甚少。在此，我们研究了KSHV感染对原代表皮微血管淋巴管内皮细胞（LEC）代谢谱的影响以及这种影响的功能相关性。我们发现致癌簇中的KSHV微小RNA协同作用，减少感染细胞中的线粒体生物合成并诱导有氧糖酵解。KSHV微小RNA的表达降低氧气消耗、增加乳酸分泌和葡萄糖摄取、稳定HIF1α并减少线粒体拷贝数。重要的是，这种代谢转变对于潜伏期维持很重要，并提供生长优势。从机制上我们表明，KSHV通过微小RNA介导的EGLN2和HSPA9下调来改变宿主细胞能量代谢。我们的数据表明，KSHV微小RNA通过同时调节两条独立途径诱导代谢转变；通过激活HIF1进行转录重编程以及通过下调线粒体导入机制减少线粒体生物合成。这些发现表明病毒微小RNA参与细胞代谢的调节，并突出了抑制病毒潜伏期的新潜在途径。
