Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication.
Liver X Receptors Suppress Activity of Cholesterol and Fatty Acid Synthesis Pathways To Oppose Gammaherpesvirus Replication.
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DOI：
10.1128/mbio.01115-18
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发表时间：
2018-07-17
期刊：
影响因子：
6.4
通讯作者：
Tarakanova VL
中科院分区：
文献类型：
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作者：
Lange PT;Schorl C;Sahoo D;Tarakanova VL
γ-疱疹病毒是致癌病原体，在约95%的成年人群中持续存在。细胞代谢途径已成为许多病毒感染的重要调节因素，包括γ-疱疹病毒感染，其需要几种脂质合成途径以实现最佳复制。肝X受体（LXRs）是转录因子，是细胞脂肪酸和胆固醇合成途径的关键调节因子。毫不奇怪，LXRs是心血管疾病中有吸引力的治疗靶点。在此我们描述了LXRs在原代巨噬细胞γ-疱疹病毒感染背景下的抗病毒作用。我们表明，感染后I型干扰素增加了LXR的表达。令人惊讶的是，LXR靶基因并没有相应的诱导。相反，LXRs抑制了靶基因的表达，导致脂肪酸和胆固醇合成减少，这两种代谢途径支持γ-疱疹病毒复制。本报告将LXR介导的对胆固醇和脂质合成的限制定义为一种在先天免疫细胞中限制病毒复制的内在代谢机制。
宿主的脂肪酸和胆固醇合成途径在多种生物系统中发挥重要作用。重要的是，这两种代谢途径也被许多病毒利用以促进病毒复制。在本报告中，我们表明原代巨噬细胞中肝X受体对这些途径的抑制创造了一种内在的抗病毒状态，通过限制病毒利用这两种代谢途径来减弱γ-疱疹病毒的复制。
Gammaherpesviruses are oncogenic pathogens that persist in ~95% of the adult population. Cellular metabolic pathways have emerged as important regulators of many viral infections, including infections by gammaherpesviruses that require several lipid synthetic pathways for optimal replication. Liver X receptors (LXRs) are transcription factors that are critical regulators of cellular fatty acid and cholesterol synthesis pathways. Not surprisingly, LXRs are attractive therapeutic targets in cardiovascular disease. Here we describe an antiviral role for LXRs in the context of gammaherpesvirus infection of primary macrophages. We show that type I interferon increased LXR expression following infection. Surprisingly, there was not a corresponding induction of LXR target genes. Rather, LXRs suppressed the expression of target genes, leading to decreased fatty acid and cholesterol synthesis, two metabolic pathways that support gammaherpesvirus replication. This report defines LXR-mediated restriction of cholesterol and lipid synthesis as an intrinsic metabolic mechanism to restrict viral replication in innate immune cells. Fatty acid and cholesterol synthesis pathways of the host play important roles in diverse biological systems. Importantly, these two metabolic pathways are also usurped by a number of viruses to facilitate viral replication. In this report, we show that suppression of these pathways by liver X receptors in primary macrophages creates an intrinsic antiviral state that attenuates gammaherpesvirus replication by limiting viral access to the two metabolic pathways.