Viperin Regulates Cellular Lipid Metabolism during Human Cytomegalovirus Infection

Human cytomegalovirus (HCMV) has been shown to induce increased lipogenesis in infected cells, and this is believed to be required for proper virion envelopment. We show here that this increase is a consequence of the virus-induced redistribution of the host protein viperin to mitochondria and its capacity to interact with and block the function of the mitochondrial trifunctional protein (TFP), the enzyme that mediates fatty acid-β-oxidation. The resulting decrease in cellular ATP levels activates the enzyme AMP-activated protein kinase (AMPK), which induces expression of the glucose transporter GLUT4, resulting in increased glucose import and translocation to the nucleus of the glucose-regulated transcription factor ChREBP. This induces increased transcription of genes encoding lipogenic enzymes, increased lipid synthesis and lipid droplet accumulation, and generation of the viral envelope. Viperin-dependent lipogenesis is required for optimal production of infectious virus. We show that all of these metabolic outcomes can be replicated by direct targeting of viperin to mitochondria in the absence of HCMV infection, and that the motif responsible for Fe-S cluster binding by viperin is essential. The data indicate that viperin is the major effector underlying the ability of HCMV to regulate cellular lipid metabolism.研究表明，人类巨细胞病毒（Human cytomegalovirus, HCMV）可诱导受染细胞的脂肪生成增强，该过程被认为对病毒体的正常包膜形成至关重要。本研究证实，这种脂肪生成增强是病毒诱导宿主蛋白viperin（viperin）重定位至线粒体，并与其相互作用、阻断线粒体三功能蛋白（mitochondrial trifunctional protein, TFP）功能的结果；而线粒体三功能蛋白正是介导脂肪酸β氧化的关键酶。细胞内ATP水平随之下降会激活腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK），后者可诱导葡萄糖转运蛋白GLUT4（GLUT4）的表达，进而增加葡萄糖摄取，并使葡萄糖调节转录因子ChREBP（ChREBP）转位至细胞核。这一系列事件最终会促进脂肪生成相关酶编码基因的转录上调，增强脂质合成与脂滴积累，最终促成病毒包膜的生成。依赖viperin的脂肪生成过程对感染性病毒的最优产出必不可少。本研究还证实，在未感染HCMV的情况下，仅将viperin靶向定位至线粒体即可复现上述所有代谢表型，且viperin结合铁硫簇（Fe-S cluster）的基序是这一过程所必需的。综上，本研究数据表明，viperin是人类巨细胞病毒调控细胞脂质代谢能力的核心效应分子。