腺病毒E4ORF1诱导的MYC激活促进宿主细胞合成代谢性葡萄糖代谢和病毒复制。
Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication.
作者信息
Thai Minh, Graham Nicholas A, Braas Daniel, Nehil Michael, Komisopoulou Evangelia, Kurdistani Siavash K, McCormick Frank, Graeber Thomas G, Christofk Heather R
机构信息
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cell Metab. 2014 Apr 1;19(4):694-701. doi: 10.1016/j.cmet.2014.03.009.
Virus infections trigger metabolic changes in host cells that support the bioenergetic and biosynthetic demands of viral replication. Although recent studies have characterized virus-induced changes in host cell metabolism (Munger et al., 2008; Terry et al., 2012), the molecular mechanisms by which viruses reprogram cellular metabolism have remained elusive. Here, we show that the gene product of adenovirus E4ORF1 is necessary for adenovirus-induced upregulation of host cell glucose metabolism and sufficient to promote enhanced glycolysis in cultured epithelial cells by activation of MYC. E4ORF1 localizes to the nucleus, binds to MYC, and enhances MYC binding to glycolytic target genes, resulting in elevated expression of specific glycolytic enzymes. E4ORF1 activation of MYC promotes increased nucleotide biosynthesis from glucose intermediates and enables optimal adenovirus replication in primary lung epithelial cells. Our findings show how a viral protein exploits host cell machinery to reprogram cellular metabolism and promote optimal progeny virion generation.
病毒感染会引发宿主细胞的代谢变化，以满足病毒复制对生物能量和生物合成的需求。尽管最近的研究已对病毒诱导的宿主细胞代谢变化进行了表征（芒格等人，2008年；特里等人，2012年），但病毒重新编程细胞代谢的分子机制仍不清楚。在此，我们表明腺病毒E4ORF1的基因产物对于腺病毒诱导的宿主细胞葡萄糖代谢上调是必需的，并且足以通过激活MYC来促进培养的上皮细胞中糖酵解的增强。E4ORF1定位于细胞核，与MYC结合，并增强MYC与糖酵解靶基因的结合，导致特定糖酵解酶的表达升高。E4ORF1对MYC的激活促进了从葡萄糖中间体增加核苷酸生物合成，并使腺病毒在原代肺上皮细胞中实现最佳复制。我们的研究结果表明病毒蛋白如何利用宿主细胞机制重新编程细胞代谢并促进最佳子代病毒体的产生。
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