Glutamine Metabolism Is Essential for Human Cytomegalovirus Infection
Glutamine Metabolism Is Essential for Human Cytomegalovirus Infection
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DOI：
10.1128/jvi.02123-09
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发表时间：
2010-02-15
影响因子：
5.4
通讯作者：
Alwine, James C.
中科院分区：
文献类型：
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作者：
Chambers, Jeremy W.;Maguire, Tobi G.;Alwine, James C.
感染人巨细胞病毒（HCMV）的人成纤维细胞在葡萄糖饥饿期间比未感染的细胞更有活力，这表明使用了替代碳源。我们已经确定，感染细胞需要谷氨酰胺来产生ATP，而未感染的细胞则不需要。这表明在感染过程中，谷氨酰胺被用来填补三羧酸（TCA）循环（过敏）。与此一致的是，感染细胞中谷氨酰胺摄取和氨生成水平增加，谷氨酰胺酶和谷氨酸脱氢酶的活性也增加，谷氨酰胺酶和谷氨酸脱氢酶是将谷氨酰胺转化为α -酮戊二酸以进入TCA循环所需的酶。感染后24小时开始缺乏谷氨酰胺的细胞不能产生感染性病毒粒子。在谷氨酰胺缺乏的细胞中，TCA中间体α -酮戊二酸盐、草酰乙酸盐和丙酮酸盐可以挽救ATP和病毒的产生，这证实了在感染细胞中，一个允许谷氨酰胺过敏使用的程序被诱导。因此，HCMV感染激活了将无重叠底物从葡萄糖转换为谷氨酰胺所需的机制，以适应病毒感染的生物合成和能量需求，并允许葡萄糖被生物合成使用。
Human fibroblasts infected with human cytomegalovirus ( HCMV) were more viable than uninfected cells during glucose starvation, suggesting that an alternate carbon source was used. We have determined that infected cells require glutamine for ATP production, whereas uninfected cells do not. This suggested that during infection, glutamine is used to fill the tricarboxylic acid (TCA) cycle (anaplerosis). In agreement with this, levels of glutamine uptake and ammonia production increased in infected cells, as did the activities of glutaminase and glutamate dehydrogenase, the enzymes needed to convert glutamine to alpha-ketoglutarate to enter the TCA cycle. Infected cells starved for glutamine beginning 24 h postinfection failed to produce infectious virions. Both ATP and viral production could be rescued in glutamine-starved cells by the TCA intermediates alpha-ketoglutarate, oxaloacetate, and pyruvate, confirming that in infected cells, a program allowing glutamine to be used anaplerotically is induced. Thus, HCMV infection activates the mechanisms needed to switch the anaplerotic substrate from glucose to glutamine to accommodate the biosynthetic and energetic needs of the viral infection and to allow glucose to be used biosynthetically.