Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries.
Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries.
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DOI：
10.1128/mbio.00029-16
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发表时间：
2016-03-29
期刊：
影响因子：
6.4
通讯作者：
Sinclair JH
中科院分区：
文献类型：
--
作者：
Karniely S;Weekes MP;Antrobus R;Rorbach J;van Haute L;Umrania Y;Smith DL;Stanton RJ;Minczuk M;Lehner PJ;Sinclair JH
人巨细胞病毒(HCMV)感染会对细胞代谢产生深远影响。就像在肿瘤细胞中一样，HCMV感染会增加糖酵解，葡萄糖碳从线粒体的三羧酸循环转移到脂肪酸的生物合成。然而，与许多肿瘤细胞不同的是，在许多肿瘤细胞中，有氧糖酵解伴随着线粒体氧化磷酸化的抑制，而HCMV诱导线粒体的生物发生和呼吸。在这里，我们亲和纯化线粒体，并使用定量质谱仪来确定线粒体蛋白质组在HCMV感染后的变化。我们发现，线粒体转录和翻译系统是在病毒复制周期的早期诱导的。具体地说，参与线粒体核糖体生物发生的蛋白质在HCMV感染后高度上调。用氯霉素抑制线粒体翻译或敲除HCMV诱导的核糖体生物发生因子MRM3可消除HCMV介导的线粒体编码蛋白的增加，并显著抑制生物能量限制条件下病毒的生长。我们的发现证明了HCMV如何操纵线粒体生物发生来支持其复制。人巨细胞病毒(HCMV)是一种β疱疹病毒，在先天性感染和免疫抑制人群中是导致发病率和死亡率的主要原因。人巨细胞病毒感染可显著改变细胞代谢。与肿瘤细胞类似，在感染了HCMV的细胞中，糖酵解增加，葡萄糖碳从三羧酸循环转移到脂肪酸生物合成。然而，与肿瘤细胞不同的是，即使在有氧糖酵解的情况下，HCMV也能诱导线粒体的生物合成。在这里，我们对线粒体进行亲和纯化，并使用定量质谱仪来确定线粒体蛋白质组在HCMV感染后的变化。我们发现线粒体转录和翻译系统是在病毒复制周期的早期诱导的。具体地说，参与线粒体核糖体生物发生的蛋白质在HCMV感染后高度上调。用氯霉素抑制线粒体翻译或敲除HCMV诱导的核糖体生物发生因子MRM3可消除HCMV介导的线粒体编码蛋白的增加，并显著抑制病毒的生长。我们的发现证明了HCMV如何操纵线粒体生物发生来支持其复制。
Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of morbidity and mortality during congenital infection and among immunosuppressed individuals. HCMV infection significantly changes cellular metabolism. Akin to tumor cells, in HCMV-infected cells, glycolysis is increased and glucose carbon is shifted from the tricarboxylic acid cycle to fatty acid biosynthesis. However, unlike in tumor cells, HCMV induces mitochondrial biogenesis even under aerobic glycolysis. Here, we have affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We find that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.