Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase
Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase
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5′-AMP 激活蛋白激酶对卡波西肉瘤相关疱疹病毒感染和复制的抑制
DOI：
10.1128/jvi.00624-16
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发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Gao, Shou-Jiang
中科院分区：
文献类型：
--
作者：
Cheng, Fan;He, Meilan;Gao, Shou-Jiang
宿主细胞内抗病毒限制因子抑制病毒感染和复制。5 '-AMP-活化蛋白激酶（AMPK）是调节代谢稳态的细胞能量传感器。活化的AMPK抑制许多RNA病毒的复制，但增强牛痘病毒的进入。然而，AMPK在疱疹病毒感染中的作用尚不清楚。在这项研究中，我们发现，组成型AMPK活性限制卡波西肉瘤相关疱疹病毒（KSHV）裂解复制原代人脐静脉内皮细胞，而KSHV感染并没有显着影响内源性AMPK活性。AMPK α 1的敲低显著增强了病毒裂解基因的表达和感染性病毒体的产生，而组成型活性AMPK的过表达具有相反的效果。因此，AMPK抑制剂化合物C增强病毒裂解基因表达和病毒体产生，但AMPK激动剂5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）抑制两者。此外，一种常见的糖尿病药物，二甲双胍，其携带AMPK激动剂活性，大大抑制病毒裂解基因的表达和感染性病毒体的产生，这表明二甲双胍作为KSHV感染和复制的治疗剂的用途。总之，这些结果确定宿主AMPK作为KSHV限制因子，可以作为一个潜在的治疗靶点。重要的是宿主细胞编码特定的蛋白质，以限制病毒的感染和复制。卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）是一种与多种癌症相关的人类肿瘤病毒。在本研究中，我们已经确定了5 '-AMP-活化蛋白激酶（AMPK），细胞的能量传感器，作为一个限制因素的KSHV裂解复制在初次感染。AMPK的激活通过调节病毒基因的表达抑制KSHV裂解性复制，而AMPK的抑制则增强KSHV裂解性复制。AICAR和二甲双胍都是目前临床上用于治疗与代谢紊乱相关的病症的AMPK激动剂，它们抑制KSHV裂解性复制。因此，我们的工作已经确定AMPK作为潜在的治疗靶点，AICAR和二甲双胍作为KSHV相关癌症的潜在治疗药物。
The host intracellular antiviral restriction factors inhibit viral infection and replication. The 5'=-AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. Activated AMPK inhibits the replication of numerous RNA viruses but enhances the entry of vaccinia virus. However, the role of AMPK in herpesvirus infection is unclear. In this study, we showed that the constitutive AMPK activity restricted Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in primary human umbilical vein endothelial cells while KSHV infection did not markedly affect the endogenous AMPK activity. Knockdown of the AMPK alpha 1 considerably enhanced the expression of viral lytic genes and the production of infectious virions, while overexpression of a constitutively active AMPK had the opposite effects. Accordingly, an AMPK inhibitor, compound C, augmented viral lytic gene expressions and virion productions but an AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), suppressed both. Furthermore, a common diabetes drug, metformin, which carries an AMPK-agonistic activity, drastically inhibited the expression of viral lytic genes and the production of infectious virions, suggesting the use of metformin as a therapeutic agent for KSHV infection and replication. Together, these results identify the host AMPK as a KSHV restriction factor that can serve as a potential therapeutic target.IMPORTANCEHost cells encode specific proteins to restrict viral infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. In this study, we have identified 5'=-AMP-activated protein kinase (AMPK), a cellular energy sensor, as a restriction factor of KSHV lytic replication during primary infection. Activation of AMPK suppresses, while inhibition of AMPK enhances, KSHV lytic replication by regulating the expression of viral genes. AICAR and metformin, both of which are AMPK agonists currently used in clinics for the treatment of conditions associated with metabolic disorders, inhibit KSHV lytic replication. Thus, our work has identified AMPK as a potential therapeutic target and AICAR and metformin as potential therapeutic agents for KSHV-associated cancers.