Sirtuins are evolutionarily conserved viral restriction factors.
Sirtuins are evolutionarily conserved viral restriction factors.
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DOI：
10.1128/mbio.02249-14
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发表时间：
2014-12-16
期刊：
影响因子：
6.4
通讯作者：
Cristea IM
中科院分区：
文献类型：
--
作者：
Koyuncu E;Budayeva HG;Miteva YV;Ricci DP;Silhavy TJ;Shenk T;Cristea IM
这七种人sirtuins是一个广泛表达和进化保守的NAD+依赖性脱酰基酶/单ADP核糖基转移酶家族，其调节许多细胞和生物体功能，包括代谢、细胞周期和寿命。在这里，我们报告的发现，所有七个sirtuins具有广泛的抗病毒特性。我们证明，小干扰RNA（siRNA）介导的敲除个别sirtuins和药物介导的抑制sirtuin酶活性增加病毒后代的生产在受感染的人细胞。在DNA和RNA病毒中均观察到对病毒生长的这种影响。重要的是，sirtuin激活药物抑制不同病毒的复制，正如我们对人类巨细胞病毒（一种缓慢复制的DNA病毒）和甲型H1N1流感病毒（一种快速繁殖的RNA病毒）所证明的那样。此外，沉默调节蛋白的防御功能在进化上是保守的，因为大肠杆菌中的沉默调节蛋白同源物CobB可以抵抗噬菌体。总之，我们的研究结果建立sirtuins作为免疫防御系统的广谱和进化上保守的组件，提供了一个框架，阐明一套新的宿主细胞防御机制和开发sirtuin调节剂与抗病毒活性。我们生活在病毒的海洋中，其中一些是人类病原体。这些致病性病毒表现出许多差异：DNA或RNA基因组，包膜或裸露的病毒体，核或细胞质复制，多种疾病症状等，大多数抗病毒药物靶向特定的病毒蛋白。因此，它们通常只对一种病毒起作用，并且它们的功效可能会因耐药变体的快速进化而受到影响。需要鉴定具有广谱抗病毒功能的宿主蛋白，其为限制病毒抗性进化的治疗性治疗提供有效靶标。在这里，我们报告说sirtuins为广谱抗病毒治疗的发展提供了这样一个机会，因为我们的研究结果强调了这些酶作为古老的防御因子，可以抵御各种病毒病原体。
The seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD+-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue in Escherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity. We live in a sea of viruses, some of which are human pathogens. These pathogenic viruses exhibit numerous differences: DNA or RNA genomes, enveloped or naked virions, nuclear or cytoplasmic replication, diverse disease symptoms, etc. Most antiviral drugs target specific viral proteins. Consequently, they often work for only one virus, and their efficacy can be compromised by the rapid evolution of resistant variants. There is a need for the identification of host proteins with broad-spectrum antiviral functions, which provide effective targets for therapeutic treatments that limit the evolution of viral resistance. Here, we report that sirtuins present such an opportunity for the development of broad-spectrum antiviral treatments, since our findings highlight these enzymes as ancient defense factors that protect against a variety of viral pathogens.