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A novel role of SIRT1 in gammaherpesvirus latency and replication

机译：SIRT1在伽马疱疹病毒潜伏期和复制中的新作用

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摘要

Viruses often hijack cellular functions to facilitate their infection and replication. SIRT1, one of the most widely studied sirtuins, functions as both metabolic sensor and transcriptional regulator. SIRT1 has broad cellular functions including metabolic homeostasis, stress response, tumorigenesis and autophagy. The role of SIRT1 in the life cycle of viruses remains unclear. Like all herpesviruses, oncogenic gammaherpesvirus KSHV has both latent and lytic phases. In a recent study, we have shown that SIRT1 binds to the promoter and silence the expression of KSHV replication and transcription activator (RTA), a key activator of viral lytic replication. Chemical inhibition or knock down of SIRT1 is sufficient to initiate the lytic replication program by increasing active histone H3 trimethyl Lys4 (H3K4me3) mark and decreasing repressive histone H3 trimethyl Lys27 (H3K27me3) mark in the RTA promoter. SIRT1 also interacts with RTA and inhibits RTA transactivation of its own promoter and those of downstream target genes. Our findings reveal that SIRT1 regulates KSHV latency by inhibiting different stages of viral lytic replication, and link a metabolic sensor and transcriptional regulator SIRT1 to KSHV life cycle.
机译：病毒经常劫持细胞功能以促进其感染和复制。 SIRT1是研究最广泛的sirtuins之一，既起着代谢传感器的作用，又起着转录调节剂的作用。 SIRT1具有广泛的细胞功能，包括代谢稳态，应激反应，肿瘤发生和自噬。 SIRT1在病毒生命周期中的作用尚不清楚。像所有疱疹病毒一样，致癌性伽马疱疹病毒KSHV具有潜伏期和裂解期。在最近的研究中，我们表明SIRT1与启动子结合并沉默KSHV复制和转录激活因子（RTA）的表达，后者是病毒裂解复制的关键激活因子。通过抑制RTA启动子中的活性组蛋白H3三甲基Lys4（H3K4me3）标记并降低阻遏性组蛋白H3三甲基Lys27（H3K27me3）标记，化学抑制或抑制SIRT1足以启动裂解复制程序。 SIRT1还与RTA相互作用，并抑制其自身启动子和下游靶基因的RTA反式激活。我们的发现表明，SIRT1通过抑制病毒裂解复制的不同阶段来调节KSHV潜伏期，并将代谢传感器和转录调节剂SIRT1链接到KSHV生命周期。

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