PDF(Pubmed)
Abstract：
Herpes simplex virus 1 (HSV-1) is a neurotropic virus that remains latent in neuronal cell bodies but reactivates throughout an individual\'s life, causing severe adverse reactions, such as herpes simplex encephalitis (HSE). Recently, it has also been implicated in the etiology of Alzheimer\'s disease (AD). The absence of an effective vaccine and the emergence of numerous drug-resistant variants have called for the development of new antiviral agents that can tackle HSV-1 infection. Host-targeting antivirals (HTAs) have recently emerged as promising antiviral compounds that act on host-cell factors essential for viral replication. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, exhibits a marked inhibitory activity against HSV-1. Furthermore, we show that HSV-1 infection leads to enhanced protein citrullination through transcriptional activation of three PAD isoforms: PAD2, PAD3, and PAD4. Interestingly, PAD3-depletion by specific drugs or siRNAs dramatically inhibits HSV-1 replication. Finally, an analysis of the citrullinome reveals significant changes in the deimination levels of both cellular and viral proteins, with the interferon (IFN)-inducible proteins IFIT1 and IFIT2 being among the most heavily deiminated ones. As genetic depletion of IFIT1 and IFIT2 strongly enhances HSV-1 growth, we propose that viral-induced citrullination of IFIT1 and 2 is a highly efficient HSV-1 evasion mechanism from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection and demonstrate that PAD inhibitors efficiently suppress HSV-1 infection in vitro, which may provide the rationale for their repurposing as HSV-1 antiviral drugs.
摘要：
单纯疱疹病毒1（HSV-1）是一种神经亲病毒，在神经元细胞体中仍然潜伏，但在个体的整个生命中重新激活，导致严重的不良反应，如单纯疱疹性脑炎（HSE）。最近,它也与阿尔茨海默病（AD）的病因有关。缺乏有效的疫苗和许多耐药变体的出现要求开发新的抗病毒药物来应对HSV-1感染。宿主靶向抗病毒药物（HTAs）最近已成为有希望的抗病毒化合物，可作用于病毒复制所必需的宿主细胞因子。在这里，我们展示了一类新的针对肽基精氨酸脱亚胺酶（PAD）的HTA，一个催化蛋白质瓜氨酸化的钙依赖性酶家族，对HSV-1表现出显著的抑制活性。此外，我们显示HSV-1感染通过转录激活三种PAD亚型:PAD2,PAD3和PAD4导致蛋白瓜氨酸化增强.有趣的是,通过特定药物或siRNA消除PAD3显著抑制HSV-1复制。最后,对瓜氨酸的分析揭示了细胞和病毒蛋白脱亚胺水平的显著变化，干扰素（IFN）诱导蛋白IFIT1和IFIT2是脱亚胺作用最严重的蛋白之一。由于IFIT1和IFIT2的遗传耗竭强烈增强了HSV-1的生长，我们认为病毒诱导的IFIT1和2瓜氨酸化是一种高效的HSV-1逃避宿主抗病毒抗性的机制。总的来说,我们的发现指出瓜氨酸化在颠覆细胞对病毒感染的反应中的关键作用，并证明PAD抑制剂在体外有效抑制HSV-1感染，这可能为它们重新用作HSV-1抗病毒药物提供了理由。
