Herpes simplex virus 1 (HSV-1) is a human DNA virus that causes cold sores, keratitis, meningitis, and encephalitis. Ubiquitination is a post-translational protein modification essential for regulation of cellular events, such as proteasomal degradation, signal transduction, and protein trafficking. The process is also involved in events for establishing viral infection and replication. The first step in ubiquitination involves ubiquitin (Ub) binding with Ub-activating enzyme (E1, also termed UBE1) via a thioester linkage. Our results show that HSV-1 infection alters protein ubiquitination pattern in host cells, as evidenced by MS spectra and co-immunoprecipitation assays. HSV-1 induced ubiquitination of UBE1a isoform via an isopeptide bond with Lys604. Moreover, we show that ubiquitination of K604 in UBE1a enhances UBE1a activity; that is, the activity of ubiquitin-transfer to E2 enzyme. Subsequently, we investigated the functional role of UBE1a and ubiquitination of K604 in UBE1a. We found that UBE1-knockdown increased HSV-1 DNA replication and viral production. Furthermore, overexpression of UBE1a, but not a UBE1a K604A mutant, suppressed viral replication. Furthermore, we found that UBE1a and ubiquitination at K604 in UBE1a retarded expression of HSV-1 major capsid protein, ICP5. Our findings show that UBE1a functions as an antiviral factor that becomes activated upon ubiquitination at Lys604.

中文翻译：

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单纯疱疹病毒1感染诱导UBE1a泛素化

单纯疱疹病毒1（HSV-1）是一种人类DNA病毒，可引起唇疱疹，角膜炎，脑膜炎和脑炎。泛素化是翻译后蛋白质修饰，对于调节细胞事件（如蛋白酶体降解，信号转导和蛋白质运输）至关重要。该过程还涉及建立病毒感染和复制的事件。泛素化的第一步涉及泛素（Ub）通过硫酯键与Ub激活酶（E1，也称为UBE1）结合。我们的研究结果表明，HSV-1感染改变了宿主细胞中蛋白质的泛素化模式，如MS光谱和免疫共沉淀分析所证明。HSV-1通过与Lys604的异肽键诱导UBE1a亚型的泛素化。此外，我们表明，UBE1a中K604的泛素化增强了UBE1a的活性；那是，泛素转移至E2酶的活性。随后，我们研究了UBE1a的功能作用和K604在UBE1a中的泛素化。我们发现，UBE1-knockdown增加了HSV-1 DNA复制和病毒产生。此外，UBE1a的过表达，而不是UBE1a K604A突变体的过表达，抑制了病毒复制。此外，我们发现UBE1a和UBE1a中K604处的泛素化抑制了HSV-1主要衣壳蛋白ICP5的表达。我们的发现表明，UBE1a作为抗病毒因子起作用，在Lys604处泛素化后被激活。抑制病毒复制。此外，我们发现UBE1a和UBE1a中K604处的泛素化抑制了HSV-1主要衣壳蛋白ICP5的表达。我们的发现表明，UBE1a作为抗病毒因子起作用，在Lys604处泛素化后被激活。抑制病毒复制。此外，我们发现UBE1a和UBE1a中K604处的泛素化抑制了HSV-1主要衣壳蛋白ICP5的表达。我们的发现表明，UBE1a作为抗病毒因子起作用，在Lys604处泛素化后被激活。