Regulation of HSV Gene Expression by HCF

本项目研究宿主细胞因子-1(hcf-1)在调节单纯疱疹病毒(HSV)寿命中的作用。 周而复始。HSV是一种重要的人类病原体，导致包括疼痛皮损在内的一系列疾病， 角膜疤痕和危及生命的脑炎。上皮细胞的产生性或裂解性感染是由 病毒转录因子VP16，从病毒粒子释放到细胞质中。在那里，VP16结合了HCF- 1，移位到细胞核，共同激活HSV即刻早期(IE)基因。HSV也 在感觉神经元上定植，在那里它可以建立潜伏期，重新出现为周期性的局部性溶解发作 复制。尽管进行了广泛的分析，但阻止潜伏的裂解复制的分子障碍 神经元仍然难以捉摸。IE基因表达不足可能是一个重要的致病因素。HCF-1 存在于大多数细胞的细胞核中，作为细胞增殖和生长所必需的转录辅助因子 胞质分裂。然而，在神经元中，HCF-1是胞浆的，但由于DMA-1的作用，它会移动到细胞核。 损害剂、毒素或机械压力。同样的刺激诱导潜伏的单纯疱疹病毒重新进入裂解 复制，暗示HCF-1定位和HSV裂解复制之间存在因果关系。这 提案研究了控制HCF-1在不同地区的定位和功能的机制 原子核。我们专注于HPIP和Brd7，这两种细胞蛋白与HCF-1的保守结构域结合。HPIP 是一种穿梭因子，将HCF-1从细胞核输出到胞浆。我们的研究表明，HPIP在 胞质和线粒体都有，在Aim 1WE中，信号将允许HPIP在这两个之间进行划分 并更准确地定义了线粒体内的定位。Brd7是一款 染色质结合的溴结构域蛋白和异位表达引起核仁的重大变化 结构，导致应力传感器p53的稳定和HCF-1在新的核仁中的掺入 结构。当细胞发生DMAdble链断裂时，也会发生类似的变化，我们假设 HCF-1和Brd7是应答基因组侮辱的关键分子。目标2研究分子 Brd7和HCF-1启动核仁破裂的机制和目标3解决生理学 与细胞周期、rRNA转录和HSV裂解复制有关的后果。

This project addresses the role of host cell factor-1 (HCF-1) in regulating the herpes simplex virus (HSV) life cycle. HSV is an important human pathogen responsible for a spectrum of diseases including painful lesions, corneal scarring and life-threatening encephalitis. Productive or lytic infection in epithelial cells is initiated by the viral transcription factor VP16, which is released from the virion into the cytosol. There VP16 binds HCF- 1, translocates to the nucleus and together activates the HSV immediate-early (IE) genes. HSV also colonizes sensory neurons where it can establish latency, re-emerging as periodicepisodes of localized lytic replication. In spite of extensive analyses, the molecular roadblocks preventing lytic replication in latent neurons remain elusive. Insufficient IE gene expression is likely to be an important contributing factor. HCF-1 is found in the nucleus of most cells, acting as an essential transcriptional cofactor for cell proliferation and cytokinesis. In neurons, however, HCF-1 is cytoplasmic but moves to the nucleus in response to DMA- damaging agents, toxins or mechanical stress. The same stimuli induce latent HSV to re-enter lytic replication, implying a causal relationship between HCF-1 localization and HSV lytic replication. This proposal investigates mechanisms that control localization and function of HCF-1 in different regions of the nucleus. We focus on HPIP and Brd7, two cellular proteins that bind to conserved domains of HCF-1. HPIP is a shuttle factor that exports HCF-1 from the nucleus to the cytosol. Our studies show that HPIP is found in both cytosol and mitochondrial and in Aim 1we will the signals that allow HPIP to partition between these cytoplasmic compartments and more precisely define the localization within mitochondria. Brd7 is a chromatin-binding bromodomain protein and ectopic expression causes major changes in nucleolar structure, leading to stabilization of the stress-sensor p53 and incorporation of HCF-1 in novel nucleolar structures. Similar alterations occur when cells sustain DMAdouble-strand breaks and we hypothesize that HCF-1 and Brd7 are key players in the response to genomic insults. Aim 2 investigates the molecular mechanisms by which Brd7 and HCF-1 initiate nucleolar breakdown and Aim 3 addresses the physiological consequences with regard to cell cycle, rRNA transcription and HSV lytic replication.