Exploring serine arginine rich splicing factors and serine arginine protein kinase on rhinovirus infection in airway epithelial cell function

探索富含丝氨酸精氨酸剪接因子和丝氨酸精氨酸蛋白激酶对鼻病毒感染气道上皮细胞的功能

• 批准号: 1954253
• 金额: --
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1954253
• 关键词: Exploring; serine; arginine; rich; splicing

Studentship strategic priority area:Basic Bioscience Underpinning HeathKeywords:Rhinovirus C, splicing factors, paediatric chronic asthma How respiratory epithelial gene expression is altered in order to optimize viral production for the picornavirus, rhinovirus C is still uncertain. Studies have suggested that viruses can do this by the dysregulation of post-transcriptional RNA processing and export, mRNA stability and mRNA translation on the ribosome. We have recently completed a transcriptomics analysis of nasal epithelial cells obtained from children with pre-asthma infected with rhinovirus A and C. Rhinovirus A and C have different cellular entry mechanisms and unsurprisingly we have found several differences in the gene expression pattern of know host proteins that could explain the differences in the severity of response to these viruses. In addition to the known pathways involved in immune response and host defence we have uncovered potential molecular mechanisms for how these viruses may usurp the epithelial cell's machinery. Namely by altering:. serine/arginine protein kinase 1 (SRPK1) - a regulator of both constitutive and alternative host RNA splicing by regulating intracellular localization of splicing factors and. serine/arginine-rich splicing factors (e.g. SRSF6) - these proteins and their phosphorylation by specific protein kinases, particularly SRPK1, constitute control circuits to regulate both constitutive and alternative pre-mRNA splicing and coordinate splicing with transcription in cells. These proteins can also control mRNA export, stability andtranslation.Surprisingly we have observed a good correlation between expression levels of SRPK1 and some SRSFs including SRSF2, SRSF6, SRSF9 and SRSF11. It is also intriguing that SRPK1 has been reported to phosphorylate some SRSFs including SRSF2 and SRSF6. Although, SRSF protein phosphorylation by SRPK1 directly regulates alternative splicing little is known about the function of SRSF6. Finally SRPK1 inhibitors have antiviral activities against Hepatitis C virus, HIV and Sindbis virus and cytomegalovirus. The significance of these in vivo transcriptomic changes caused by rhinoviral infection of human nasal epithelial cells on SRSFs phosphorylation/activity (host cell RNA splicing) and its consequent on epithelial cell function and host defence and rhino-viral replication is not known.This project aims:1. To determine whether the SRPK1 - SRSF6 axis controls specific host splicing events.2. To understand whether the regulation of the SRPK1 - SRSF6 axis is important to upper airway epithelial function.3. To understand whether the regulation of the SRPK1 - SRSF6 axis is important to how rhinovirus exerts controls over epithelial gene expression to optimise viral production.

关键字：鼻病毒C，剪接因子，儿科慢性哮喘呼吸道上皮基因表达如何改变以优化小核糖核酸病毒的病毒生产，鼻病毒C仍然不确定。研究表明，病毒可以通过转录后RNA加工和输出、mRNA稳定性和核糖体上mRNA翻译的失调来做到这一点。我们最近完成了对哮喘前期感染鼻病毒a和C的儿童鼻上皮细胞的转录组学分析。鼻病毒a和C具有不同的细胞进入机制，我们发现已知宿主蛋白的基因表达模式存在一些差异，这可以解释对这些病毒反应严重程度的差异。除了已知的参与免疫反应和宿主防御的途径外，我们还发现了这些病毒如何篡夺上皮细胞机制的潜在分子机制。即通过改变：丝氨酸/精氨酸蛋白激酶1 (SRPK1) -通过调节剪接因子的细胞内定位来调节组成型和替代型宿主RNA剪接。富含丝氨酸/精氨酸的剪接因子（如SRSF6） -这些蛋白及其被特定蛋白激酶磷酸化，特别是SRPK1，构成控制电路，调节细胞中组成和替代pre-mRNA剪接，并协调剪接与转录。这些蛋白还可以控制mRNA的输出、稳定性和翻译。令人惊讶的是，我们发现SRPK1的表达水平与包括SRSF2、SRSF6、SRSF9和SRSF11在内的一些srsf有很好的相关性。同样有趣的是，据报道SRPK1可以磷酸化一些srsf，包括SRSF2和SRSF6。虽然SRPK1对SRSF蛋白的磷酸化直接调控选择性剪接，但对SRSF6的功能知之甚少。SRPK1抑制剂对丙型肝炎病毒、HIV、Sindbis病毒和巨细胞病毒具有抗病毒活性。鼻病毒感染人鼻上皮细胞引起的这些体内转录组变化对SRSFs磷酸化/活性（宿主细胞RNA剪接）及其对上皮细胞功能、宿主防御和鼻病毒复制的影响尚不清楚。本项目目标：1.；确定SRPK1 - SRSF6轴是否控制特定的宿主剪接事件。了解SRPK1 - SRSF6轴的调控是否对上气道上皮功能有重要作用。了解SRPK1 - SRSF6轴的调控是否对鼻病毒如何控制上皮基因表达以优化病毒生产很重要。