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

学生战略优先领域：基础生物科学支持健康关键词：鼻病毒C，剪接因子，儿科慢性哮喘如何改变呼吸道上皮基因表达，以优化微小核糖核酸病毒的病毒生产，鼻病毒C仍不确定。研究表明，病毒可以通过转录后RNA加工和输出、核糖体上的mRNA稳定性和mRNA翻译的失调来实现这一点。我们最近完成了对感染了鼻病毒A和C的哮喘前期儿童的鼻黏膜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，不出所料，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的不同。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)-通过调节剪接因子和细胞内定位来调节构成和选择性宿主RNA剪接的调节。富含丝氨酸/精氨酸的剪接因子(如SRSF6)--这些蛋白质及其被特定蛋白激酶，特别是SRPK1的磷酸化，构成了控制电路，调节细胞中结构性和选择性的前mRNA剪接，并协调剪接和转录。令人惊讶的是，我们观察到SRPK1的表达水平与SRSF2、SRSF6、SRSF9和SRSF11等SRSFs之间存在很好的相关性。另一个耐人寻味的是，SRPK1被报道能磷酸化一些SRSFs，包括SRSF2和SRSF6。虽然SRSF蛋白被SRPK1磷酸化直接调节选择性剪接，但对SRSF6的功能知之甚少。SRPK1抑制剂对丙型肝炎病毒、HIV、辛德比斯病毒和巨细胞病毒具有抗病毒活性。这些由鼻病毒感染人鼻上皮细胞引起的体内转录变化对SRSFs的磷酸化/活性(宿主细胞RNA剪接)及其对上皮细胞功能和宿主防御和犀牛病毒复制的影响尚不清楚。本项目的目的：1.确定SRPK1-SRSF6轴是否控制特定的宿主剪接事件。了解SRPK1-SRSF6轴的调节是否对上呼吸道上皮细胞功能有重要影响。为了了解SRPK1-SRSF6轴的调节对于鼻病毒如何控制上皮基因表达以优化病毒生产是否重要。

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.