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Kinase Regulation of Nuclear Speckle Function and Splicing during Influenza Virus Infection

流感病毒感染期间核斑点功能和剪接的激酶调节

基本信息

批准号：
10491841
负责人：
MELANIE H. COBB
金额：
$ 56.88万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-25 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491841
关键词：
Alternative Splicing Biochemical Biochemistry Biological Assay Cell Nucleus Cells Chemicals Complement Data Economic Burden Event Gene Expression Genes Genetic Transcription Goals Grant Human Immune response Impairment Infection Influenza Virus Infected Cells Integration Host Factors Label Link Maintenance Mass Spectrum Analysis Mediating Messenger RNA Methods Microscopy Morphology Nuclear Nuclear Proteins Nuclear RNA Phosphorylation Phosphotransferases Positioning Attribute Process Protein Kinase Proteins RNA RNA Processing RNA Splicing RNA-Binding Proteins Regulation Role Shapes Transcript Viral Viral Genes Viral Proteins Virus Virus Diseases Virus Replication Western Blotting Work experience genetic manipulation health economics high resolution imaging influenza infection influenzavirus insight knock-down mRNA Precursor therapeutic target trafficking transcriptome sequencing viral RNA

项目摘要

PROJECT SUMMARY The goals of this proposal are to uncover how pre-mRNA splicing and nuclear speckles are controlled by the kinase TAO2, and to determine why TAO2 is required for successful Influenza virus (IAV) replication. Recent work has identified the understudied protein kinase TAO2 as a host factor essential for splicing and speckle localization of the IAV M RNA. A pool of TAO2 localizes to nuclear speckles and its loss, by chemical inhibition or protein depletion, alters nuclear speckle composition, splicing and export of IAV M RNA, and therefore impairs IAV replication. Inhibition of TAO2 also disrupts splicing of a subset of host mRNAs, without altering bulk host mRNA. These data uncover a new cellular activity for TAO2 and identify inhibition of TAO2 as a potential approach for controlling IAV infection. Preliminary data suggest that TAO2 interacts with several splicing factors and other RNA binding proteins. The work outlined in this proposal seeks a comprehensive understanding of the nuclear activities of TAO2 in human cells and the functional consequence of these activities for host and viral RNA expression. Specifically, a three-pronged approach will be taken to: (1) characterize functional TAO2 interaction partners and substrates of phosphorylation amongst nuclear proteins and determine if IAV infection alters these interactions or if TAO2 interacts directly with any IAV-encoded proteins; (2) define the role of TAO2 in maintaining the integrity of nuclear speckles and (3) characterize the global impact of TAO2 on the human splicing machinery and the consequence of this function for alternative splicing. These goals will be achieved through a combination of genetic manipulation of cells, biochemistry, mass spectrometry and microscopy. Importantly, the conclusions obtained from these studies will have implications for general mechanisms of RNA splicing and nuclear speckle formation and function and will further inform the understanding of host requirements and vulnerabilities for influenza infection.

项目总结