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Novel Translational Control Mechanisms in Host Range Restriction of Poxvirus

痘病毒宿主范围限制的新型翻译控制机制

基本信息

批准号：
10463680
负责人：
Junpeng Deng
金额：
$ 42.24万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463680
关键词：
Address Binding Codon Nucleotides Complex Crystallization DNA DNA Binding DNA Binding Domain Dangerousness Data Development Genes Genetic Variation Host Defense Human Genome Immune response Infection Interferons Knock-out Knowledge Mammalian Cell Mediating Modeling Molecular Orthopoxvirus Pathway interactions Pattern recognition receptor Peptide Initiation Factors Phenylalanine Play Poxviridae Process Protein Biosynthesis Proteins Regulation Resistance Ribosomal RNA Ribosomes Rodent Role Signal Transduction Species Specificity Specificity Structure Transfection Transfer RNA Translation Initiation Translations Vaccinia virus Viral Viral Pathogenesis Virus Virus Diseases antagonist antiviral drug development arms race cellular targeting cytosolic receptor ds-DNA emerging pathogen experimental study genome-wide inhibitor insight novel overexpression poxvirus vectors pressure response ribosome profiling tRNA Methyltransferases transcriptome sequencing vector vaccine

项目摘要

All viruses rely on host translational machinery for protein synthesis. As such, translation control constitutes a universal host defense against viruses. A new understanding on how host regulates translation in response to viral infection and how viruses evade this host response will provide fundamental insight into viral pathogenesis and benefit the development of new antiviral strategies. Poxviruses include some dangerous emerging pathogens as well as some promising vaccine vectors. Unlike many other viruses, poxvirus host range is not affected by the entry step but restricted by intracellular processes. Particularly, cellular translational control pathways have a profound impact on poxvirus host range, and poxvirus inhibitors of these pathways could manifest as critical host-range factors. The best-known example is PKR-mediated control of translation initiation and its antagonism by two vaccinia virus (VACV) host-range proteins E3 and K3. Much less is understood about a PKR-independent pathway targeted by two critical VACV host-range proteins, K1 and C7. VACV with deletion in both K1 and C7 fails to replicate in most mammalian cells due to a shut-off of viral and host protein synthesis. Intriguingly, the translational shut-off is independent of PKR and RNaseL and appears not to involve any translation initiation factors. A paralogous pair of interferon-stimulated genes, SAMD9 and SAMD9L (SAMD9&L), were recently identified by us and others as the specific targets of K1 and C7. However, how they regulate protein synthesis and restrict poxvirus host range is unknown and is the focus of this proposal. We have made sustained contributions to the understanding of K1/C7 and their cellular targets for over a decade, including the determination of the structures of K1/C7 and the identification of SAMD9L as a cellular target of K1/C7. In addition, we have obtained compelling preliminary data that led to our novel hypotheses, which will be addressed separately with the following specific aims. Aim 1. To determine how SAMD9 is activated to inhibit protein synthesis. Aim 2. To determine how activated SAMD9 inhibits protein synthesis. Aim 3. To determine the molecular basis underlying the host species-specific SAMD9&L inhibition by OPXV inhibitors.

所有的病毒都依赖宿主的翻译机制来合成蛋白质。因此，翻译