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

• 批准号: 10267770
• 负责人: Junpeng Deng
• 金额: $ 44.11万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/10267770
• 关键词: Address; Antiviral Agents; Antiviral Therapy; 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; Race; 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; arm; cellular targeting; cytosolic receptor; ds-DNA; emerging pathogen; experimental study; genome-wide; inhibitor/antagonist; insight; novel; overexpression; poxvirus vectors; pressure; response; ribosome profiling; tRNA Methyltransferases; transcriptome sequencing; vector vaccine

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.

所有病毒都依靠宿主翻译机制来蛋白质合成。因此，翻译 控制构成了对病毒的普遍防御。对主持人的新理解 根据病毒感染的响应调节翻译，以及病毒如何逃避这种宿主反应 提供对病毒发病机理的基本洞察力，并有益于新抗病毒的发展 策略。 痘病毒包括一些危险的新兴病原体以及一些有希望的疫苗 向量。与许多其他病毒不同，Poxvirus宿主范围不受进入步骤的影响，而是 受细胞内过程的限制。特别是，细胞翻译控制途径具有 对痘病毒宿主范围和这些途径的痘病毒抑制剂的深远影响可能 表现为关键的宿主范围因素。最著名的例子是PKR介导的控制 翻译起始及其拮抗两种离子病毒（VACV）宿主范围蛋白E3的拮抗作用 和K3。关于由两个关键目标针对的独立于PKR的途径所理解的要少得多 VacV宿主范围蛋白K1和C7。 K1和C7中删除删除的VAVV均无法复制 在大多数哺乳动物细胞中，由于病毒和宿主蛋白质合成的关闭而引起的。有趣的是， 翻译关闭与PKR和RNASEL无关，似乎不涉及任何 翻译起始因子。一对寄生的干扰素刺激的基因SAMD9和 SAMD9L（SAMD9＆L）最近被美国和其他人确定为K1的特定目标 和C7。但是，它们如何调节蛋白质合成和限制痘病毒宿主范围是 未知，是该提议的重点。 我们为理解K1/C7及其细胞做出了持续的贡献 目标已有十多年了，包括确定K1/C7的结构 将SAMD9L鉴定为K1/C7的细胞靶标。另外，我们获得了引人注目的 初步数据导致了我们的新假设，该假设将与 遵循特定目标。 目的1。确定如何激活SAMD9以抑制蛋白质合成。 目标2。确定活化的SAMD9如何抑制蛋白质的合成。 目标3。确定宿主特异性SAMD9＆L的分子基础 OPXV抑制剂抑制。