Cellular responses to retroviral capsid recognition

细胞对逆转录病毒衣壳识别的反应

• 批准号: 10436986
• 负责人: Michael Aaron Mandell
• 金额: $ 41.48万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-17 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436986
• 关键词: Address; Alleles; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antiviral Response; Antiviral Therapy; Autophagocytosis; Autophagosome; Binding; Biochemical; Biogenesis; Biological; Capsid; Cells; Complex; DNA; Data; Degradation Pathway; Detection; Development; Disease; Evolution; Family; Flavivirus; Foundations; Genes; Genetic; Goals; HIV; HIV Infections; HIV-1; Homeostasis; Host Defense; Human; Immune; Immune signaling; Immunologics; Individual; Infection; Inflammation; Inflammatory; Interferon-alpha; Interferons; Knowledge; Life Cycle Stages; Ligation; Light; Link; Malignant Neoplasms; Marshal; Mediating; Membrane; Methodology; Modeling; Molecular; Natural Immunity; Outcome; Pathogenicity; Pathway interactions; Pattern Recognition; Pattern recognition receptor; Persons; Phosphotransferases; Play; Positioning Attribute; Primate Retrovirus; Primates; Process; Production; Protein Family; Protein Isoforms; Proteins; Proteomics; Publishing; Quality Control; Regulation; Reporting; Retroviridae; Risk; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Protein; System; TBK1 gene; TRIM Family; TRIM5 gene; Testing; Therapeutic; Viral; Virus; Virus Diseases; Work; base; cytokine; human disease; immune activation; innovation; insight; novel; response; scaffold

PROJECT SUMMARY: TRIM5 is a multi-functional antiviral protein whose various actions in host defense are still being uncovered. Understanding the molecular mechanisms underlying these antiviral actions is an essential step towards the possible development of TRIM5-based host-directed antiviral therapies. TRIM5 is best known as an antiviral effector against diverse families of viruses including flaviviruses and retroviruses. TRIM5 also has roles in antiviral signaling that can trigger the expression of cytokines including type 1 interferon in response to retroviral pattern recognition. We previously reported a third major role for TRIM5: it acts as a positive regulator of autophagosome biogenesis and it physically interacts with proteins acting in multiple steps of the autophagy pathway. This raises the question of what the autophagy pathway and/or the autophagy machinery might be contributing to TRIM5’s antiviral activities. In this project, we will answer this question and work towards the long-term goal of understanding how TRIM5 coordinates its actions in defending against retroviral infection. Our preliminary data demonstrate that cells lacking autophagy-related proteins (ATGs) involved in upstream autophagy regulation, autophagosome membrane elongation, and autophagic cargo selection are unable to carry out TRIM5-directed inflammatory signaling. Whereas autophagy is typically considered a degradative process, in this setting the ATGs tested contributed to assembling active TRIM5 signaling complexes. This suggests that TRIM5 orchestrates novel, non-canonical functions of the ATGs with which it interacts. These findings support a hypothesis in which TRIM5’s actions in inflammatory signaling and in establishing an antiviral state are linked to its actions in autophagy. We will use cell biological, immunological, and proteomic approaches to test this hypothesis. We will uncover the role(s) of the autophagy pathway and individual autophagy-related proteins in TRIM5-dependent antiviral signaling (Aims 1 and 2). Our third Aim will uncover a novel TRIM5 signaling pathway connected to the inflammatory and autophagy- regulatory kinase TBK1, which we identified as a retrovirus-responsive TRIM5 interactor through proteomic analysis. Understanding TRIM5 signaling is significant, since TRIM5 signaling could explain why certain TRIM5 alleles confer protection against HIV infection in people despite human TRIM5’s relative inability to directly restrict HIV. As outcomes, we anticipate that our proposed studies will: i) reveal novel pathways for antiviral defense; ii) enable our understanding of how cells respond to detection of retroviral infection; and iii) provide mechanistic insight into how TRIM5, a protein that has shaped the evolution of primate retroviruses, acts in antiviral defense and innate immunity. We also expect that our findings will shed light on the broader TRIM family of proteins (TRIMs). This protein family consists of roughly 80 genes in humans. Like TRIM5, many TRIMs also have roles in antiviral defense, inflammation, and autophagy; thus understanding TRIM5 may provide a firm foundation for the study of other TRIMs.

TRIM 5是一种多功能抗病毒蛋白，其在宿主防御中的各种作用是 仍然没有被发现。了解这些抗病毒作用的分子机制是一个 这是可能开发基于TRIM 5的宿主定向抗病毒疗法的重要一步。TRIM 5是 最为人所知的是抗多种病毒家族的抗病毒效应物，包括黄病毒和逆转录病毒。 TRIM 5还在抗病毒信号传导中发挥作用，可以触发细胞因子的表达，包括1型 干扰素对逆转录病毒模式识别的反应。我们之前报道了TRIM 5的第三个主要作用： 作为自噬体生物发生的正调节剂，它与蛋白质相互作用， 自噬途径的多个步骤。这就提出了一个问题，即自噬途径和/或 自噬机制可能有助于TRIM 5的抗病毒活性。在这个项目中，我们将回答这个问题。 问题，并努力实现长期目标，了解TRIM 5如何协调其行动， 抵御逆转录病毒感染。我们的初步数据表明，缺乏自噬相关的细胞 参与上游自噬调节、自噬体膜延伸和自噬细胞增殖的蛋白质（ATG） 自噬货物选择无法进行TRIM 5介导的炎症信号传导。而自噬 通常被认为是降解过程，在这种情况下，测试的ATG有助于组装活性 TRIM 5信号复合物。这表明，TRIM 5协调了新的，非经典的功能， 与之相互作用的ATG。这些发现支持了一个假设，即TRIM 5在炎症中的作用是通过调节细胞内的蛋白质水平来实现的。 信号传导和建立抗病毒状态与其在自噬中的作用有关。我们将使用细胞生物学， 免疫学和蛋白质组学方法来检验这一假设。我们将揭示自噬的作用 在TRIM 5依赖性抗病毒信号传导中的自噬通路和个体自噬相关蛋白（目的1和2）。我们 第三个目标将揭示一种新的TRIM 5信号通路与炎症和自噬有关， 调节激酶TBK 1，我们通过蛋白质组学鉴定， 分析.理解TRIM 5信号是重要的，因为TRIM 5信号可以解释为什么某些TRIM 5 尽管人类TRIM 5相对不能直接保护人类免受HIV感染， 限制艾滋病毒。作为结果，我们预计我们提出的研究将：i）揭示抗病毒的新途径 防御; ii）使我们能够理解细胞如何对逆转录病毒感染的检测做出反应;以及iii）提供 TRIM 5是一种塑造灵长类逆转录病毒进化的蛋白质， 抗病毒防御和先天免疫。我们还希望我们的研究结果将有助于更广泛的TRIM 蛋白质家族（TRIMs）这个蛋白质家族由人类大约80个基因组成。与TRIM 5一样，许多 TRIMs还在抗病毒防御、炎症和自噬中发挥作用;因此，了解TRIM 5可能 为研究其他与贸易有关的投资措施提供了坚实的基础。