Cellular responses to retroviral capsid recognition

细胞对逆转录病毒衣壳识别的反应

• 批准号: 10296179
• 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/10296179
• 关键词: Address; Alleles; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antiviral 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; 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.

项目摘要：TRIM5是一种多功能抗病毒蛋白，其在宿主防御中的各种作用包括 仍未被发现。了解这些抗病毒作用的分子机制是一种 为可能开发基于TRIM5的宿主导向的抗病毒疗法迈出了重要的一步。TRIM5是 最为人所知的是一种抗病毒效应器，可对抗多种病毒家族，包括黄病毒和逆转录病毒。 TRIM5还在抗病毒信号中发挥作用，可以触发包括1型在内的细胞因子的表达 干扰素对逆转录病毒模式识别的反应。我们之前报道了TRIM5的第三个主要角色：IT 作为自噬小体生物发生的正调节因子，它与作用于 自噬途径的多个步骤。这就提出了一个问题，自噬途径和/或 自噬机制可能参与了TRIM5‘S的抗病毒作用。在这个项目中，我们将回答这个问题 质疑并朝着长期目标努力，了解TRIM5如何协调其在 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、自噬体膜伸长的蛋白质(ATG)，以及 自噬货物的选择不能执行TRIM5定向的炎症信号。而自噬 通常被认为是一个退化的过程，在这种情况下，测试的ATG有助于主动组装 TRIM5信号复合体。这表明，TRIM5编排了新的、非规范的 它与之交互的ATG。这些发现支持了一种假说，即TRIM5‘S在炎症中起作用 信号传递和抗病毒状态的建立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验证这一假说。我们将揭开自噬的作用(S) TRIM5依赖的抗病毒信号通路和个体自噬相关蛋白(目标1和2)。我们的 第三个目标将揭示与炎症和自噬有关的新的TRIM5信号通路- 调节蛋白激酶TBK1，我们通过蛋白质组学鉴定为逆转录病毒应答的TRIM5相互作用因子 分析。理解TRIM5信号很重要，因为TRIM5信号可以解释为什么某些TRIM5 等位基因对艾滋病毒感染的保护作用，尽管人类TRIM5‘S相对不能直接 限制艾滋病病毒。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)使我们了解细胞如何对检测到逆转录病毒感染作出反应；以及iii)提供 机制洞察TRIM5，一种塑造灵长类逆转录病毒进化的蛋白质，如何在 抗病毒防御和先天免疫。我们还预计，我们的发现将有助于更广泛的调整 蛋白质家族(TRIMs)。这个蛋白质家族由人类大约80个基因组成。像TRIM5一样，很多人 TRIMs还在抗病毒防御、炎症和自噬方面发挥作用；因此，理解TRIM5可能 为其他TRIMs的研究提供了坚实的基础。