Cellular responses to retroviral capsid recognition

细胞对逆转录病毒衣壳识别的反应

基本信息

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
项目类别：
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

项目摘要

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，其在宿主防御中的多种作用包括了解这些抗病毒作用背后的分子机制仍然是一个未知数。开发基于 TRIM5 的宿主定向抗病毒疗法的重要一步是。最著名的是针对不同病毒家族（包括黄病毒和逆转录病毒）的抗病毒效应物。 TRIM5 还在抗病毒信号传导中发挥作用，可触发细胞因子（包括 1 型）的表达我们之前报道了 TRIM5 的第三个主要作用：干扰素对逆转录病毒模式识别的反应。作为自噬体生物发生的正调节因子，它与作用于自噬体的蛋白质发生物理相互作用。自噬途径的多个步骤这就提出了自噬途径和/或自噬途径的问题。自噬机制可能有助于 TRIM5 的抗病毒活性，在这个项目中，我们将回答这个问题。问题并努力实现了解 TRIM5 如何协调其行动的长期目标我们的初步数据表明，细胞缺乏自噬相关。参与上游自噬调节、自噬体膜伸长和自噬货物选择无法执行 TRIM5 指导的炎症信号传导。通常被认为是一个降解过程，在这种情况下，测试的 ATG 有助于组装活性 TRIM5 信号复合物这表明 TRIM5 协调了新颖的、非规范的功能。这些发现支持 TRIM5 在炎症中发挥作用的假设。信号传导和建立抗病毒状态与其在自噬中的作用有关，我们将利用细胞生物学，我们将通过免疫学和蛋白质组学方法来检验这一假设。 TRIM5 依赖性抗病毒信号传导途径和个体自噬相关蛋白（我们的目标 1 和 2）。第三个目标将揭示一条与炎症和自噬相关的新型 TRIM5 信号通路调节激酶 TBK1，我们通过蛋白质组学鉴定为逆转录病毒响应 TRIM5 相互作用蛋白了解 TRIM5 信号传导非常重要，因为 TRIM5 信号传导可以解释为什么某些 TRIM5 信号传导。尽管人类 TRIM5 相对无法直接作为结果，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响应逆转录病毒感染；以及 iii) 提供深入了解 TRIM5（一种影响灵长类逆转录病毒进化的蛋白质）如何在我们还希望我们的研究结果能够为更广泛的 TRIM 提供启示。蛋白质家族 (TRIM) 与 TRIM5 一样，该蛋白质家族由大约 80 个基因组成。 TRIM 在抗病毒防御、炎症和自噬中也发挥作用，因此了解 TRIM5 可能是一个重要的方面。为其他 TRIM 的研究奠定了坚实的基础。