Cellular responses to retroviral capsid recognition

细胞对逆转录病毒衣壳识别的反应

• 批准号: 10626905
• 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/10626905
• 关键词: Address; Alleles; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antiviral Response; Antiviral Therapy; Autophagocytosis; Autophagosome; Binding; Biochemical; Biogenesis; Biological; Capsid; Cell Survival; Cells; Complex; Cytoplasm; Cytoprotection; 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; Link; Malignant Neoplasms; Mediating; Membrane; Methodology; Modeling; Molecular; Natural Immunity; Outcome; Pathogenicity; Pathway interactions; Pattern Recognition; Pattern recognition receptor; Persons; Phosphotransferases; Play; Positioning Attribute; Predisposition; Primate Retrovirus; Process; Production; Protein Family; Protein Isoforms; Proteins; Proteomics; Publishing; Quality Control; Regulation; Reporting; Retroviridae; Risk; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; System; TBK1 gene; TRIM Family; TRIM5 gene; Testing; Therapeutic; Viral; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Work; cytokine; human disease; immune activation; innovation; insight; novel; response; scaffold; transmission process

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是 仍然被发现。了解这些抗病毒作用的分子机制是一种 迈向可能开发基于TRIM5的宿主指导抗病毒疗法的基本步骤。 Trim5是 最著名的是针对抗病毒病毒家族的抗病毒效应子，包括黄素病毒和逆转录病毒。 TRIM5在抗病毒信号中还具有作用，可以触发包括1型的细胞因子的表达 干扰素响应逆转录病毒模式识别。我们以前报道了TRIM5的第三个主要角色：IT 充当自噬体生物发生的阳性调节剂，并与作用在 自噬途径的多个步骤。这提出了一个问题，即自噬途径和/或 自噬机械可能会导致TRIM5的抗病毒活动。在这个项目中，我们将回答 质疑和朝着理解TRIM5如何协调其行为的长期目标的努力 防御逆转录病毒感染。我们的初步数据表明，缺乏自噬相关的细胞 蛋白质（ATG）参与上游自噬调节，自噬体膜伸长和 自噬的货物选择无法执行TRIM5定向的炎症信号传导。而自噬 通常被认为是降解过程，在这种情况下，已测试的ATG有助于组装活动 TRIM5信号复合物。这表明TRIM5策划了新颖的非规范功能 与之相互作用的ATG。这些发现支持了一个假设，其中TRIM5在炎症中的作用 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检验该假设的方法。我们将发现自噬的作用 TRIM5依赖性抗病毒信号传导中的途径和单个自噬相关蛋白（目标1和2）。我们的 第三个目标将发现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确定为逆转录病毒响应TRIM5相互作用。 分析。理解TRIM5信号传导很重要，因为TRIM5信号传导可以解释为什么某些trim5 等位基因会议保护人们对艾滋病毒感染的保护，要求人类Trim5的相对无力直接 限制艾滋病毒。作为结果，我们预计我们的拟议研究将：i）揭示抗病毒的新途径 防御; ii）使我们能够理解细胞如何应对逆转录病毒感染的反应；和iii）提供 机械洞察Trim5是如何塑造灵长类动物进化的蛋白质如何作用于 抗病毒防御和先天免疫。我们还期望我们的发现将揭示更宽的修剪 蛋白质家族（修剪）。该蛋白质家族由人类大约80个基因组成。像Trim5一样，许多 装饰在抗病毒防御，注射和自噬中也有作用。因此了解Trim5可能 为研究其他装饰提供坚定的基础。

项目成果

Quantitative single-cell analysis of Leishmania major amastigote differentiation demonstrates variably extended expression of the lipophosphoglycan (LPG) virulence factor in different host cell types.

• DOI: 10.1371/journal.pntd.0010893
• 发表时间: 2022-10
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8

The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.

逆转录病毒限制因子 TRIM5/TRIM5α 调节线粒体质量控制。

• DOI: 10.1080/15548627.2022.2084863
• 发表时间: 2023
• 期刊: Autophagy
• 影响因子: 13.3
• 作者: Saha,Bhaskar;Mandell,MichaelA
• 通讯作者: Mandell,MichaelA

Interactomic analysis reveals a homeostatic role for the HIV restriction factor TRIM5α in mitophagy.

• DOI: 10.1016/j.celrep.2022.110797
• 发表时间: 2022-05-10
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Saha, Bhaskar;Salemi, Michelle;Williams, Geneva L.;Oh, Seeun;Paffett, Michael L.;Phinney, Brett;Mandell, Michael A.
• 通讯作者: Mandell, Michael A.