Ubiquitylation and the Regulation of Immune Homeostasis

泛素化与免疫稳态的调节

• 批准号: 7117352
• 负责人: AVERIL I MA
• 金额: $ 43.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117352
• 关键词: biological signal transduction; enzyme activity; gene expression; genetically modified animals; homeostasis; host organism interaction; immune response; inflammation; intestine disorder; laboratory mouse; protein degradation; protein protein interaction; protein signal sequence; protein structure function; toll like receptor; ubiquitin

DESCRIPTION (provided by applicant): Toll like receptors (TLRs) on eukaryotic cells mediate the recognition of microbial molecules and regulate host responses to microbial pathogens. Proper regulation of TLR signals not only restricts the intensity and duration of inflammatory responses, but may also maintain immune homeostasis in the intestine, where a plethora of microbial pathogens co-exist with host cells. Recent studies from our labs indicate that A20 is a novel protein that is required for terminating TLR induced signals on myeloid cells and for preventing excessive inflammatory responses in vivo. Our preliminary data suggest that A20 is essential for restricting TLR signals in vivo. Moreover, our findings suggest that A20 may be a novel enzyme that performs this critical function by directly modulating the ubiquitylation status of TLR signaling proteins such as TRAF6. These modifications may cause both de-activation and degradation of TLR signaling proteins. These exciting preliminary findings provide us with unique opportunities to test our central hypothesis that A20 regulates ubiquitylation of signaling proteins, TLR signals, and immune homeostasis. This application represents a synergistic effort between the genetic and cellular expertises of the Ma lab and the biochemical expertise of the Pickart lab to determine: (i) whether A20 is essential for regulating TLR responses in mice; (ii) whether A20 regulates ubiquitylation of critical TLR signaling proteins; and (iii) how A20 recognizes ubiquitylated proteins and may function as both a de-ubiquitylating enzyme and an E3. Results from these studies promise to yield significant insights into how A20 links the regulation of ubiquitylation with disease.

描述（由申请人提供）：真核细胞上的受体（TLR）像受体（TLR）介导了微生物分子的识别并调节宿主对微生物病原体的反应。 TLR信号的适当调节不仅限制了炎症反应的强度和持续时间，而且还可以在肠道中维持免疫稳态，那里有大量的微生物病原体与宿主细胞共存。我们实验室的最新研究表明，A20是一种新的蛋白质，是终止TLR在髓样细胞上诱导信号并预防体内过度炎症反应所必需的。我们的初步数据表明，A20对于限制体内TLR信号至关重要。此外，我们的发现表明A20可能是一种新型酶，通过直接调节TLR信号蛋白（如TRAF6）的泛素化状态来执行此关键功能。 这些修饰可能导致TLR信号蛋白的去激活和降解。这些令人兴奋的初步发现为我们提供了独特的机会来检验我们的中心假设，即A20调节信号蛋白，TLR信号和免疫稳态的泛素化。该应用代表了MA实验室的遗传和细胞专业知识与Pickart Lab的生化专业知识之间的协同努力，以确定：（i）A20对于调节小鼠的TLR反应至关重要； （ii）A20是否调节临界TLR信号蛋白的泛素化； （iii）A20如何识别泛素化的蛋白质，并可能起到去泛素化酶和E3的作用。这些研究的结果有望对A20如何将泛素化的调节与疾病联系起来。