GSK3b and dsRNA in CD8 cells

CD8 细胞中的 GSK3b 和 dsRNA

• 批准号: 10536526
• 负责人: Mercedes Rincon
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536526
• 关键词: Autoimmune Diseases; CD8-Positive T-Lymphocytes; Cells; Double-Stranded RNA; Failure; GAG Gene; GTP-Binding Protein alpha Subunits, Gs; Hexachlorobenzene; Homeostasis; Immune response; Infection; Innate Immune Response; Interferons; Mitochondria; Molecular; Pathway interactions; Pattern; Phosphorylation; Play; Production; Regulation; Role; Source; T cell response; T-Lymphocyte; Testing; Transcript; Virus; Virus Diseases; cytokine; novel; pathogen; response

PROJECT SUMMARY Double-stranded RNA (dsRNA) is a well-known pathogen-associated molecular pattern (PAMP) generated during viral infections that triggers the innate immune response and plays a critical role in virus protection through the direct effect on type I IFN. However, in recent years it has been clear that this pathway can also be induced by endogenous dsRNA, with mitochondria transcripts being one of the major sources of endogenous dsRNA. The presence of endogenous dsRNA suggests that there must be mechanisms in place to keep on check their accumulation to avoid triggering RLRs pathways. Although there is a number of studies on how the production of type I IFN resulting from endogenous dsRNA can indirectly modulate T cell response, no previous studies have examined dsRNA in T cells. Our recent studies have revealed the presence of endogenous dsRNA in CD8 cells upon activation, and mitochondria seems to be the primary source. In addition, we identify a new mechanism that CD8 cells use to restrict the levels of dsRNA generated: inactivation of mitochondria GSK3 by phosphorylation on Ser389. Interestingly, failure to inactivate GSK3 by phospho-Ser389 results in a greater accumulation of mitochondrial dsRNA in activated CD8 cells. Importantly, we also found that failure to inactivate GSK3 by phospho-Ser389 results in higher levels of IFN produced by CD8 cells. We hypothesize that mitochondrial dsRNAs are generated during activation of CD8 cells, can trigger the RLR pathway and contribute to sustain IFN production. We also propose that mitochondrial GSK3 interferes with the mitochondrial degradosome and that inactivation of mitochondrial GSK3 through phosphorylation on Ser389 in response to dsRNA is essential for maintaining dsRNA-homeostasis and restricting IFN production. We will test this hypothesis with the following specific aims: 1) to show that mitochondrial dsRNA is generated during activation of CD8 cells and contributes to the production of IFN. 2) to show that inactivation of GSK3 through Ser389- phosphorylation plays a role in the homeostasis of mitochondrial dsRNA during activation of CD8 cells. The results from the proposed studies could be a major breakthrough since they will show how endogenous dsRNA can contribute to sustain cytokine production in activated CD8 cells, and its potential impact on autoimmune disease.

项目概要 双链 RNA (dsRNA) 是一种众所周知的病原体相关分子模式 (PAMP) 病毒感染期间产生，可触发先天免疫反应，并在病毒感染中发挥关键作用 通过直接作用于 I 型干扰素来提供保护。然而，近年来，这一途径已明确 也可以由内源性 dsRNA 诱导，线粒体转录物是 dsRNA 的主要来源之一 内源性双链RNA。内源 dsRNA 的存在表明必须有适当的机制来 继续检查它们的积累以避免触发 RLR 途径。尽管有大量研究表明 内源性 dsRNA 产生的 I 型干扰素如何间接调节 T 细胞反应，没有 之前的研究已经检查了 T 细胞中的 dsRNA。我们最近的研究揭示了内源性的存在 CD8 细胞中的 dsRNA 激活后，线粒体似乎是主要来源。此外，我们还确定 CD8 细胞用来限制 dsRNA 生成水平的新机制：线粒体失活 GSK3 通过 Ser389 磷酸化。有趣的是，磷酸化 Ser389 未能灭活 GSK3 会导致 活化的 CD8 细胞中线粒体 dsRNA 的积累量更大。重要的是，我们还发现未能 通过磷酸化 Ser389 灭活 GSK3 会导致 CD8 细胞产生更高水平的 IFN。我们假设 线粒体 dsRNA 在 CD8 细胞激活过程中产生，可以触发 RLR 通路并有助于 以维持干扰素的产生。我们还提出线粒体 GSK3 干扰线粒体 降解体和线粒体 GSK3 通过 Ser389 磷酸化来失活 dsRNA 对于维持 dsRNA 稳态和限制 IFNγ 的产生至关重要。我们将测试这个 具有以下具体目的的假设：1）表明线粒体 dsRNA 在激活过程中生成 CD8 细胞并有助于 IFNγ 的产生。 2) 表明 GSK3 通过 Ser389- 失活 磷酸化在 CD8 细胞激活过程中线粒体 dsRNA 的稳态中发挥作用。这 拟议研究的结果可能是一个重大突破，因为它们将展示内源性 dsRNA 如何 有助于维持活化 CD8 细胞中细胞因子的产生，及其对自身免疫的潜在影响 疾病。