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.

项目摘要 双链RNA（DSRNA）是一种众所周知的病原体相关分子模式（PAMP） 在病毒感染过程中产生的，触发先天免疫反应并在病毒中起关键作用 通过直接对I型IFN的影响进行保护。但是，近年来很明显这条途径 也可以由内源性dsRNA诱导，线粒体转录本是主要来源之一 内源性dsRNA。内源性dsRNA的存在表明必须有机制 继续检查其积累，以避免触发RLRS路径。尽管有许多研究 内源性DSRNA产生的I型IFN的产生如何间接调节T细胞反应，否 先前的研究检查了T细胞中的DSRNA。我们最近的研究揭示了内源性的存在 激活后CD8细胞中的dsRNA，线粒体似乎是主要来源。此外，我们确定 CD8细胞用来限制DSRNA水平的新机制：线粒体失活 Ser389上的磷酸化GSK3。有趣的是，磷酸-Ser389未能使GSK3失活导致 线粒体DSRNA在活化的CD8细胞中的积累越来越大。重要的是，我们还发现 磷酸 - 塞尔389的灭活GSK3会导致CD8细胞产生的较高水平的IFN。我们假设这一点 线粒体DSRNA是在CD8细胞激活期间产生的，可以触发RLR途径并贡献 维持IFN生产。我们还建议线粒体GSK3会干扰线粒体 通过Ser389上的磷酸化对线粒体GSK3的降解体和线粒体的灭活，以响应 dsRNA对于维持dsRNA常肠症和限制IFN产生至关重要。我们将测试这个 以下特定目的的假设：1）表明在激活过程中产生线粒体dsRNA CD8细胞的产生，有助于产生IFN。 2）表明GSK3通过Ser389-灭活 在CD8细胞激活过程中，磷酸化在线粒体DSRNA的体内稳态中起作用。这 拟议研究的结果可能是一个重大突破，因为它们将显示内源性dsRNA如何 可以有助于维持活化的CD8细胞中的细胞因子产生及其对自身免疫的潜在影响 疾病。