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.

项目总结 双链rna(Dsrna)是一种广为人知的病原体相关分子模式。 在病毒感染期间产生，触发先天免疫反应，并在病毒中起关键作用 通过对I型干扰素的直接作用进行保护。然而，近年来已经很明显，这条途径 也可以由内源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，必须有适当的机制来 继续检查它们的积累，以避免触发RLRs通路。尽管有许多关于 内源性dsRNA产生的I型干扰素如何间接调节T细胞反应，NO 之前的研究已经检测了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被激活，线粒体似乎是主要的来源。此外，我们确定 CD8细胞用来限制dsRNA产生水平的一种新机制：线粒体失活 丝氨酸389上的Gsk3被磷酸化。有趣的是，未能通过磷酸化丝氨酸389使gsk3失活会导致 激活的CD8细胞中线粒体dsRNA的积累更多。重要的是，我们还发现未能 用磷酸化的丝氨酸389灭活GSK3干扰素可导致CD8细胞产生更高水平的干扰素。我们假设 线粒体dsRNAs是在CD8细胞激活过程中产生的，可以触发RLR途径并参与 来维持干扰素的产生。我们还认为线粒体GSK3干扰了线粒体 降解体和线粒体Gsk3在丝氨酸389上的磷酸化失活 双链RNA对于维持双链RNA的稳态和限制干扰素的产生是必不可少的。我们将对此进行测试 有以下特定目的的假说：1)表明线粒体dsrna是在激活过程中产生的 并参与干扰素的产生。2)证明通过Ser389使Gsk3失活- 在CD8细胞激活过程中，磷酸化在线粒体dsRNA的动态平衡中起作用。这个 拟议的研究结果可能是一项重大突破，因为它们将显示内源性dsRNA如何 有助于维持激活的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。