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）是已知的病原体相关分子模式（PAMP） 在病毒感染期间产生，触发先天免疫反应，并在病毒感染中起关键作用。 通过对I型IFN的直接作用进行保护。然而，近年来，很明显，这一途径 也可以由内源性dsRNA诱导，线粒体转录物是其主要来源之一。 内源dsRNA。内源性dsRNA的存在表明，必须有适当的机制， 继续检查它们的积累，以避免触发RLR途径。虽然有很多关于 内源性双链RNA如何产生I型干扰素间接调节T细胞应答， 先前的研究已经检测了T细胞中的dsRNA。我们最近的研究表明， 在活化后，CD8细胞中的dsRNA和线粒体似乎是主要来源。此外，我们还发现， CD8细胞用来限制dsRNA产生水平的新机制：线粒体失活 GSK3通过在Ser389上磷酸化而磷酸化。有趣的是，磷酸化Ser389不能抑制GSK3的表达， 线粒体dsRNA在活化的CD8细胞中的更大积累。重要的是，我们还发现， 磷酸化丝氨酸389修饰的SKG3导致CD8细胞产生更高水平的IFN γ。我们假设 线粒体dsRNA在CD8细胞活化过程中产生，可触发RLR途径，并有助于 以维持IFN的产生。我们还提出，线粒体GSK3 β干扰了线粒体 降解体和线粒体GSK3激酶通过Ser389磷酸化失活 dsRNA对于维持dsRNA稳态和限制IFN γ产生是必需的。我们将测试这个 具有以下特定目的的假设：1）显示线粒体dsRNA在活化过程中产生， 的CD8细胞，并有助于生产IFN γ。2)为了表明通过Ser389- 磷酸化在CD8细胞活化期间线粒体dsRNA的稳态中起作用。的 这项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是如何在细胞内表达的。 可以有助于维持活化的CD8细胞中细胞因子的产生，以及其对自身免疫性疾病的潜在影响。 疾病