Sting Trafficking and Signaling Beyond Interferon

毒刺贩运和干扰素以外的信号传导

• 批准号: 10368072
• 负责人: Nan Yan
• 金额: $ 52.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-22 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368072
• 关键词: Address; Affect; Area; Autoimmune Diseases; Autophagocytosis; Biology; Calcium; Calcium Signaling; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Development; Disease; Gene Expression; Genes; Goals; Golgi Apparatus; Herpesvirus 1; Human; IRF3 gene; In Vitro; Infection; Innate Immune Response; Interferon Type I; Interferons; Ligand Binding; Lipids; Location; Lung diseases; Lysosomes; Mediating; Membrane; Microbe; Molecular; Mus; Mutant Strains Mice; NPC1 gene; Pathology; Pathway interactions; Phosphotransferases; Physiological; Physiology; Pilot Projects; Play; Point Mutation; Process; Proteins; Proteomics; Resources; Rest; Role; Route; Signal Pathway; Signal Transduction; Sting Injury; T-Cell Proliferation; T-Lymphocyte; TBK1 gene; TOLLIP gene; Time; Vascular Diseases; Vesicle; Work; cofactor; cytopenia; gain of function; gain of function mutation; human disease; in vivo; infancy; insight; interest; mouse model; mutant; recruit; therapeutic target; trafficking; transcription factor

Project summary STING-mediated type I interferon (IFN) signaling plays an important role in innate immune response in infection and autoimmune disease. The STING signaling pathway is unique in that it requires STING trafficking from the ER through ERGIC/Golgi to vesicles, during which time STING recruits kinase TBK1 and transcription factor IRF3 which subsequently activates IFN gene expression. STING trafficking also activates other non-IFN pathways under pathophysiological conditions such as cell death and autophagy, although the mechanism is unclear. We showed that dominant STING gain-of-function mutations constitutively activate STING trafficking in vitro and causes lung disease and T cell cytopenia independently of IFN signaling in vivo. In preliminary studies we performed a time-resolved proteomic study using STING-APEX2 and identified several cofactors at various membrane locations along the trafficking route. Our main hypothesis is that STING trafficking is a primordial way for STING to regulate multiple cellular processes including IFN and non-IFN pathways, such as calcium signaling, cell death and autophagy. The non-IFN functions of STING are likely important for human physiology because at least one such function is implicated in human disease STING-associated vasculopathy with onset in infancy (SAVI). We will study the function of STING trafficking and non-IFN functions through the following three specific aims: In Aim 1, we will study the cellular process of STING trafficking by discovering new cofactors along the trafficking route and elucidating their mechanism of action. In Aim 2, we will investigate one particular non-IFN function, the UPR, that is mediated by STING trafficking in T cells, using the dominant gain-of-function Sting- N153S mouse with active disease pathology. In Aim 3, we will broadly explore non-IFN functions of STING in a variety of physiological conditions, using a new point mutant mouse Sting-S365A, which selectively blocks STING-mediated IFN signaling while retaining normal trafficking and other signaling capabilities. Studies proposed here will address a previously understudied but important area of STING biology and reveal new functions of STING with pathophysiological relevance.

项目摘要 STING介导的I型干扰素（IFN）信号在感染的天然免疫应答中起重要作用 和自身免疫性疾病。STING信号传导途径是独特的，因为它需要从细胞中运输STING。 ER通过ERGIC/高尔基体进入囊泡，在此期间STING招募激酶TBK 1和转录因子 IRF 3随后激活IFN基因表达。STING贩运也激活其他非IFN 在病理生理条件下，如细胞死亡和自噬，虽然机制是 不清楚我们发现，显性STING功能获得性突变组成性激活STING运输， 并且在体内独立于IFN信号传导而引起肺病和T细胞血细胞减少。在初步研究中 我们使用STING-APEX 2进行了时间分辨蛋白质组学研究，并在不同的时间点鉴定了几种辅因子。 膜位置沿着贩运路线。我们的主要假设是，STING贩运是一种原始的方式， 对于STING调节多种细胞过程，包括IFN和非IFN途径，如钙信号传导， 细胞死亡和自噬。STING的非IFN功能可能对人体生理学很重要，因为 至少有一种这样的功能与婴儿期发病的人类疾病STING相关血管病变有关 （SAVI）.我们将通过以下三个具体步骤来研究STING的运输功能和非IFN功能 目的：在目的1中，我们将通过发现新的辅因子沿着STING运输的细胞过程， 贩运路线并阐明其作用机制。在目标2中，我们将研究一种特定的非IFN 功能，UPR，这是由T细胞中的STING运输介导的，使用显性功能获得性Sting- 具有活动性疾病病理学的N153 S小鼠。在目标3中，我们将广泛地探索STING的非IFN功能， 各种生理条件下，使用一种新的点突变小鼠Sting-S365 A，它选择性地阻断 STING介导的IFN信号传导，同时保留正常的运输和其他信号传导能力。研究 这里提出的将解决以前研究不足，但STING生物学的重要领域，并揭示新的 STING的功能与病理生理学相关性。