Sting Trafficking and Signaling Beyond Interferon

毒刺贩运和干扰素以外的信号传导

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要刺激介导的I型干扰素（IFN）信号传导在感染中先天免疫反应中起重要作用和自身免疫性疾病。刺激信号通路的独特之处在于它需要从通过Ergic/Golgi到囊泡，在此期间，Sting招募了激酶TBK1和转录因子 IRF3随后激活IFN基因表达。刺痛交通还激活其他非IFN 病理生理状况（例如细胞死亡和自噬）下的途径，尽管该机制是不清楚。我们表明，主要的功能收益突变构成激活刺痛的运输体外并独立于体内IFN信号传导而引起肺部疾病和T细胞细胞质。在初步研究中我们使用Sting-apex2进行了时间分辨的蛋白质组学研究沿贩运路线的膜位。我们的主要假设是刺痛是一种原始的方式为了调节包括IFN和非IFN途径在内的多个细胞过程，例如钙信号传导，细胞死亡和自噬。 sting的非IFN功能对于人类生理可能很重要，因为至少一种这样的功能与人类疾病相关的血管病与婴儿期发作有关（savi）。我们将通过以下三个特定目的：在AIM 1中，我们将通过发现沿着沿线的新辅助因子来研究刺激贩运的细胞过程贩运路线和阐明其作用机理。在AIM 2中，我们将研究一个特定的非IFN 功能，通过在T细胞中刺激运输的UPR，使用主要功能获得的刺激 N153S小鼠具有活性疾病病理学。在AIM 3中，我们将广泛探索在使用新的点突变体STING-S365A，多种生理条件，它有选择地阻止刺激介导的IFN信号传导，同时保留正常运输和其他信号传导功能。研究这里提出的将介绍先前研究的sting生物学的重要领域，并揭示新的与病理生理相关性的刺激功能。