Role of TRIF and EGFR in STING Signaling

TRIF 和 EGFR 在 STING 信号转导中的作用

基本信息

批准号：
9086042
负责人：
GANES C. SEN
金额：
$ 23.78万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-10 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086042
关键词：
Adaptor Signaling Protein Affect Bacteria Bacterial Infections Binding Binding Proteins Cancer Patient Cell Nucleus Cell membrane Cell physiology Cells Complex Cytokine Gene Cytoplasm Cytoplasmic Protein Cytoplasmic Tail DNA Defense Mechanisms Dimerization Double-Stranded RNA EGF gene Endocytosis Endosomes Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Genetic Transcription Herpesvirus 1 Immune Immune response Immune system Infection Infectious Agent Inflammatory Inflammatory Response Interferon Type I Interferons Intracellular Membranes Ligand Binding Ligands Listeria monocytogenes Mammalian Cell Maps Mediating Membrane Microbe Mitochondria Molecular Mus Myeloid Cells Nuclear Proteins Nucleic Acids Pathogenesis Pattern Pattern recognition receptor Phosphorylation Protein Kinase Protein Tyrosine Kinase Proteins Recruitment Activity Reporting Resistance Role Signal Pathway Signal Transduction Signaling Protein Stress TBK1 gene TLR3 gene TLR4 gene TLR7 gene Toll-like receptors Transcription Factor AP-1 Tyrosine Phosphorylation Viral Genome Virus Virus Diseases activating transcription factor base cell injury cytokine gene induction inhibitor/antagonist microbial microvesicles novel pathogen public health relevance receptor research study response small molecule transcription factor ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Innate immune response to infectious agents or local cell damage constitutes a major mammalian defense mechanism. Inflammatory cytokines and interferons are produced, mainly by myeloid cells, in response to bacterial or viral infection and they limit the microbial infection by either acting directly on the infected cells or activating immune cells of the adaptive immune system. There are multiple cytoplasmic pattern recognition receptors for sensing cytoplasmic DNA produced by either infecting microbes or damaged nuclei or mitochondria. All of these receptors use STING as the common signaling adaptor protein. This proposal is for investigating two novel features of STING signaling that were revealed by our preliminary experiments. Although TRIF is a known adaptor protein for TLR3 and TLR4 signaling, we discovered that it promotes STING signaling as well. Our aim is to determine how TRIF functions in the STING signaling pathway and how it affects resistance against HSV-1, a virus that triggers the STING signaling pathway. We have also observed that, like several TLRs, STING requires tyrosine phosphorylation to trigger its signaling activity. Moreover, the protein tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is required for STING Tyr phosphorylation and its ability to induce cytokine genes. Our second aim is to investigate the mechanism of EGFR-mediated STING Tyr phosphorylation and its role in downstream signaling. Our proposed studies will illuminate new features of STING signaling, which is essential for eliciting innate immune response to cytoplasmic DNA.

描述（由适用提供）：对传染剂或局部细胞损害的先天免疫响应构成了主要的哺乳动物防御机制。炎症细胞因子和干扰物主要由髓样细胞产生，以响应细菌或虚拟感染而产生，它们通过直接作用于感染细胞或激活自适应免疫系统的免疫细胞来限制微生物感染。有多种细胞质模式识别受体，用于感染被感染的微生物或受损的核或线粒体产生的细胞质DNA。所有这些接收器都使用STING作为常见的信号适配器蛋白。该建议是为了调查我们的初步实验所揭示的刺激信号传导的两个新型特征。尽管TRIF是TLR3和TLR4信号传导的已知衔接蛋白，但我们发现它也促进了刺激信号传导。我们的目的是确定TRIF在刺激信号通路中的功能及其如何影响对HSV-1的抗性，HSV-1是一种触发刺激信号通路的病毒。我们还观察到，像几个TLR一样，刺激需要酪氨酸磷酸化才能触发其信号活性。此外，表皮生长因子受体（EGFR）的蛋白酪氨酸激酶活性是刺激Tyr磷酸化及其诱导细胞因子基因的能力所必需的。我们的第二个目的是研究EGFR介导的Tyr Tyr磷酸化的机理及其在下游信号传导中的作用。我们提出的研究将阐明刺激信号的新特征，这对于引发对细胞质DNA的先天免疫响应至关重要。