Role of TRIF and EGFR in STING Signaling

 描述（由申请人提供）：对感染因子或局部细胞损伤的先天免疫应答构成了哺乳动物的主要防御机制。炎症性细胞因子和干扰素主要由骨髓细胞响应细菌或病毒感染而产生，并且它们通过直接作用于感染的细胞或激活适应性免疫系统的免疫细胞来限制微生物感染。存在多种细胞质模式识别受体，用于感测由感染的微生物或受损的细胞核或线粒体产生的细胞质DNA。所有这些受体都使用STING作为共同的信号衔接蛋白。这个提议是为了研究我们的初步实验所揭示的STING信号的两个新特征。虽然TRIF是已知的TLR 3和TLR 4信号转导的衔接蛋白，但我们发现它也促进STING信号转导。我们的目标是确定TRIF如何在STING信号通路中发挥作用，以及它如何影响对HSV-1的抗性，HSV-1是一种触发STING信号通路的病毒。我们还观察到，与几种TLR一样，STING需要酪氨酸磷酸化来触发其信号传导活性。此外，表皮生长因子受体（EGFR）的蛋白酪氨酸激酶活性是STING 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STING Tyr磷酸化的机制及其在下游信号传导中的作用。我们提出的研究将阐明STING信号传导的新特征，这对于引发对细胞质DNA的先天免疫应答至关重要。

 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.