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The role of the protein tyrosine phosphatase PTP1B in mediating Toll-like receptors TLR7 and TLR9 function

蛋白酪氨酸磷酸酶 PTP1B 在介导 Toll 样受体 TLR7 和 TLR9 功能中的作用

基本信息

批准号：
277455535
负责人：
Professorin Dr. Melanie Brinkmann
金额：
--
依托单位：
Institut für Genetik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/277455535?language=en
关键词：
role protein tyrosine phosphatase PTP1B

项目摘要

Toll-like receptors (TLRs) exemplify a key cell biological concept: Subcellular localisation determines the outcome of biological processes. It has been widely demonstrated that TLR function needs to be precisely regulated to prevent adverse effects upon recognition of self ligands, which can lead to autoimmune or inflammatory disorders. In recent years, the trafficking and localisation of TLRs has emerged as a primary discriminatory mechanism between self versus non-self, as well as the induction of distinct signalling cascades. Currently, the precise regulation of endosomally located nucleic acid-sensing TLRs and their crucial cofactor UNC93B is still incompletely understood.We have accumulated several lines of evidence that the protein tyrosine phosphatase PTP1B is a novel player in the innate immune response elicited by endosomally located TLRs 7 and 9. PTP1B was identified in a proteomics approach as a novel interacting partner of UNC93B. We can show that the type I interferon response in plasmacytoid dendritic cells upon TLR7/9 stimulation and murine cytomegalovirus (MCMV) infection is impaired in the absence of PTP1B in vitro. In contrast, the proinflammatory cytokine response is intact in PTP1B deficient cells and mice upon TLR7/9 stimulation. Collectively, our data suggest a potential role for PTP1B as a critical positive regulator of the TLR7- and TLR9-dependent type I IFN response. In the proposed project we will define the role of PTP1B in TLR7 and TLR9 function in primary innate immune cells with the following aims: (1) Using cell biological and immunological methods we will elucidate whether PTP1B regulates either trafficking of TLR7/9 to specific subcellular compartments or the downstream type I IFN signalling pathway induced by TLR7/9 upon ligand binding.(2) We will decipher whether the phosphatase activity of PTP1B is crucial for its positive regulatory role on TLR signalling and aim to identify the substrate(s) or further binding partners of PTP1B.(3) In vitro, PTP1B is important for the type I IFN response to MCMV infection. We will analyse the role of PTP1B in the innate immune response to infection with MCMV and the Gram-positive bacterium Staphylococcus aureus in vivo.With these studies we expect to gain mechanistic insights into the regulation of nucleic acid-sensing TLRs and obtain knowledge about the specialised compartments associated with TLR signalling. Elucidating the molecular pathways that regulate TLR function will ultimately broaden therapeutic opportunities to treat autoimmune disease.

toll样受体（TLRs）体现了一个关键的细胞生物学概念：亚细胞定位决定了生物过程的结果。已经广泛证明，TLR功能需要精确调节，以防止对自身配体识别的不利影响，从而导致自身免疫性或炎症性疾病。近年来，tlr的贩运和定位已成为自我与非自我之间的主要歧视机制，以及诱导不同的信号级联反应。目前，内体细胞定位的核酸敏感tlr及其关键辅因子UNC93B的精确调控尚不完全清楚。我们已经积累了几条证据，表明蛋白酪氨酸磷酸酶PTP1B在由内体细胞定位的TLRs 7和9引发的先天免疫反应中是一个新的参与者。PTP1B通过蛋白质组学方法被鉴定为UNC93B的一个新的相互作用伙伴。我们可以证明，在体外缺乏PTP1B的情况下，浆细胞样树突状细胞在TLR7/9刺激和小鼠巨细胞病毒（MCMV）感染下的I型干扰素应答受到损害。相比之下，PTP1B缺陷细胞和小鼠在TLR7/9刺激下的促炎细胞因子反应是完整的。总的来说，我们的数据表明PTP1B作为TLR7-和tlr9依赖性I型IFN反应的关键正调节因子的潜在作用。在该项目中，我们将确定PTP1B在TLR7和TLR9在原代先天免疫细胞中的作用，目的如下：(1)使用细胞生物学和免疫学方法，我们将阐明PTP1B是否调节TLR7/9向特定亚细胞区室的运输或TLR7/9在配体结合后诱导的下游I型IFN信号通路。(2)我们将破译PTP1B的磷酸酶活性是否对其对TLR信号的积极调节作用至关重要，并旨在确定PTP1B的底物或进一步的结合伙伴。(3)在体外，PTP1B对I型IFN对MCMV感染的应答很重要。我们将分析PTP1B在MCMV和革兰氏阳性细菌金黄色葡萄球菌感染的先天免疫反应中的作用。通过这些研究，我们期望获得对核酸敏感TLR调控的机制见解，并获得与TLR信号传导相关的专门区室的知识。阐明调节TLR功能的分子途径将最终拓宽自身免疫性疾病的治疗机会。