Molecular and genetic dissection of the cytosolic ADP-Heptose-ALPK1-TIFA signaling pathway

胞质 ADP-庚糖-ALPK1-TIFA 信号通路的分子和遗传解析

• 批准号: 2087974
• 金额: --
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2087974
• 关键词: Molecular; genetic; dissection; cytosolic; ADP

ADP-DD-heptose is a bacterial metabolite required for the synthesis of lipopolysaccharide, a component of the cell wall of gram negative bacteria. Recently, a new innate immune signal transduction pathway present in the cytosol of human cells has been identified. In this pathway ADP-DD-heptose activates alpha protein kinase 1 (ALPK1), an atypical protein kinase that is unrelated to the main subfamily of protein kinases. ALPK1 phosphorylates the protein TIFA, inducing it's oligomerisation and interaction with TRAF6. TRAF6 then undergoes oligomerisation activating it's E3 ligase activity. Similar to the role of TRAF6 in other innate immune signalling pathways, the TRAF6 E3 ligase was proposed to generate Lys63-linked ubiquitin oligomers thereby activating the master protein kinase TAK1 which drives all the subsequent events that lead to the production and secretion of the inflammatory mediators to combat the bacterial infection. We have confirmed that the expression of TRAF6 is essential for the operation of the pathway, but surprisingly found that the E3 ligase activity of TRAF6 is not. This finding indicates that much still remins to be discovered about this novel signalling pathway. Interestingly, particular mutations in ALPK1 have been found to to be the cause of several human diseases, including spiroadenoma, spiroadenocarcinoma and ROSAH, an immune disease that was only discovered in 2019. The aim of the project is to dissect the molecular details of the cytosolic ADP-DD-Heptose-ALPK1-TIFA signaling pathway, to identify novel components of the pathway and to understand how mutations in ALPK1 cause human disease. The project will involve training in a variety of state of the art techniques in molecular and cell biology, protein chemistry, cell signalling and immunology.. Project provides training in Quantitative Skills

adp - dd -庚糖是合成脂多糖所需的细菌代谢物，脂多糖是革兰氏阴性菌细胞壁的一种成分。近年来，在人细胞胞浆中发现了一种新的先天免疫信号转导途径。在该途径中，adp - dd -庚糖激活α蛋白激酶1 (ALPK1)，这是一种与蛋白激酶主要亚家族无关的非典型蛋白激酶。ALPK1磷酸化TIFA蛋白，诱导其寡聚化并与TRAF6相互作用。然后TRAF6经历寡聚化，激活它的E3连接酶活性。与TRAF6在其他先天免疫信号通路中的作用类似，TRAF6 E3连接酶被提出产生lys63连接的泛素低聚物，从而激活主蛋白激酶TAK1，该激酶驱动所有后续事件，导致炎症介质的产生和分泌，以对抗细菌感染。我们已经证实了TRAF6的表达对于该通路的运行是必不可少的，但令人惊讶的是，我们发现TRAF6的E3连接酶活性并不是。这一发现表明，关于这种新的信号通路，还有很多有待发现的地方。有趣的是，ALPK1的特定突变被发现是几种人类疾病的原因，包括螺旋体腺瘤、螺旋体腺癌和ROSAH，这是一种2019年才发现的免疫疾病。该项目的目的是剖析细胞质adp - dd - heptoase -ALPK1- tifa信号通路的分子细节，鉴定该通路的新组分，并了解ALPK1突变如何导致人类疾病。该项目将涉及分子和细胞生物学、蛋白质化学、细胞信号和免疫学等各种最新技术的培训。项目提供定量技能培训