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Signal transduction of the actin-binding protein cortactin in bacterial pathogenesis

肌动蛋白结合蛋白 cortactin 在细菌发病机制中的信号转导

基本信息

批准号：
289286761
负责人：
Dr. Nicole Tegtmeyer
金额：
--
依托单位：
Lehrstuhl für Mikrobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/289286761?language=en
关键词：
Signal transduction actin binding protein

项目摘要

Many microbial pathogens manipulate signal transduction processes of their eukaryotic hosts for their own benefit and disease development. The cytoskeleton assembly plays a fundamental role in many vital cellular processes, such as membrane dynamics, migration, adhesion and transport. Thus, by targeting the cytoskeleton and various kinases, pathogens can radically and rapidly reprogram their host target cell and can trigger disease-associated processes (Müller*, Tegtmeyer* et al. 2012). Among the proteins involved in the host cytoskeletal network, cortactin appears as one of the favourite targets of microbial effectors. Initial studies on pathogenic Escherichia coli, Neisseria, Listeria, Shigella, Campylobacter, Helicobacter and Staphylococcus, have shown that cortactin may play a role in invasion, actin-based motility, pedestal formation and cell scattering. We have recently shown that this frequently coincides with a change in the localization and/or phosphorylation of cortactin (Tegtmeyer et al. 2011). Thus, cortactin is emerging as important cellular target of microbes, suggesting that it can be regarded as an Achilles heel of the actin cytoskeleton. However, the molecular mechanisms involved in this scenario are widely unknown. In particular, cortactin is a target of various kinases, but it remained unclear which candidate tyrosines (Y-421, Y-470, Y-486) and/or serines (S-113, S-405, S-418) are phosphorylated during infection and which downstream signalling pathways are regulated by individual phospho-sites in cortactin. In particular, we would like to investigate the role of bacterial factors in the modulation of cortactin with emphasis on how they manipulate cortactin phosphorylation to hijack specific cellular signalling pathways. This approach will allow us to reconstruct the sequence of events occurring at the pathogen-host cell interface, and to identify novel key pathogenicity determinants, which are important for the future development of new antimicrobial treatment regimes. * (equal contribution, shared first authorship)

许多微生物病原体操纵其真核宿主的信号转导过程以获得自身利益和疾病发展。细胞骨架的组装在细胞膜动力学、迁移、粘附和转运等重要过程中起着重要作用。因此，通过靶向细胞骨架和各种激酶，病原体可以从根本上迅速重新编程其宿主靶细胞，并可以触发疾病相关过程（Müller*，Tegtmeyer* 等人，2012）。在参与宿主细胞骨架网络的蛋白质中，coronin似乎是微生物效应物最喜欢的靶标之一。对致病性大肠杆菌、奈瑟氏菌、李斯特菌、志贺氏菌、弯曲杆菌、螺杆菌和葡萄球菌的初步研究表明，corneum可能在侵袭、基于肌动蛋白的运动、基座形成和细胞分散中发挥作用。我们最近已经表明，这经常与coronin的定位和/或磷酸化的变化相一致（Tegtmeyer et al. 2011）。因此，corneum是新兴的微生物的重要细胞靶标，这表明它可以被视为肌动蛋白细胞骨架的阿喀琉斯之踵。然而，这种情况所涉及的分子机制尚不清楚。特别是，皮质蛋白是各种激酶的靶标，但仍不清楚哪些候选酪氨酸（Y-421、Y-470、Y-486）和/或丝氨酸（S-113、S-405、S-418）在感染期间被磷酸化，以及哪些下游信号传导途径由皮质蛋白中的各个磷酸化位点调节。特别是，我们想调查的作用，细菌因素的调制corneumn的重点是如何操纵corneumn磷酸化劫持特定的细胞信号通路。这种方法将使我们能够重建发生在病原体-宿主细胞界面的事件序列，并确定新的关键致病性决定因素，这对未来开发新的抗菌治疗方案至关重要。 * （平等贡献，共同第一作者）