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

许多微生物病原体为了自身的利益和疾病的发展而操纵真核宿主的信号转导过程。细胞骨架组装在许多重要的细胞过程中起着重要作用，如膜动力学、迁移、粘附和运输。因此，通过靶向细胞骨架和各种激酶，病原体可以从根本上快速地对宿主靶细胞进行重编程，并触发疾病相关过程（m<s:1> ller*, Tegtmeyer* et al. 2012）。在参与宿主细胞骨架网络的蛋白质中，接触蛋白似乎是微生物效应物最喜欢的靶标之一。对致病性大肠埃希菌、奈瑟菌、李斯特菌、志贺氏菌、弯曲菌、幽门螺杆菌和葡萄球菌的初步研究表明，接触可能在侵袭、肌动蛋白运动、基座形成和细胞散射中发挥作用。我们最近的研究表明，这经常与接触蛋白的定位和/或磷酸化的变化相吻合（Tegtmeyer等人，2011）。因此，接触蛋白正成为微生物重要的细胞靶标，这表明它可以被视为肌动蛋白细胞骨架的致命弱点。然而，在这种情况下涉及的分子机制是广泛未知的。特别是，接触蛋白是多种激酶的靶标，但目前尚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，以及哪些下游信号通路由接触蛋白中单个磷酸化位点调节。特别是，我们想研究细菌因子在皮质蛋白调节中的作用，重点是它们如何操纵皮质蛋白磷酸化来劫持特定的细胞信号通路。这种方法将使我们能够重建在病原体-宿主细胞界面发生的事件序列，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非常重要。*（同等贡献，共享第一作者）

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)