我们前期研究发现鼠伤寒沙门菌双组份系统转录因子PhoP在多个赖氨酸残基上存在可逆的乙酰化修饰，且乙酰化修饰抑制PhoP的DNA结合能力或磷酸化，并最终调控沙门菌的毒力。初步研究显示PhoP还存在甲基化和磷酸化等修饰，那么这些翻译后修饰是否存在生物学功能，如何响应外界环境并动态变化，以及调控PhoP活性的机制等问题亟需解决。为此，本项目将以PhoP为研究对象，研究不同生长条件下PhoP翻译后修饰种类和位点，探索这些翻译后修饰响应环境压力的规律，阐明代谢中间产物和翻译后修饰酶对PhoP翻译后修饰的协同调节机制。从而揭示翻译后修饰之间的相互作用网络以及调控PhoP活性的机理，为理解沙门菌致病机制提供新思路，以及为其他病原菌致病机制研究做出科学范例。

Protein post-translational modification (PTM) is one of important regulatory approaches in eukaryotes, and is a critical topic in the study of proteomics. PTMs have been found to be extensively occurred in prokaryotes and play an important role in cellular signal transduction, metabolism and bacterial pathogenesis. In our previous study, we have identified multiple lysine residues acetylation on a two component system regulator PhoP in Salmonella Typhimurium, and acetylation regulates the activities of PhoP, ultimately modulates bacterial virulence. Our preliminary data also show the existence and importance of methylation and phosphorylation on PhoP. However, it is still unclear whether there are other PTMs on PhoP and how these modifications coordinately regulate the activities of PhoP. To address these key questions, this proposal is aimed to study the global PTMs of PhoP in S. Typhimurium under different conditions, identify the law of dynamic change of PTMs and reveal the molecular regulatory mechanism of PTMs on PhoP. Moreover, we will explore the crosstalks between different PTMs and their roles in regulation of PhoP activities. The information derived from this application will provide a new perspective for understanding the pathogenesis of Salmonella.