PLoS Pathogens:上海交通大学姚玉峰课题组揭示乙酰化修饰对细菌转

2016年3月4日，国际病原物顶级学术期刊《PLOS Pathogens》杂志上以封面论文形式在线发表上海交通大学基础医学院免疫学与微生物学系姚玉峰课题组的最新研究成果Acetylation of lysine 201 inhibits the DNA-binding ability of PhoP to regulate Salmonella virulence。该研究是由博士生任洁、桑昱为论文共同第一作者，姚玉峰教授为论文通讯作者。

无论在发达国家还是发展中国家，沙门菌都是食源性疾病以及腹泻病的主要致病菌。沙门菌感染最常见的症状是肠热症、急性肠炎，一些血清型还会诱导形成败血症、骨髓炎、脑膜炎等。沙门菌全局性双组分调控系统(TCS)的调节蛋白PhoP调控基因组5%基因的表达，参与细菌毒力、适应低浓度Mg2+和弱酸环境以及多种细胞活动。姚玉峰课题组发现蛋白质乙酰化修饰可调控PhoP的活性，PhoP羧基末端螺旋-转角-螺旋模体上第201位保守的赖氨酸(K201)是乙酰化修饰位点，该位点被乙酰化修饰后抑制PhoP与下游基因启动子结合能力。此外，当细菌处于低浓度Mg2+、酸压力以及巨噬细胞中，K201的乙酰化水平急剧降低。K201乙酰化导致鼠伤寒沙门菌引起的动物模型中肠炎和系统性感染显著降低，这意味着K201的去乙酰化状态对沙门菌的致病性非常重要。因此，K201的可逆乙酰化修饰可保证沙门菌迅速地适应外界各种环境压力信号。这些结果支持目前的观点，即处于DNA结合结构域上可逆的赖氨酸乙酰化修饰，作为一个新的调控基因表达的机制，参与细菌毒力的调控，这种机制可能在许多微生物中都普遍存在。相关阅读：J Infect Dis:上海交大姚玉峰课题组发现乙酰化修饰调控沙门菌毒力机制

病原细菌学研究组长期致力于病原菌乙酰化修饰调控机制的研究。该文详细地阐明了乙酰化修饰对细菌转录因子活性的调控机制，揭示了原核生物中乙酰化修饰的功能，为病原菌致病机制提供了新的研究方向。

原文链接：

Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence

原文摘要：

The two-component system PhoP-PhoQ is highly conserved in bacteria and regulates virulence in response to various signals for bacteria within the mammalian host. Here, we demonstrate that PhoP could be acetylated by Pat and deacetylated by deacetylase CobB enzymatically in vitro and in vivo in Salmonella Typhimurium. Specifically, the conserved lysine residue 201(K201) in winged helix–turn–helix motif at C-terminal DNA-binding domain of PhoP could be acetylated, and its acetylation level decreases dramatically when bacteria encounter low magnesium, acid stress or phagocytosis of macrophages. PhoP has a decreased acetylation and increased DNA-binding ability in the deletion mutant of pat. However, acetylation of K201 does not counteract PhoP phosphorylation, which is essential for PhoP activity. In addition, acetylation of K201 (mimicked by glutamine substitute) in S. Typhimurium causes significantly attenuated intestinal inflammation as well as systemic infection in mouse model, suggesting that deacetylation of PhoP K201 is essential for Salmonella pathogenesis. Therefore, we propose that the reversible acetylation of PhoP K201 may ensure Salmonella promptly respond to different stresses in host cells. These findings suggest that reversible lysine acetylation in the DNA-binding domain, as a novel regulatory mechanism of gene expression, is involved in bacterial virulence across microorganisms.

DOI: 10.1371/journal.ppat.1005458

作者：姚玉峰