Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence.
Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence.
复制标题
赖氨酸 201 的乙酰化抑制 PhoP 调节沙门氏菌毒力的 DNA 结合能力
DOI：
10.1371/journal.ppat.1005458
复制
发表时间：
2016-03
期刊：
影响因子：
6.7
通讯作者：
Yao YF
中科院分区：
文献类型：
--
作者：
Ren J;Sang Y;Tan Y;Tao J;Ni J;Liu S;Fan X;Zhao W;Lu J;Wu W;Yao YF
双组分系统PhoP-PhoQ在细菌中高度保守，并响应哺乳动物宿主内细菌的各种信号调节毒力。在这里，我们表明，PhoP可以乙酰化的帕特和脱乙酰基酶CobB酶在体外和体内的鼠伤寒沙门氏菌。PhoP蛋白C端DNA结合域的螺旋-转角-螺旋基序中保守的赖氨酸残基201（K201）可被乙酰化，当细菌受到低镁、酸胁迫或巨噬细胞吞噬作用时，其乙酰化水平显著降低。PhoP在pat缺失突变体中乙酰化程度降低，DNA结合能力增强。然而，K201的乙酰化并不抵消PhoP磷酸化，这是PhoP活性所必需的。此外，K201在S.鼠伤寒沙门氏菌在小鼠模型中引起显著减弱的肠道炎症以及全身感染，表明PhoP K201的脱乙酰化对于沙门氏菌的发病机制是必需的。因此，我们认为PhoP K201的可逆乙酰化可以确保沙门氏菌迅速响应宿主细胞中的不同应激。这些发现表明，可逆的赖氨酸乙酰化的DNA结合域，作为一种新的基因表达调控机制，参与细菌的毒力在微生物。
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.