A novel mode of regulation of the Staphylococcus aureus Vancomycin-resistance-associated response regulator VraR mediated by Stk1 protein phosphorylation
A novel mode of regulation of the Staphylococcus aureus Vancomycin-resistance-associated response regulator VraR mediated by Stk1 protein phosphorylation
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DOI：
10.1016/j.bbrc.2014.03.128
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发表时间：
2014-04-25
影响因子：
3.1
通讯作者：
Molle, Virginie
中科院分区：
文献类型：
--
作者：
Canova, Marc J.;Baronian, Gregory;Molle, Virginie
金黄色葡萄球菌万古霉素耐药相关反应调节因子VraR被认为是一种重要的反应调节因子，是VraTSR三组分信号转导系统的成员，该系统调节细胞壁应激刺激子的表达以响应许多不同的细胞壁活性抗生素。鉴于其在调节基因表达以应对抗生素挑战中的关键作用，VraR必须受到严格调控。我们在这里报告的第一次在S。金黄色葡萄球菌会聚的两个主要信号转导系统，丝氨酸/苏氨酸蛋白激酶和二（三）组分系统。我们证明，VraR可以被葡萄球菌丝氨酸/苏氨酸蛋白激酶Stk 1磷酸化，磷酸化会对其DNA结合特性产生负面影响。质谱分析和定点诱变鉴定Thr 106，Thr 119，Thr 175和Thr 178为磷酸受体。色葡萄与野生型相比，表达模拟组成性磷酸化的VraR衍生物VraR_Asp的金黄色葡萄球菌Delta vraR突变体仍然表现出对不同细胞壁活性抗生素的显著降低的抗生素抗性，这表明VraR磷酸化可能代表葡萄球菌中两（三）组分系统的新的且可能更普遍的调节机制。(C)2014爱思唯尔公司All rights reserved.
The Staphylococcus aureus Vancomycin-resistance-associated response regulator VraR is known as an important response regulator, member of the VraTSR three-component signal transduction system that modulates the expression of the cell wall stress stimulon in response to a number of different cell wall active antibiotics. Given its crucial role in regulating gene expression in response to antibiotic challenges, VraR must be tightly regulated. We report here for the first time in S. aureus convergence of two major signal transduction systems, serine/threonine protein kinase and two (three)-component systems. We demonstrate that VraR can be phosphorylated by the staphylococcal Ser/Thr protein kinase Stk1 and that phosphorylation negatively affects its DNA-binding properties. Mass spectrometric analyses and site-directed mutagenesis identified Thr106, Thr119, Thr175 and Thr178 as phosphoacceptors. A S. aureus Delta vraR mutant expressing a VraR derivative that mimics constitutive phosphorylation, VraR_Asp, still exhibited markedly decreased antibiotic resistance against different cell wall active antibiotics, when compared to the wild-type, suggesting that VraR phosphorylation may represent a novel and presumably more general mechanism of regulation of the two (three)-component systems in staphylococci. (C) 2014 Elsevier Inc. All rights reserved.