Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15461-6. doi: 10.1073/pnas.1205952109. Epub 2012 Aug 27.
Protein posttranslational modifications (PTMs), particularly phosphorylation, dramatically expand the complexity of cellular regulatory networks. Although cysteine (Cys) in various proteins can be subject to multiple PTMs, its phosphorylation was previously considered a rare PTM with almost no regulatory role assigned. We report here that phosphorylation occurs to a reactive cysteine residue conserved in the staphylococcal accessary regulator A (SarA)/MarR family global transcriptional regulator A (MgrA) family of proteins, and is mediated by the eukaryotic-like kinase-phosphatase pair Stk1-Stp1 in Staphylococcus aureus. Cys-phosphorylation is crucial in regulating virulence determinant production and bacterial resistance to vancomycin. Cell wall-targeting antibiotics, such as vancomycin and ceftriaxone, inhibit the kinase activity of Stk1 and lead to decreased Cys-phosphorylation of SarA and MgrA. An in vivo mouse model of infection established that the absence of stp1, which results in elevated protein Cys-phosphorylation, significantly reduces staphylococcal virulence. Our data indicate that Cys-phosphorylation is a unique PTM that can play crucial roles in bacterial signaling and regulation.
蛋白质翻译后修饰（PTMs），特别是磷酸化，极大地扩展了细胞调控网络的复杂性。尽管各种蛋白质中的半胱氨酸（Cys）可以受到多种 PTM 的影响，但以前认为其磷酸化是一种罕见的 PTM，几乎没有赋予其任何调控作用。我们在这里报告，磷酸化发生在葡萄球菌辅助调节因子 A（SarA）/MarR 家族全局转录调节因子 A（MgrA）家族的蛋白质中的一个保守的反应性半胱氨酸残基上，并且由金黄色葡萄球菌中的真核样激酶-磷酸酶对 Stk1-Stp1 介导。Cys 磷酸化在调节毒力决定因子的产生和细菌对万古霉素的耐药性方面至关重要。靶向细胞壁的抗生素，如万古霉素和头孢曲松，抑制 Stk1 的激酶活性，导致 SarA 和 MgrA 的 Cys 磷酸化减少。体内感染小鼠模型表明，缺失 stp1 会导致蛋白质 Cys 磷酸化升高，从而显著降低金黄色葡萄球菌的毒力。我们的数据表明，Cys 磷酸化是一种独特的 PTM，可在细菌信号转导和调控中发挥关键作用。
