Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance

Fei Sun, Yue Ding, Quanjiang Ji, Zhongjie Liang, Xin Deng, Catherine C.L. Wong, Chengqi Yi, Liang Zhang, Sherrie Xie, Sophie Alvarez, Leslie M. Hicks, Cheng Luo, Hualiang Jiang, Lefu Lan, Chuan He

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102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15461-15466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number38
DOIs
StatePublished - Sep 18 2012

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Keywords

  • Ser/Thr kinase PknB
  • Transcriptional regulation

ASJC Scopus subject areas

  • General

Cite this

Sun, F., Ding, Y., Ji, Q., Liang, Z., Deng, X., Wong, C. C. L., Yi, C., Zhang, L., Xie, S., Alvarez, S., Hicks, L. M., Luo, C., Jiang, H., Lan, L., & He, C. (2012). Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance. Proceedings of the National Academy of Sciences of the United States of America, 109(38), 15461-15466. https://doi.org/10.1073/pnas.1205952109