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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 38; pp. 15461 - 15466
• Main Authors: Sun, Fei, Ding, Yue, Ji, Quanjiang, Liang, Zhongjie, Deng, Xin, Wong, Catherine C. L, Yi, Chengqi, Zhang, Liang, Xie, Sherrie, Alvarez, Sophie, Hicks, Leslie M, Luo, Cheng, Jiang, Hualiang, Lan, Lefu, He, Chuan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.09.2012; National Acad Sciences
• Subjects: Abscess - microbiology; Amino Acid Sequence; Amino acids; animal models; Animals; Antibiotic resistance; Antibiotics; Bacteria; Bacterial Proteins - chemistry; Biological Sciences; ceftriaxone; Cell extracts; Cells; cysteine; Cysteine - chemistry; Drug resistance; Drug Resistance, Microbial; Gene Expression Regulation, Bacterial; Mice; Molecular Sequence Data; Phosphatases; Phosphorylation; Physical Sciences; Physiological regulation; post-translational modification; Protein Binding; Protein Kinase C - metabolism; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - metabolism; Proteins; Rodents; Sequence Homology, Amino Acid; Signal transduction; Staphylococcus aureus; Staphylococcus aureus - metabolism; Trans-Activators - chemistry; transcription factors; Transcription Factors - chemistry; vancomycin; Vancomycin - pharmacology; Virulence; Virulence Factors - metabolism; Yeast
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1205952109

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.