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PNAS 109 (38): 15461-15466

Copyright © 2012 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHYSICAL SCIENCES / MICROBIOLOGY / CHEMISTRY

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

Fei Suna, Yue Dingb, Quanjiang Jia, Zhongjie Liangb, Xin Denga, Catherine C. L. Wongc, Chengqi Yia, Liang Zhanga, Sherrie Xiea, Sophie Alvarezd, Leslie M. Hicksd, Cheng Luob, Hualiang Jiangb, Lefu Lanb,1, and Chuan Hea,1

aDepartment of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637; bShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; c The Scripps Research Institute, San Diego, CA 92121; and d Donald Danforth Plant Science Center, St. Louis, MO 63132

Edited by Richard P. Novick, New York University School of Medicine, New York, NY, and approved July 27, 2012 (received for review April 8, 2012)

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.

Key Words: Ser/Thr kinase PknB • transcriptional regulation

Author contributions: F.S., L.L., and C.H. designed research; F.S., Y.D., Q.J., Z.L., X.D., C.C.L.W., S.X., and L.L. performed research; F.S., Y.D., Q.J., Z.L., X.D., C.C.L.W., C.Y., L.Z., S.A., L.M.H., C.L., H.J., and L.L. contributed new reagents/analytic tools; F.S., Q.J., Z.L., L.L., and C.H. analyzed data; and F.S., L.L., and C.H. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1205952109/-/DCSupplemental.

1To whom correspondence may be addressed. E-mail: llan{at}mail.shcnc.ac.cn or chuanhe{at}uchicago.edu.

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