title: Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance.
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.
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Ji
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.forename: Chengqi
authors.initials: C
authors.lastname: Yi
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Sherrie
authors.initials: S
authors.lastname: Xie
authors.forename: Sophie
authors.initials: S
authors.lastname: Alvarez
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Hicks
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000038:Abscess / Q000382:microbiology; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D004352:Drug Resistance, Microbial; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*; D014640:Vancomycin / Q000494:pharmacology; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C088021:SarA protein, bacterial; C534537:SarZ protein, Staphylococcus aureus; D015534:Trans-Activators; D014157:Transcription Factors; D037521:Virulence Factors; D014640:Vancomycin; C061570:protein kinase N; D017346:Protein Serine-Threonine Kinases; C546823:Stk1 protein, Staphylococcus aureus; D011493:Protein Kinase C; D003545:Cysteine