title: Metabolic sensor governing bacterial virulence in Staphylococcus aureus.
abstract: An effective metabolism is essential to all living organisms, including the important human pathogen Staphylococcus aureus. To establish successful infection, S. aureus must scavenge nutrients and coordinate its metabolism for proliferation. Meanwhile, it also must produce an array of virulence factors to interfere with host defenses. However, the ways in which S. aureus ties its metabolic state to its virulence regulation remain largely unknown. Here we show that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, binds to and activates the catabolite control protein E (CcpE) of S. aureus. Using structural and site-directed mutagenesis studies, we demonstrate that two arginine residues (Arg145 and Arg256) within the putative inducer-binding cavity of CcpE are important for its allosteric activation by citrate. Microarray analysis reveals that CcpE tunes the expression of 126 genes that comprise about 4.7% of the S. aureus genome. Intriguingly, although CcpE is a major positive regulator of the TCA-cycle activity, its regulon consists predominantly of genes involved in the pathogenesis of S. aureus. Moreover, inactivation of CcpE results in increased staphyloxanthin production, improved ability to acquire iron, increased resistance to whole-blood-mediated killing, and enhanced bacterial virulence in a mouse model of systemic infection. This study reveals CcpE as an important metabolic sensor that allows S. aureus to sense and adjust its metabolic state and subsequently to coordinate the expression of virulence factors and bacterial virulence.
authors.affiliation: Department of Molecular Pharmacology and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology and.
authors.forename: Feifei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology and.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Di
authors.affiliation: Department of Molecular Pharmacology and.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China;
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637; and.
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Basic Sciences University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; yangcg@simm.ac.cn llan@mail.shcnc.ac.cn.
authors.forename: Cai-Guang
authors.initials: CG
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology and yangcg@simm.ac.cn llan@mail.shcnc.ac.cn.
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
mesh_terms: D000038:Abscess / Q000382:microbiology; D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D019343:Citric Acid / Q000378:metabolism; D018360:Crystallography, X-Ray; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D007501:Iron / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010858:Pigmentation / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D014158:Transcription, Genetic / Q000502:physiology; D014774:Virulence / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D012097:Repressor Proteins; C069286:catabolite control proteins, bacteria; D019343:Citric Acid; D001120:Arginine; D007501:Iron; D000154:Aconitate Hydratase
keywords: Staphylococcus aureus; bacterial virulence; iron acquisition; metabolism; virulence gene expression