Metabolic sensor governing bacterial virulence in Staphylococcus aureus

doi:10.1073/pnas.1411077111

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Metabolic sensor governing bacterial virulence in Staphylococcus aureus
	Ding, Yue 4; Liu, Xing 5; Chen, Feifei 4; Di, Hongxia 4; Xu, Bin4 ; Zhou, Lu 1; Deng, Xin 2,6; Wu, Min 3; Yang, Cai-Guang5 ; Lan, Lefu4
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2014-11-18
卷号	111 期号:46 页码:E4981-E4990
关键词	Staphylococcus aureus metabolism iron acquisition virulence gene expression bacterial virulence
ISSN号	0027-8424
DOI	10.1073/pnas.1411077111
文献子类	Article
英文摘要	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.
资助项目	National Natural Science Foundation of China[21472207] ; National Natural Science Foundation of China[31270126] ; National Natural Science Foundation of China[91313303] ; Shanghai Committee of Science and Technology[12JC1410200] ; Shanghai Committee of Science and Technology[12ZR1453200] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507009-015] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507-004] ; Hundred Talents Program of the Chinese Academy of Sciences[00000000]
WOS关键词	TRANSCRIPTIONAL REGULATORS ; CAPSULAR POLYSACCHARIDES ; PATHOGENIC BACTERIA ; CARBON METABOLISM ; BACILLUS-SUBTILIS ; STATIONARY-PHASE ; CYCLE ACTIVITY ; CELL-GROWTH ; IN-VITRO ; PROTEINS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000345153300013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276831]
专题	药理学第三研究室
通讯作者	Yang, Cai-Guang
作者单位	1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China; 2.Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA; 3.Univ N Dakota, Sch Med & Hlth Sci, Dept Basic Sci, Grand Forks, ND 58203 USA 4.Chinese Acad Sci, Dept Mol Pharmacol, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China; 6.Univ Chicago, Dept Chem, Chicago, IL 60637 USA;
推荐引用方式 GB/T 7714	Ding, Yue,Liu, Xing,Chen, Feifei,et al. Metabolic sensor governing bacterial virulence in Staphylococcus aureus[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2014,111(46):E4981-E4990.
APA	Ding, Yue.,Liu, Xing.,Chen, Feifei.,Di, Hongxia.,Xu, Bin.,...&Lan, Lefu.(2014).Metabolic sensor governing bacterial virulence in Staphylococcus aureus.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,111(46),E4981-E4990.
MLA	Ding, Yue,et al."Metabolic sensor governing bacterial virulence in Staphylococcus aureus".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111.46(2014):E4981-E4990.