Peptide Mediated Cell-Cell Communications in Streptococcus mutans

变形链球菌中肽介导的细胞间通讯

• 批准号: 9532812
• 负责人: SASWATI BISWAS
• 金额: $ 36.34万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9532812
• 关键词: ATP-Binding Cassette Transporters; Attention; Binding; C-terminal; Cell Communication; Cell Density; Cell surface; Cells; Cleaved cell; Communicable Diseases; Communication; Competence; Complex; Dental Plaque; Dental caries; Developed Countries; Developing Countries; Development; Direct Repeats; Disease; Economic Burden; Endocarditis; Environment; Evaluation; Future; Genes; Genetic; Glycine; Goals; Gram-Positive Bacteria; In Vitro; Integration Host Factors; Knowledge; Light; Mediating; Membrane; Microbial Biofilms; Molecular; N-terminal; Names; Oral; Organism; Pathogenicity; Pathway interactions; Peptide Hydrolases; Peptide Leader Sequences; Peptide Signal Sequences; Peptides; Phenotype; Pheromone; Phosphorylation; Phosphotransferases; Physiological Processes; Process; Production; Promoter Regions; Protease Domain; Regulation; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Specificity; Streptococcus; Streptococcus mutans; Substrate Specificity; Surface; System; Testing; Translating; Virulence; analog; bacteriocin; base; biological adaptation to stress; density; extracellular; inorganic phosphate; intercellular communication; novel; oral bacteria; oral pathogen; oral streptococci; protein-histidine kinase; quorum sensing; response; sensor; stress tolerance; tooth surface; trait

ABSTRACT: Streptococcus mutans, an organism strongly associated with dental caries, utilizes a peptide-based cell density dependent signaling system known as quorum-sensing (QS). This signaling pathway is responsible for controlling major virulence traits such as bacteriocin production, biofilm formation, competence development, and stress tolerance. In S. mutans, one of the peptides responsible for cell-cell communication is competence- stimulating peptide (CSP). CSP acts as a signaling molecule to activate a two-component signal transduction pathway called ComDE. CSP is synthesized inside the cell as a pre-peptide of 46-residues long, in which the N-terminal 25-residue functions as a leader peptide. During secretion through a dedicated ABC transporter, the leader peptide is cleaved and the matured 21-residue long peptide (CSP21) is concentrated in the milieu. Our group was the first to identify the dedicated ABC transporter (NlmTE) necessary for CSP secretion. We also discovered that CSP21 is further processed by a highly conserved cell-surface associated protease, which we named SepM. We found that SepM cleaves CSP21 at the C-terminal end to create an 18-residue long active signaling molecule (CSP18). When extracellular concentration of CSP18 reaches a critical density, the ComD sensor kinase is activated by the peptide. The activated ComD then stimulates the ComE response regulator and a variety of genes necessary for the observed phenotypic changes are induced by the activated ComE. While the ComDE pathway is well studied at the phenotypic level, the molecular mechanisms by which CSP activates this signaling pathway have not been evaluated. In this application we propose to study the molecular mechanisms of CSP mediated cell-cell communication in S. mutans. Successful completion of this study could shed light on the molecular basis for inhibition of S. mutans biofilm formation through disruption of cell-cell communication.

摘要： 变形链球菌，一种与龋齿密切相关的生物体，利用基于肽的细胞密度 依赖的信号系统称为群体感应（QS）。这种信号通路负责 控制主要毒力性状，如细菌素产生、生物膜形成、感受态发育， 和压力耐受性。In S.变异体，负责细胞间通讯的肽之一是感受态- 刺激肽（CSP）。CSP作为信号分子激活双组分信号转导 称为ComDE的途径。CSP在细胞内合成为46个残基长的前肽，其中 N-末端25个残基作为前导肽发挥作用。在通过专用ABC转运蛋白分泌期间， 前导肽被切割，成熟的21-残基长肽（CSP 21）在环境中浓缩。 我们的小组是第一个确定CSP分泌所必需的专用ABC转运蛋白（NlmTE）的。我们 还发现CSP 21被一种高度保守的细胞表面相关蛋白酶进一步加工， 我们命名为SepM。我们发现SepM在C末端切割CSP 21，产生一个18个残基长的 活性信号分子（CSP 18）。当CSP 18的细胞外浓度达到临界密度时， ComD传感器激酶被肽激活。激活的ComD然后刺激ComE反应 调节子和观察到的表型变化所必需的多种基因由激活的 来了虽然ComDE途径在表型水平上得到了很好的研究，但其分子机制仍有待进一步研究。 哪种CSP激活该信号通路尚未被评估。在本申请中，我们建议研究 CSP介导S.变异人成功完成 本研究为进一步阐明S.变形菌生物膜形成， 破坏细胞间的通讯。