Peptide Mediated Cell-Cell Communications in Streptococcus mutans

摘要： 变形链球菌是一种与龋齿密切相关的微生物，它利用基于多肽的细胞密度。 独立的信号系统称为群体感应(QS)。这条信号通路负责 控制主要毒力性状，如细菌素产生、生物膜形成、能力发育、 以及压力耐受性。在变形链球菌中，负责细胞间交流的多肽之一是能力- 刺激肽(CSP)。CSP作为一种信号分子激活双组分信号转导 一条称为ComDE的路径。CSP是在细胞内合成的46个残基的前肽，其中 N-末端25个残基作为前导肽。在通过专用ABC转运体分泌的过程中， 前导肽被切割，成熟的21个残基的长肽(CSP21)集中在环境中。 我们小组首次发现了CSP分泌所必需的ABC转运蛋白(NlmTE)。我们 还发现CSP21进一步被一种高度保守的细胞表面相关蛋白酶加工，该酶 我们将其命名为SEPM。我们发现SEPM在C-末端裂解CSP21，产生一个18个残基的长 活性信号分子(CSP18)。当胞外CSP18浓度达到临界密度时， COMD感受器激酶被该多肽激活。然后，被激活的COMD刺激COME响应 调节子和各种观察到的表型变化所必需的基因都是由激活的 来。虽然ComDE途径在表型水平上得到了很好的研究，但其分子机制是通过 究竟是哪一种CSP激活了这一信号通路，目前尚无定论。在本申请中，我们建议研究 CSP介导变形链球菌细胞间通讯的分子机制。成功完成 本研究可能通过抑制变形链球菌生物被膜的形成来阐明其分子基础。 细胞间通讯中断。

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.