Role of Clp proteins in pathophysiology of Streptococcus mutans

摘要 变形链球菌被认为是龋病的主要病原菌。变形链球菌也是一种 感染性心内膜炎的重要因素。这种有机体通过形成各种不同的、 牙面上的多种生物膜，称为牙菌斑。在充满敌意的环境中生存 口腔中的变形链球菌已经形成了一种强大的应激耐受反应，这种反应依赖于调节 蛋白质对受损或错误折叠的蛋白质的分解。细菌中受调控的蛋白分解主要受 酪蛋白水解酶(CLP)-一种蛋白质家族，由一种小的细胞质丝氨酸蛋白酶组成， 称为ClpP，以及各种ATPase。ClpP与伙伴ATPase结合形成功能复合体，该复合体 专门针对降解或易位的蛋白质。而ClpP使损坏/错误折叠的 蛋白质，它是决定底物专一性的ATPase成分。在变形链球菌中，CLP系统， 除了对胁迫的耐受反应外，生物膜的形成、细菌素的产生、 能力发展、细胞间通讯和噬菌体抗药性。中电系统运作良好 在大肠杆菌中研究，它编码两种主要的ATPase：ClpA和ClpX。而链球菌， 包括变形链球菌在内，它们不编码ClpA，但编码ClpX。此外，另外两个ATPase，ClpC和 在大肠杆菌中不存在的CLPE只存在于链球菌和其他菌种中。很少有 已知链球菌的底物专一性或蛋白质降解的分子机制 将军。这个项目的第一个主要目标是在分子水平上了解ClpX是如何识别和 降解底物蛋白并调节各种毒力性状。第二个主要目标是理解 CLPE在变形链球菌应激反应和病理生理学中的作用 一种重要的ATPase。我们预计，该项目的完成将导致小说的鉴定 变形链球菌蛋白质质量控制的调控途径和新角色。此外，所获得的知识 该项目还可以推广到其他重要的病原体，如肺炎链球菌和链球菌。 并可能导致一种新的调控途径的鉴定。

ABSTRACT Streptococcus mutans is considered the major etiological agent in dental caries. S. mutans is also an important agent of infective endocarditis. The organism colonizes the oral cavity by forming diverse, multispecies biofilms on the tooth surface, known as dental plaque. To survive in the hostile environment of the oral cavity, S. mutans has developed a robust stress tolerance response that depends on regulated proteolysis of damaged or misfolded proteins. Regulated proteolysis in bacteria is primarily controlled by the Clp (caseinolytic protease)-family of proteins that are composed of a small cytoplasmic serine protease, called ClpP, and various ATPases. ClpP associates with a partner ATPase to form a functional complex that specifically targets proteins for degradation or translocation. While ClpP degrades the damaged/misfolded protein, it is the ATPase component that determines the substrate specificity. In S. mutans, the Clp-system, in addition to stress tolerance responses, is also required for biofilm formation, bacteriocin production, competence development, cell-cell communications, and bacteriophage resistance. The Clp-system is well studied in Escherichia coli in which it encodes two major ATPases: ClpA and ClpX. While streptococci, including S. mutans, do not encode ClpA, they do encode ClpX. Furthermore, two other ATPases, ClpC and ClpE, which are absent in E. coli, are uniquely present in streptococci and other Fermicutes. Very little is known about the substrate specificity or the molecular mechanisms of protein degradation in streptococci in general. The first major goal of this project is to understand at the molecular level how ClpX recognizes and degrades substrate proteins and regulates various virulence traits. The second major aim is to understand the role of ClpE in stress response and pathophysiology in S. mutans since our studies indicate that ClpE is an important ATPase. We anticipate that completion of this project will lead to the identification of novel regulatory pathways and new players for protein quality control in S. mutans. Moreover, knowledge acquired from this project can also be extended to other important pathogens such as S. pneumoniae and S. pyogenes, and may lead to the identification of a novel regulatory pathway.