Role of Clp proteins in pathophysiology of Streptococcus mutans

摘要 变形链球菌被认为是龋齿的主要病原体。变形链球菌也是 感染性心内膜炎的重要病原体。该生物体通过形成多种、 牙齿表面的多物种生物膜，称为牙菌斑。为了在恶劣的环境中生存 在口腔中，变形链球菌已经形成了强大的应激耐受反应，这取决于调节 受损或错误折叠蛋白质的蛋白水解。细菌中调节的蛋白水解作用主要由 Clp（酪蛋白分解酶）- 由小型细胞质丝氨酸蛋白酶组成的蛋白质家族， 称为 ClpP 和各种 ATP 酶。 ClpP 与伙伴 ATP 酶结合形成功能复合物， 专门针对蛋白质进行降解或易位。虽然 ClpP 会降解损坏/错误折叠的 蛋白质，它是决定底物特异性的 ATP 酶成分。在变形链球菌（S. mutans）的 Clp 系统中， 除了应激耐受反应之外，生物膜形成、细菌素生产也需要， 能力发展、细胞间通讯和噬菌体抗性。 Clp系统很好 在大肠杆菌中进行了研究，它编码两种主要的 ATP 酶：ClpA 和 ClpX。而链球菌， 包括变形链球菌，不编码 ClpA，它们编码 ClpX。此外，另外两种 ATP 酶 ClpC 和 ClpE 在大肠杆菌中不存在，但在链球菌和其他费米菌中独特存在。很少的是 了解链球菌的底物特异性或蛋白质降解的分子机制 一般。该项目的第一个主要目标是在分子水平上了解 ClpX 如何识别和 降解底物蛋白并调节各种毒力特征。第二个主要目标是了解 ClpE 在变形链球菌应激反应和病理生理学中的作用，因为我们的研究表明 ClpE 是 一种重要的 ATP 酶。我们预计该项目的完成将导致识别新的 变异链球菌蛋白质质量控制的调控途径和新参与者。此外，所获得的知识 该项目还可以扩展到其他重要病原体，例如肺炎链球菌和金黄色葡萄球菌。 化脓性，并可能导致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.