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体。S. mutans也是一种 感染性心内膜炎重要因素。该生物体通过形成多种多样的， 牙齿表面的多物种生物膜，称为牙菌斑。在充满敌意的环境中生存 口腔S.变形杆菌已经发展出一种强大的应激耐受反应， 受损或错误折叠的蛋白质的蛋白水解。细菌中受调节的蛋白质水解主要由 Clp（酪蛋白分解蛋白酶）-由小的细胞质丝氨酸蛋白酶组成的蛋白质家族， ClpP和各种ATP酶。ClpP与伴侣ATP酶结合形成功能复合物， 特异性靶向蛋白质降解或移位。虽然ClpP降解了受损/错误折叠的 蛋白质，它是决定底物特异性的ATP酶组分。In S.变异株，Clp系统， 除了胁迫耐受性反应之外，也是生物膜形成，细菌素产生， 能力发展、细胞间通讯和噬菌体抗性。CLP系统是好的 在大肠杆菌中研究，其中它编码两种主要ATP酶：ClpA和ClpX。而链球菌， 包括S.变异体不编码ClpA，它们编码ClpX。此外，另外两种ATP酶ClpC和 ClpE，在E.大肠杆菌中，是唯一存在于链球菌和其他Fermicutes。之甚少 关于底物特异性或链球菌中蛋白质降解的分子机制， 将军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性状。第二个主要目的是了解 ClpE在S.因为我们的研究表明ClpE是 重要的ATP酶我们预计，该项目的完成将导致新的识别 调节途径和新的球员蛋白质质量控制在S。变异人此外，获得的知识 从这个项目也可以扩展到其他重要的病原体，如S。pneumoniae和S. 化脓性链球菌，并可能导致一种新的调节途径的鉴定。

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.