The molecular control of bacterial programmed cell death

对金黄色葡萄球菌Cid和lrg操纵子的研究提供了重要的 洞察细菌毛脲水解酶活性和自溶的调节控制 导致了一个模型，其中该系统在功能上类似于 更复杂的真核生物中的程序性细胞死亡(PCD)。虽然CID和LRG 蛋白质已被证明分别类似于噬菌体Holin和抗Holin， 它们是控制细胞在裂解阶段死亡和裂解的基础。 噬菌体感染，其所利用的精确分子/生化机制 细胞死亡和裂解过程中的细菌对应物仍有待确定。在当前 建议，我们在实验室最近的研究基础上证明细胞质 酸化和丙酮酸代谢是细菌细胞死亡的关键方面，以探测 Cid和LRG蛋白的特殊功能。在第一个具体目标中，我们将利用一种分子 用遗传学方法研究CIDA/B蛋白与丙酮酸的关系 控制细菌细胞死亡的代谢酶。第二个目标将利用生物物理 测试CID和LRG介导的运输是 控制细菌细胞死亡。第三个也是最终目标将探讨CIDR介导的调控 这一系统，重点是鉴定的效应分子(S)，导致其 活动。总体而言，这些目标中描述的实验产生的结果将说明 细菌PCD的分子机制及其代谢调控 它的调节所需的要素，最终导致改进的治疗策略 细菌感染。

Studies of the Staphylococcus aureus cid and lrg operons have provided important insight into the regulatory control of bacterial murein hydrolase activity and autolysis and have led to a model in which this system is functionally analogous to the control elements of programmed cell death (PCD) in more complex eukaryotic organisms. Although the Cid and Lrg proteins have been shown to be similar to bacteriophage holins and antiholins, respectively, which are fundamental to the control of cell death and lysis during the lytic stage of a bacteriophage infection, the precise molecular/biochemical mechanisms utilized by their bacterial counterparts during cell death and lysis remain to be determined. In the current proposal, we have built on recent studies in our laboratory demonstrating that cytoplasmic acidification and pyruvate metabolism are critical aspects of bacterial cell death to probe the specific functions of the Cid and Lrg proteins. In the first specific aim we will utilize a molecular genetic approach to examine the relationship between the CidA/B proteins and pyruvate metabolic enzymes in the control of bacterial cell death. The second aim will utilize a biophysical approach to test the model that Cid- and Lrg-mediated transport is a fundamental aspect of the control of bacterial cell death. The third and final aim will explore the CidR-mediated regulation of this system with a focus on the identification of the effector molecule(s) that induces its activity. Overall, the results generated by the experiments described in these aims will illuminate the molecular mechanisms underlying bacterial PCD and uncover the metabolic control elements required for its regulation, ultimately leading to improved therapeutic strategies to fight bacterial infections.