Virulence Regulation by the Mycobacterium tuberculosis Proteasome

描述（由申请人提供）：全球每年约有200万人死于结核病。抗结核分枝杆菌（Mtb）感染的关键防御是巨噬细胞产生一氧化氮（NO）。虽然NO能控制结核分枝杆菌的生长，但它很少能使来自宿主的细菌绝育，这表明结核分枝杆菌具有抵抗NO毒性的机制。Mtb蛋白酶体就是抵抗NO所必需的一种机制。蛋白酶体是一种多亚基，桶状复合物，降解蛋白质，在生命的所有领域都是保守的。除了提供对NO的抗性外，Mtb蛋白酶体在小鼠中引起致命感染是必要的。我们目前正试图了解蛋白质水解与NO抗性以及保护Mtb免受其他宿主防御的关系。在我们的研究中，我们有两个重大发现：Mtb蛋白酶体调节(1)一种酶的稳定性，这种酶被预测用于催化细胞分裂素的产生，其活性与NO抗性有关；(2)一种新的铜电阻规则的表达式。我们正在努力描述蛋白酶体如何参与这些途径，这方面的知识可能有助于我们更好地了解世界上最致命的疾病之一的发病机制。

DESCRIPTION (provided by applicant): Tuberculosis kills about 2 million people globally every year. A key defense against Mycobacterium tuberculosis (Mtb) infections is the production of nitric oxide (NO) by macrophages. Although NO controls Mtb growth, it rarely sterilizes the bacterium from the host, suggesting Mtb has mechanisms to resist NO toxicity. The Mtb proteasome is one such mechanism that is required for resistance to NO. The proteasome is a multi-subunit, barrel shaped complex that degrades proteins and is conserved in all domains of life. In addition to providing resistance to NO, the Mtb proteasome is necessary to cause lethal infections in mice. We are currently trying to understand how proteolysis is linked to NO resistance as well as protecting Mtb against other host defenses. We have made two substantial discoveries during our studies: the Mtb proteasome regulates (1) the stability of an enzyme predicted to catalyze the production of cytokinins, the activity of which is linked to NO resistance; and (2) the expression of a novel copper-resistance regulon. We are working to characterize how the proteasome participates in these pathways, the knowledge of which may help us better understand the pathogenesis of one of the world's deadliest diseases.