PROTEASOMAL REGULATION AND PROTEIN QUALITY CONTROL IN M. TUBERCULOSIS

结核病每年在全球造成近200万人死亡。多年来，我们一直认为， 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）蛋白酶体是结核杆菌在动物体内生存所必需的。 蛋白酶体是多亚基、桶形蛋白酶，其以高度调节的方式降解蛋白质。 我们目前正在研究蛋白质水解是如何调节的，从蛋白质是如何被标记的唯一已知的 细菌蛋白质对蛋白质的翻译后修饰，然后如何将这些标记的蛋白质递送到 蛋白酶体核心蛋白酶。其次，本建议将试图了解一个基本的功能， 由蛋白酶体降解调节的蛋白质质量控制系统。了解这个系统如何 有助于结核病生理学的研究可能会发现对抗结核病感染的新方法。这些研究将 揭示了蛋白酶体如何感知细胞外信号，以优化致命感染所需的细菌生长。

Tuberculosis kills nearly 2 million people globally every year. Over the years, we have determined that the Mycobacterium tuberculosis (Mtb) proteasome is essential to allow the tubercle bacilli to persist in animals. Proteasomes are multi-subunit, barrel shaped proteases that degrade proteins in a highly regulated manner. We are currently examining how proteolysis is regulated, from how proteins are tagged with the only known bacterial protein-on-protein post-translational modification to how those tagged proteins are then delivered into the proteasome core protease. Secondly, this proposal will seek to understand the functions of an essential protein quality control system that is regulated by proteasomal degradation. Identifying how this system contributes to Mtb physiology may identify new ways to combat tuberculosis infections. Thus, these studies will reveal how a proteasome senses extracellular signals to optimize bacterial growth required for lethal infections.