PI31: a regulator of proteasome adaptation to stress

摘要 蛋白酶体催化的蛋白分解是大多数重要真核生物的中心调节元件 细胞过程。蛋白酶体功能在多个水平上被调节，包括多个 蛋白酶体全酶，全酶的相对和绝对量的变化，以及直接 全酶活性的控制。蛋白酶体全酶由一个蛋白酶核心复合体组成。 (20S蛋白酶体)可互换地结合到多个调节复合体中的任何一个。这样做的目的是 研究是为了发现PI31的生理作用，PI31是人们了解最少、研究最少的 蛋白酶体调节因子，并确定其功能和调控的分子和细胞基础。 该项目的前提是PI31介导依赖蛋白酶体的细胞变化 蛋白质在细胞应激过程中的降解。我们将测试PI31施加的一般假设 这种作用是通过调节蛋白酶体的含量、组成和/或功能来应对压力的。 我们还将检验PI31的作用受可逆的PI31翻译后调控的假设 由特定的应激诱导信号提示的修饰。我们将采用一套配套的 细胞和分子方法来确定PI31完成其作用的机制， PI31翻译后修饰对这些机制的调节及其生理意义 这些影响的重要性。 蛋白酶体催化的蛋白质降解在正常细胞功能中的普遍作用 监管解释了为什么许多疾病与蛋白酶体功能异常或 疾病细胞如何利用正常的蛋白酶体活动来发挥优势。这样的知识就是 目前基于蛋白酶体的治疗癌症的基础。更深入地了解 正常的蛋白酶体功能和调节将极大地促进对 人类疾病的分子基础，并为疾病的治疗提供新的策略。

ABSTRACT Proteasome-catalyzed proteolysis is a central regulatory element of most essential eukaryotic cellular processes. Proteasome function is regulated at many levels including the assembly of multiple proteasome holoenzymes, alterations of the relative and absolute amount of holoenzymes, and direct control of holoenzyme activity. Proteasome holoenzymes are composed of a protease core complex (20S proteasome) interchangeably bound to any of multiple regulatory complexes. The goals of this research are to discover the physiologic roles of PI31, the most poorly understood and least studied proteasome regulator, and to determine the molecular and cellular basis of its function and regulation. The project is based on the premise that PI31 mediates cellular changes in proteasome-dependent protein degradation during cellular stress. We will test the general hypothesis that PI31 exerts this role by regulating proteasome content, composition, and/or function in response to stress. We also will test the hypothesis that PI31 action is regulated by reversible PI31 posttranslational modifications cued by specific stress-induced signals. We will employ a complementary suite of cellular and molecular approaches to define the mechanisms by which PI31 accomplishes its role, the regulation of these mechanisms by PI31 posttranslational modifications, and the physiologic significance of these effects. The pervasive role of proteasome-catalyzed protein degradation in normal cellular function and regulation explains why many diseases are associated with abnormal proteasome function or how diseased cells exploit normal proteasome action to their advantage. Such knowledge is the foundation of current proteasome-based therapies to treat cancer. A deeper understanding of normal proteasome function and regulation will significantly advance understanding of the molecular basis of human diseases and provide new strategies for their treatment.