PI31: a regulator of proteasome adaptation to stress

摘要 蛋白酶体催化的蛋白质水解是真核生物最基本的蛋白质合成的核心调控元件， 细胞过程蛋白酶体功能在许多水平上受到调节，包括多个蛋白酶体的组装。 蛋白酶体全酶，全酶的相对和绝对量的改变，以及直接 控制全酶活性。蛋白酶体全酶由蛋白酶核心复合物组成 (20S蛋白酶体）可互换地结合到多种调节复合物中的任一种。这个的目标 研究的目的是发现PI 31的生理作用，这是最缺乏了解和研究的 蛋白酶体调节剂，并确定其功能和调节的分子和细胞基础。 该项目基于PI 31介导蛋白酶体依赖性细胞变化的前提。 细胞应激过程中的蛋白质降解。我们将测试PI 31发挥作用的一般假设， 通过调节蛋白酶体的含量、组成和/或功能来响应应激而发挥这种作用。 我们还将检验PI 31作用受可逆的PI 31翻译后调节的假设。 由特定的应力诱导信号提示的修改。我们将雇用一套互补的 细胞和分子方法来定义PI 31完成其作用的机制， 通过PI 31翻译后修饰调节这些机制， 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 和调节解释了为什么许多疾病与异常的蛋白酶体功能有关， 病变细胞如何利用正常的蛋白酶体作用发挥其优势。这样的知识， 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大大促进对 人类疾病的分子基础，并为其治疗提供新的策略。

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.