PI31: a regulator of proteasome adaptation to stress

PI31：蛋白酶体适应应激的调节因子

• 批准号: 10397549
• 负责人: George N. DeMartino
• 金额: $ 32.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397549
• 关键词: Acute; Affect; Amino Acids; Binding; CRISPR/Cas technology; Cell physiology; Cells; Cellular Stress; Characteristics; Chronic; Complex; Cues; Disease; Exposure to; Foundations; Generations; Genes; Goals; Holoenzymes; Human; Knowledge; Link; Malignant Neoplasms; Mediating; Modification; Molecular; Molecular Analysis; Neurodegenerative Disorders; Nutrient; Oxidative Stress; Peptide Hydrolases; Phosphorylation; Physiological; Post-Translational Protein Processing; Process; Proteasome Inhibitor; Proteins; Proteolysis; Regulation; Regulatory Element; Research; Role; Scheme; Signal Transduction; Starvation; Stress; System; Testing; Therapeutic; Translations; base; cell growth regulation; experimental study; human disease; insight; multicatalytic endopeptidase complex; protein aggregation; protein degradation; response; stressor

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.

抽象的 蛋白酶体催化的蛋白水解是最重要的真核生物的核心调节元件 细胞过程。蛋白酶体的功能在许多层面上受到调节，包括多种蛋白的组装 蛋白酶体全酶、全酶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）可互换地与多个调节复合物中的任何一个结合。本次活动的目标 研究的目的是发现 PI31 的生理作用，这是人们了解和研究最少的 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 PI31 介导蛋白酶体依赖性细胞变化的前提 细胞应激期间蛋白质降解。我们将检验 PI31 发挥作用的一般假设 通过调节蛋白酶体含量、组成和/或响应压力的功能来发挥这一作用。 我们还将检验 PI31 作用受可逆 PI31 翻译后调节的假设 由特定的压力诱导信号引起的改变。我们将采用一套互补的 细胞和分子方法来定义 PI31 发挥其作用的机制， PI31 翻译后修饰对这些机制的调节，以及生理学 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 调节解释了为什么许多疾病与蛋白酶体功能异常或 患病细胞如何利用正常的蛋白酶体作用来发挥其优势。这样的知识就是 当前基于蛋白酶体的癌症治疗方法的基础。更深入的了解 正常的蛋白酶体功能和调节将显着促进对蛋白酶体的理解 人类疾病的分子基础并为其治疗提供新策略。

项目成果

Mimicking Protein Kinase C Phosphorylation Inhibits Arc/Arg3.1 Palmitoylation and Its Interaction with Nucleic Acids.

模拟蛋白激酶 C 磷酸化会抑制 Arc/Arg3.1 棕榈酰化及其与核酸的相互作用。

• 发表时间: 2024-01-08
• 影响因子: 5.6
• 作者: Barylko, Barbara;Taylor 4th, Clinton A;Wang, Jason;Earnest, Svetlana;Stippec, Steve;Binns, Derk D;Brautigam, Chad A;Jameson, David M;DeMartino, George N;Cobb, Melanie H;Albanesi, Joseph P
• 通讯作者: Albanesi, Joseph P