Regulation of Ceramide Synthase by Protein-Protein Interaction

蛋白质-蛋白质相互作用对神经酰胺合酶的调节

• 批准号: 10662299
• 负责人: Can Emre Senkal
• 金额: $ 34.53万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662299
• 关键词: Area; Biochemical; Biological; Biology; Cell Death; Cells; Ceramides; Charcot-Marie-Tooth Disease; Chemoresistance; Data; Diabetes Mellitus; Disease; Down-Regulation; Enzymes; Generations; Goals; Growth; Heat shock proteins; In Vitro; Induction of Apoptosis; Innovative Therapy; Knowledge; Link; Lipids; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mediator; Metabolism; Methods; Mitochondria; Molecular; Mutation; Neurons; PUVA Photochemotherapy; Pathologic; Pathology; Pathway interactions; Phosphorylation; Play; Process; Production; Prognosis; Proteins; Proteomics; Regulation; Role; Scheme; Signal Transduction; Small Interfering RNA; Sphingolipids; Tertiary Protein Structure; Testing; Therapeutic; Vertebral column; cancer cell; chemotherapy; design; dihydroceramide desaturase; gain of function; inhibitor; loss of function; neuron development; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; protein protein interaction; response; tumor growth

Title: REGULATION OF CERAMIDE SYNTHASE BY PROTEIN-PROTEIN INTERACTION Abstract: Ceramides form the backbone of all sphingolipids, and ceramide synthases (CerS) are critical enzymes for de novo production of ceramides. In spite of the key role of CerS in ceramide generation, there is a serious deficiency in understanding how these enzymes are regulated. The long-term goal of this project is to uncover and understand the fundamental molecular mechanisms of how CerS enzymes are regulated. Using a proteomics approach, we discovered that the small heat shock protein Hsp27 interacts specifically with CerS1. Based on our preliminary data we generated the novel hypothesis that Hsp27 is a negative regulator of CerS1 activity via direct interaction that can be modulated by p38-MK2 MAPK mediated phosphorylation of Hsp27, and that down-regulation of Hsp27 induces CerS1/C18:0-ceramide mediated cellular responses. To test this hypothesis, we propose the following Specific Aims: Aim 1: Define the biochemical significance of Hsp27 mediated CerS1 regulation in cells with respect to sphingolipid metabolism and signal transduction. Aim 2: Define the biological significance of Hsp27 mediated CerS1 regulation. Aim 3: Determine the mechanism of Hsp27- CerS1 protein-protein interaction. Overall, these studies will establish Hsp27 as an endogenous modulator of CerS1 and uncover a novel mechanism of how Hsp27 regulates CerS1 and CerS1/C18:0-ceramide governed mitophagy and cancer cell death. The knowledge generated from this study will help design mechanism-based novel therapies against cancer and other pathologies in which C18:0-ceramide is the key mediator by identifying new methods to modulate CerS1 activity.

标题：蛋白质-蛋白质相互作用对神经酰胺合成酶的调节 抽象的： 神经酰胺构成所有鞘脂的骨架，而神经酰胺合酶 (CerS) 是关键酶 用于从头生产神经酰胺。尽管 CerS 在神经酰胺生成中发挥关键作用，但仍存在严重的问题 缺乏了解这些酶是如何调节的。该项目的长期目标是发现 并了解 CerS 酶如何调节的基本分子机制。使用 通过蛋白质组学方法，我们发现小热休克蛋白 Hsp27 与 CerS1 特异性相互作用。 根据我们的初步数据，我们提出了新的假设：Hsp27 是 CerS1 的负调节因子 通过直接相互作用的活性，可以通过 p38-MK2 MAPK 介导的 Hsp27 磷酸化来调节，以及 Hsp27 的下调会诱导 CerS1/C18:0-神经酰胺介导的细胞反应。为了测试这个 假设，我们提出以下具体目标： 目标 1：定义 Hsp27 的生化意义 介导细胞中有关鞘脂代谢和信号转导的 CerS1 调节。目标 2：定义 Hsp27 介导的 CerS1 调节的生物学意义。目标 3：确定 Hsp27- 的机制 CerS1 蛋白质-蛋白质相互作用。总体而言，这些研究将确定 Hsp27 作为内源性调节剂 CerS1 并揭示了 Hsp27 如何调节 CerS1 和 CerS1/C18:0-神经酰胺控制的新机制 线粒体自噬和癌细胞死亡。这项研究产生的知识将有助于设计基于机制的 针对癌症和其他疾病的新疗法，其中 C18:0-神经酰胺是关键介质，通过识别 调节 CerS1 活性的新方法。