A novel ceramide metabolic pathway in cell regulation

细胞调节中的新型神经酰胺代谢途径

• 批准号: 9111003
• 负责人: Lina M OBEID
• 金额: $ 40.44万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111003
• 关键词: Acyl Coenzyme A; Address; Apoptosis; Bacteria; Biology; Cell Death; Cells; Cellular Stress; Cellular Stress Response; Ceramides; Coenzyme A Ligases; Data; Enzymes; Family; Fatty Acids; Funding; Generations; Goals; Grant; Helper-Inducer T-Lymphocyte; In Vitro; Laboratories; Length; Light; Lipids; Mediating; Mediator of activation protein; Metabolic Pathway; Metabolism; Pathway interactions; Positioning Attribute; Proteins; Proteomics; Regulation; Role; Sphingolipids; Suggestion; Testing; Vertebral column; Work; biological adaptation to stress; diacylglycerol O-acyltransferase; dihydroceramide desaturase; gain of function; long chain fatty acid; mutant; novel; preference; protein protein interaction; public health relevance; response

 DESCRIPTION (provided by applicant): Ceramides form the backbone of all sphingolipids, and they have emerged as important regulators and mediators of cellular stress responses. Recently, however, significant complexity has arisen in ceramide metabolism and biology. Therefore, the long-term goal of this proposal is to understand specific pathways of ceramide metabolism involved in cell stress responses. Recent work in our laboratory has focused on a newly identified family of enzymes; namely ceramide synthases (CerS), which demonstrate selective preferences for the fatty acyl chains that they incorporate into ceramide. In addition, very recent and exciting work in our laboratory using proteomic approaches has led us to discover CerS-interacting proteins, and one of the most credible and exciting of these proteins is the long chain fatty acyl CoA synthetase (ACSL5). In compelling preliminary data, we demonstrate that this interaction defines a novel pathway of ceramide metabolism by which ACSL5 provides the long chain fatty acids to acylate ceramides at the 1 position to generate O-acylceramides. We also demonstrate that this likely occurs by the diacylglycerol acyltransferase DGAT2. Evidence strongly suggests storage of O-acylceramides in lipid droplets (LD), and functionally, this causes sequestration of ceramide in a pool that is biologically inaccessible for regulation of cell death pathways. This proposal, therefore, addresses the hypothesis that Ceramide is metabolized to O-acylceramide by a previously unappreciated ACSL5/DGAT2 dependent mechanism and stored in LD and that this metabolic pathway is a key regulator of ceramide-mediated biologies. To test this hypothesis we propose the following specific aims: Aim 1. Define a novel pathway of ceramide metabolism to O- acylceramide by ACSL5/DGAT2 dependent mechanism. Aim 2. Define a role for O- acylceramides (in LD) in the regulation of ceramide-mediated responses. Aim 3. Determine the mechanism of CerS/ACSL5 protein-protein interaction. Taken together these studies will uncover a novel ceramide metabolic pathway to O-acylceramide by ACSL5 and DGAT2 with important implications for cell regulation.

 描述（由适用提供）：神经酰胺构成了所有鞘脂的骨干，它们已成为细胞应力反应的重要调节剂和介体。然而，最近，神经酰胺代谢和生物学中已经出现了显着的复杂性。因此，该提案的长期目标是了解与细胞应激反应有关的神经酰胺代谢的特定途径。我们实验室的最新工作集中在新确定的酶家族上。即神经酰胺合酶（CERS），表现出对脂肪酰基链的选择性偏好，它们结合到神经酰胺中。此外，使用蛋白质组学方法在我们的实验室中非常令人兴奋的工作使我们发现了CERS相互作用的蛋白质，而这些蛋白质中最可信，最令人兴奋的蛋白质之一是长链脂肪脂肪酰基COA合成酶（ACSL5）。在引人注目的初步数据中，我们证明了这种相互作用定义了神经酰胺代谢的新途径，通过该途径，ACSL5通过该途径将长链脂肪酸提供给在1位置的酰基神经酰胺以产生O-酰基甲酰胺。我们还证明，二酰基甘油酰胺酰基转移酶DGAT2可能发生这种情况。有力的证据表明，在脂质液滴（LD）中储存O-酰基甲酰胺，并且在功能上，这会导致在生物学上无法访问的池中隔离神经酰胺。 调节细胞死亡途径。因此，该提议解决了以下假设：神经酰胺通过先前未经批准的ACSL5/DGAT2依赖机制代谢为O-酰基酰胺，并存储在LD中，并且该代谢途径是coramide介导的生物学的关键调节剂。为了检验该假设，我们提出了以下特定目的：目标1。通过ACSL5/DGAT2依赖机制定义了神经酰胺代谢对O-酰基酰胺的新途径。 AIM 2。定义O-酰基甲酰胺（在LD中）在神经酰胺介导的反应调节中的作用。 AIM 3。确定CERS/ACSL5蛋白 - 蛋白质相互作用的机制。综合这些研究将通过ACSL5和DGAT2发现新的神经酰胺代谢途径，对细胞调节具有重要意义。