Regulation of developmental signaling pathways by glycosylation and deglycosylation

通过糖基化和去糖基化调节发育信号通路

• 批准号: 10549314
• 负责人: Hamed Jafar-Nejad
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549314
• 关键词: Adult; Affect; Animals; Area; Bone Morphogenetic Proteins; Carbohydrates; Cell Surface Proteins; Development; Disease; Drosophila genus; Embryonic Development; Enzymes; Functional disorder; Glycobiology; Goals; Human; Impairment; Knowledge; Link; Maintenance; Modification; Molecular; Mus; Muscular Dystrophies; Mutation; Organism; Pathway interactions; Patients; Phenotype; Physiology; Play; Polysaccharides; Protein Glycosylation; Proteins; Regenerative Medicine; Regulation; Research; Research Design; Role; Signal Pathway; Signal Transduction; Structure; System; Tissues; Work; Xylose; body system; cell type; developmental disease; fly; glycosylation; human disease; insight; interest; notch protein; novel; novel therapeutic intervention; protein complex; receptor; sugar; tool; virtual

The majority of secreted and cell-surface proteins of all cell types studied so far are glycosylated, i.e. decorated with sugar molecules. These carbohydrate modifications play diverse structural and functional roles in organisms, and are involved in proper animal development and physiology. Mutations in various components of the glycosylation machinery have been shown to cause more than 100 human diseases, affecting virtually all organ systems. However, the glycan structures found on animal proteins are complex and heterogeneous, and each form of glycosylation can be found on tens to thousands of proteins. Therefore, it is difficult to understand the molecular mechanisms underlying the phenotypes observed in glycosylation disorders. The long-term goals of our research are to understand how carbohydrate modifications regulate animal development, to use this knowledge to provide insight into the pathophysiology of human glycosylation disorders, and to establish frameworks for novel therapeutic approaches in diseases caused or impacted by mutations affecting protein glycosylation. Our primary area of interest is the intersection between glycobiology and developmental signaling pathways, which are a small number of evolutionarily conserved, intercellular signaling mechanisms broadly used during embryonic development and adult maintenance of animals. One major focus of our research is on O-linked glycans attached to Notch proteins, which constitute the receptors for one of the most important developmental signaling pathways in animals. We have previously characterized the role of the enzymes involved in the addition of xylose-glycose-O glycans in the regulation of Drosophila development and Notch signaling. We have also studied the role of the first enzyme in this pathway (POGLUT1) in mice, and have linked POGLUT1 to two human diseases, a developmental disorder and a muscular dystrophy. In the current application, we propose to characterize the role of the enzymes downstream of POGLUT1 in mammalian development and Notch signaling. Moreover, we have found that an enzyme involved in removing N-linked glycans from proteins regulates another major signaling pathway (the bone morphogenetic protein or BMP pathway) in flies in a tissue-specific manner. Mutations in this enzyme (NGLY1) cause a multi-system developmental disorder in human patients, but the pathophysiology of the disease is not known. We propose to determine the molecular mechanisms underlying the regulation of the BMP pathway by NGLY1 in flies, and to determine which aspects of mammalian BMP signaling are regulated by this enzyme. In addition to providing insight into the roles of glycosylation in the regulation of major signaling pathways, these projects have the potential to establish novel tools to alter the activity of Notch and BMP signaling in disease contexts and in regenerative medicine.

迄今为止研究的所有细胞类型的大多数分泌蛋白和细胞表面蛋白都是糖基化的，即糖基化。 用糖分子装饰。这些碳水化合物修饰发挥不同的结构和功能作用 在生物体中，并参与适当的动物发育和生理学。各种突变 糖基化机制的组分已显示引起100多种人类疾病， 几乎影响所有器官系统然而，在动物蛋白质上发现的聚糖结构是复杂的， 糖基化是异质的，并且每种形式的糖基化可以在数万至数千种蛋白质上发现。因此有 难以理解糖基化中观察到的表型的分子机制 紊乱我们研究的长期目标是了解碳水化合物修饰如何调节 动物发育，利用这一知识提供深入了解人类糖基化的病理生理学 疾病，并建立新的治疗方法的框架，引起或影响的疾病 影响蛋白质糖基化的突变。我们主要感兴趣的领域是糖生物学 和发育信号通路，这是一个少数的进化保守，细胞间 在动物胚胎发育和成年维持期间广泛使用的信号传导机制。一 我们的研究主要集中在与Notch蛋白连接的O-连接聚糖上，这些聚糖构成了受体 是动物最重要的发育信号通路之一。我们之前描述了 参与添加木糖-葡萄糖-O聚糖的酶在果蝇调节中的作用 发育和Notch信号传导。我们还研究了第一种酶在这一途径中的作用 研究人员在小鼠中发现了POGLUT 1，并将POGLUT 1与两种人类疾病联系起来，一种是发育障碍， 肌肉萎缩症在本申请中，我们提出表征酶的作用 POGLUT 1在哺乳动物发育和Notch信号传导中的下游。此外，我们还发现， 参与从蛋白质中去除N-连接聚糖的酶调节另一种主要的信号传导途径（ 骨形态发生蛋白或BMP途径）。这种酶的突变 （NGLY 1）在人类患者中引起多系统发育障碍，但其病理生理学 疾病未知。我们建议确定调节这些蛋白质的分子机制。 通过NGLY 1在果蝇中的BMP通路，并确定哺乳动物BMP信号传导的哪些方面受到调节 这种酶。除了提供对糖基化在主要信号调节中的作用的深入了解外， 这些项目有可能建立新的工具来改变Notch和BMP的活性 在疾病背景和再生医学中的信号传导。

项目成果

Gut barrier defects, increased intestinal innate immune response, and enhanced lipid catabolism drive lethality in N -glycanase 1 deficient Drosophila.

肠道屏障缺陷、肠道先天免疫反应增强以及脂质分解代谢增强导致 N-聚糖酶 1 缺陷的果蝇致死。

• DOI: 10.1101/2023.04.07.536022
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Pandey,Ashutosh;Galeone,Antonio;Han,SeungYeop;Story,BenjaminA;Consonni,Gaia;Mueller,WilliamF;Steinmetz,LarsM;Vaccari,Thomas;Jafar-Nejad,Hamed
• 通讯作者: Jafar-Nejad,Hamed

Tracing the NGLY1 footprints: insights from Drosophila.

追踪 NGLY1 足迹：来自果蝇的见解。

• DOI: 10.1093/jb/mvab084
• 发表时间: 2022
• 期刊: Journal of biochemistry
• 影响因子: 2.7
• 作者: Pandey,Ashutosh;Jafar-Nejad,Hamed
• 通讯作者: Jafar-Nejad,Hamed

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology.

• DOI: 10.3390/cells11071155
• 发表时间: 2022-03-29
• 期刊: Cells
• 影响因子: 6
• 作者: Pandey A;Adams JM;Han SY;Jafar-Nejad H
• 通讯作者: Jafar-Nejad H