Osiris Genes as Novel Coordinators of Protein Trafficking in Drosophila Trachea

Osiris 基因作为果蝇气管蛋白质运输的新协调者

• 批准号: 10291609
• 负责人: Lan Jiang
• 金额: $ 43.9万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10291609
• 关键词: Apical; Autophagosome; Binding; Binding Proteins; Biological; Biological Assay; Biological Models; Blood Vessels; Cessation of life; Co-Immunoprecipitations; Cytoplasmic Vesicles; Defect; Deposition; Disease; Drosophila eye; Drosophila genus; Drug Metabolic Detoxication; Endoplasmic Reticulum; Endosomes; Epithelial; Epithelial Cells; Extracellular Matrix; Gases; Gene Family; Genes; Genetic; Glycocalyx; Glycolysis; Goals; Golgi Apparatus; Human; Image; Immunohistochemistry; Individual; Insecta; Invertebrates; Kidney; Knowledge; Lactoylglutathione Lyase; Lead; Life; Liquid substance; Lung; Lysosomes; Mediating; Metabolic; Morphogenesis; Morphology; Organ; Organism; Pathway interactions; Phenotype; Play; Polycystic Kidney Diseases; Process; Property; Proteins; Pyruvaldehyde; Reporting; Role; Sequence Homology; Shapes; Structure; System; Testing; Time; Trachea; Tube; Tubular formation; Vascular Diseases; Vertebrates; Vesicle; Yeasts; body system; exosome; experimental study; extracellular; gene function; human disease; in vivo; kidney vascular structure; malformation; member; monolayer; mutant; novel; protein transport; secretion process; spine bone structure; trafficking

Summary Biological tubes with appropriate sizes are critical for the proper functioning of most major human organ systems (including but not limited to kidneys, lungs, and blood vessels). Malformation of tubes leads to various human diseases, such as polycystic kidney disease and vascular diseases. Drosophila trachea is the premier system to study the fundamental mechanisms underlying tubular organ formation. The Drosophila trachea is a ramifying network of epithelial tubes with a monolayer of epithelial cells surrounding an apical lumen. During tube expansion, the apical secretion burst deposits large amounts of luminal matrix components to the apical extracellular lumen. This process is critical for tube expansion to acquire mature sizes. Previous studies on apical secretion focused on the identification of components of the vesicular trafficking pathway involved in this process. As expected, in addition to endoplasmic reticulum and Golgi, a few endosomes are also required in this process. Instead of identifying additional trafficking components, the objective of this project is to reveal the “broader coordination” of various trafficking components during apical secretion. This is a previously underappreciated mechanism in apical secretion in Drosophila trachea as well as in the overall field of vesicular trafficking. Our preliminary study on a poorly understood Osiris (Osi) gene family strongly indicates that Osi family genes function as “traffic coordinators” to direct post-Golgi protein trafficking. In addition, a recent homology search revealed that Osi genes share noticeable sequence homology to glyoxalase 1 (Glo-1). Glo-1 is well known for its function in detoxification of methylglyoxal, a metabolic byproduct of glycolysis. It has been reported that Glo-1 plays a role in vesicular trafficking as well as morphological changes in blood vessels. These discoveries lead to a plausible hypothesis that they may also have some functional overlap in tubular organs. Our central hypothesis is that Osi genes function as “traffic coordinators” to direct apical proteins by coordinated changes within secretion-related (e.g. endosomes, exosomes) and degradation-related trafficking components (e.g. lysosomes, autophagosomes). We will test this hypothesis by completing the following three specific aims: Aim. 1 Determine the function of Osi genes in apical secretion of the apical luminal matrix during tube expansion. Aim. 2: Determine the function of Osi genes as coordinators to increase numbers, volumes, activities of secretion-related trafficking components at the expense of degradation-related trafficking components in trachea. Aim. 3: Identify proteins that directly bind to Osi proteins. This project is significant because understanding the “broader coordination” between various trafficking components will fill the gap in our understanding of the regulatory hierarchy in protein trafficking.

摘要 具有适当大小的生物管对于大多数人体主要器官的正常运作至关重要 系统(包括但不限于肾脏、肺和血管)。管子的畸形会导致各种 人类疾病，如多囊肾病和血管疾病。果蝇气管是最好的 研究肾小管器官形成的基本机制的系统。 果蝇的气管是一个由单层上皮细胞组成的上皮管分支网络 围绕着根尖管腔。在管扩张期间，心尖分泌物的破裂沉积了大量的 管腔基质成分至顶端细胞外腔。这一过程对于管子膨胀到 获得成熟的尺码。以往对根尖分泌的研究主要集中在鉴定根尖分泌物的成分上。 囊泡运输途径参与了这一过程。正如预期的那样，除了内质网和 高尔基，在这个过程中也需要一些内体。而不是识别额外的人口贩运 该项目的目标是揭示各种贩运活动之间的“更广泛的协调” 顶端分泌过程中的成分。这是以前在根尖分泌中被低估的机制 在果蝇气管以及整个囊泡运输领域也是如此。 我们对一个鲜为人知的Osiris(Osiris)基因家族的初步研究有力地表明，Osiis家族 基因起着“交通协调器”的作用，引导高尔基体后蛋白质的运输。此外，最近的一项同源 搜索结果显示，Osi基因与乙醛酸酶1(Glo-1)有显著的序列同源性。Glo-1状态良好 因其对糖酵解的代谢副产物甲基乙二醛的解毒作用而闻名。一直以来 报道称，Glo-1在囊泡运输以及血管形态变化中起作用。 这些发现导致了一个看似合理的假设，即它们在肾小管中可能也有一些功能重叠 器官。我们的中心假说是Osi基因作为“交通协调器”通过以下方式引导顶端蛋白 与分泌有关的(如内体、外体)和与降解有关的贩运内的协调变化 组分(如溶酶体、自噬体体)。我们将通过完成以下三个步骤来验证这一假设 具体目标：目标。1确定Osi基因在根尖腔基质的根尖分泌中的作用 管子扩张。瞄准。2：确定Osi基因作为协调者的功能，以增加数量，体积， 以牺牲与退化有关的贩运为代价的与分泌物有关的贩运活动 气管中的成分。瞄准。3：鉴定与Osi蛋白直接结合的蛋白质。 这个项目意义重大，因为了解了各种贩运之间的“更广泛的协调” 组件将填补我们对蛋白质贩运监管等级的理解空白。