Osiris Genes as Novel Coordinators of Protein Trafficking in Drosophila Trachea

总结

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.