The Role and Regulation of Endosomal GTP Exchange Factors

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Every cell is like a busy city: it has to coordinate information flow, clear waste, and move materials to where they are needed. Like cities, cells have a complex internal transportation system that controls traffic. Special machinery ensures that the right type of material is loaded into different transport containers, and delivered to the correct destination. This project focuses on important drivers in the cellular transportation system called "sorting nexins". Many of the traffic signals and pathways present in humans are also found in baker's yeast, a simple single-celled organism. Studying sorting nexins in yeast allows us to use different genome-wide technologies to uncover pathways and machinery on a very large scale and make discoveries that would be difficult or impossible in complex organisms. In fact, an important type of sorting nexin called "retromer" was first discovered in yeast, and many key discoveries about retromer are still being made in this model system. We discovered that a family of activator proteins regulate retromer in yeast. One of these proteins, called "VARP", was also found to be important for retromer function in human cells. This gives us the unparalleled opportunity to use yeast to study VARP and establish exactly how it regulates retromer-like sorting machineries. Our work so far is already generating important insights. The yeast VARP protein that we discovered not only controls the assembly of an entirely new type of sorting nexin, but actually forms an integral part of this machinery. Our proposed research will examine how yeast VARP chooses the specific components that make up this sorting nexin, and how the parts work together to form transport carriers. We will identify how different materials such as proteins are recognized and packaged into these carriers. In addition, we will study the regulatory processes that control how and when this sorting nexin machinery operates in the cell. This research will have a number of important impacts. It will reveal general principles that control the formation and function of transport carriers that regulate the distribution of proteins within the cell, knowledge that can be transferred to the study of human cells. In the long term, it could also have economic benefits for Canada. Yeast cells are used as "mini-factories" to produce different proteins for pharmaceutical and bioprocessing applications, such as the removal of toxins from the environment. Understanding how proteins are transported within the cell can increase the efficiency of these yeast "cell factories" in the production of biopharmaceuticals and industrial enzymes.