Grant: Discovery Grants Program - Individual

Although they may not be aware, everyone recycles to sustain life on earth. This is because all eukaryotic cells, including those that constitute you and I, rely on organelles called lysosomes to recycle biomaterials. Lysosomes salvage unneeded or damaged cellular components, and clear extracellular debris or pathogens by converting them into an important source of nutrients. As such, lysosome activity is needed to sustain metabolism when cells are starved, and to remove toxic biomaterials that accumulate in cells as they age. To function, these dynamic organelles rely on nutrient transporters to return products of catabolism (amino acids, lipids, nucleic acids) to the cell for reuse. But little is know about these transporters including how they are regulated or degraded. Recently, we discovered a new process in the model organism Saccharomyces cerevisiae called the IntraLumenal Fragment (ILF) pathway that selectively degrades lysosome transporters when damaged, in response to substrate levels, or by TOR-signaling - an important mediator of cell metabolism and longevity. This process selectively sorts transporters into an area of membrane that is internalized and degraded by lumenal hydrolases upon homotypic lysosome membrane fusion. In the past 6 years, my group has made progress towards comprehensively understanding the ILF pathway and its contribution(s) to cell physiology, but many important details remain unresolved: How are transporters labeled for clearance? How are they then sorted for degradation? Using S. cerevisiae and its vacuolar lysosome as models, I will complete two objectives to answer these questions and achieve my goal of understanding the molecular underpinnings of the ILF pathway and fundamental lysosome biology. Preliminary evidence suggests that the ILF pathway shares protein labeling machinery with other cellular degradation processes but employs a unique sorting mechanism integrated within the membrane fusion machinery. To test these hypotheses, I propose an ambitious series of studies to be completed within 5 years by a motivated team of 3 PhD, 1 MSc and 2 BSc students who will master cutting-edge methods in genetics, microscopy, biochemistry and cell biology desirable skills needed to pursue related careers in biotech. Anticipated results will reveal the molecular basis of lysosome biology critical for all eukaryotic life. Future work will translate this knowledge into applications that improve tolerance to metabolic and proteostatic stressors, supporting development of related biotechnologies in Canada.