A New Cellular Protein Degradation Pathway for Lysosome Homeostasis and Remodeling

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Although they may not be aware, everyone recycles to sustain life on earth at least from the perspective of a cell biologist. This is because all eukaryotic cells, including those that constitute you and I, rely on organelles called lysosomes to recycle biomaterials. Lysosomes recycle 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. Until recently, when 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 cellular aging. This process selectively sorts transporters into an area of membrane that is internalized and degraded by lumenal hydrolases upon homotypic lysosome membrane fusion. But many open questions must be answered to comprehensively understand this novel process and its contribution(s) to cell physiology: How are transporters labeled and sorted for degradation? Does it occur during other fusion events? Can the ILF pathway degrade surface polytopic proteins? Does it contribute to longevity? Is this pathway conserved in metazoans? Primarily using S. cerevisiae and its vacuolar lysosome as models, I will complete five objectives to answer these questions and achieve my goal of understanding the molecular underpinnings of the ILF pathway, its physiology and how it may promote longevity in eukaryotic cells. This ambitious series of studies will be completed within 5 years by a motivated team of 1 postdoctoral fellow, 3 graduate students and an undergraduate student who will master cutting-edge methods in genetics, microscopy, biochemistry and cell biology - desirable skills needed to pursue careers in academia and industry. We anticipate that the ILF pathway will be equally critical to lysosomes as TOR- and TFEB-signaling, whereby it remodels membranes to accommodate changes in cell metabolism and other biology, akin to the importance of plasma membrane remodeling by endocytosis that underlies diverse physiology. Anticipated results will also help reveal the secret of nature's holy grail, and future work will translate this state-of-the-art knowledge into applications to prolong longevity, supporting development of intellectual property and related biotechnologies in Canada.