Molecular mechanisms of lysosome remodeling in response to cellular stress

The lysosome is a central catabolic station that breaks down and recycles materials from multiple pathways. Lysosome dysfunction will cause lysosomal storage diseases. In addition, Lysosome dysregulation is also widely related to many other human diseases, such as neurodegenerative disorders, cardiovascular diseases, osteoporosis, and cancers. To function properly, the composition of lysosome membrane must be precisely regulated in response to environmental cues. Dysregulation in lysosome membrane composition leads to lysosome dysfunction and the development of lysosome-related diseases. Despite extensive research into many other aspects of lysosome biology, how lysosome adjusts its own composition in response to environmental cues remains poorly understood. Surprisingly, we found that many lysosome membrane proteins are degraded under starvation. This suggests that, rather than simply global biogenesis, the lysosome membrane undergoes dramatic remodeling, challenging the long-held view of how lysosomal composition is regulated. However, the cellular machinery and molecular mechanisms governing these processes are still largely unknown, positioning this proposed research at the forefront of the field. In this proposal, we will use budding yeast as a model system to address this emerging question through two major directions:1. Characterization of vacuole membrane protein (VMP) degradation pathways. 2. Vacuole remodeling through transcriptional regulation. Collectively, the results of our studies will advance the field by uncovering the new machinery and mechanisms involved in both the degradation and production aspects of lysosomal remodeling. Furthermore, this proposed research will be a critical first step in understanding the role of lysosomal remodeling in lysosomal function and lysosome-related diseases. It will also lay the foundation for developing new therapeutic treatments that target lysosomal function by controlling its composition. Project Number: 1R35GM159962-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Xi Yang | Institution: UNIVERSITY OF DENVER (COLORADO SEMINARY), DENVER, CO | Award Amount: $407,562 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - D Study Section[MRAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11202422