The lysosome is an essential organelle responsible for the digestion and recycling of intracellular materials delivered by endomembrane trafficking and autophagy. It also plays an important role in intracellular signal transduction by regulating the localization and activity of mTOR signaling complex. Not surprisingly, lysosome dysfunction leads to ~ 50 different lysosomal storage diseases (LSDs) and contributes to aging–related neurodegenerative and cardiovascular diseases. Because of its importance, lysosomes have attracted major interests among cell biologists, and after decades’ of study of endomembrane trafficking and autophagy, we have a detailed understanding of lysosome biogenesis. However, very little is known about the regulation and quality control of lysosomes, two important questions that hold the key for maintaining healthy lysosomes and developing new LSD treatment strategies.
My lab aims to understand these two fundamental questions in both yeast and mammalian cells. Recently, we uncovered that lysosomal membrane proteins can be selectively down-regulated according to their substrate concentrations (Figure 1). Conceptually, the down-regulation pathway can be divided into four stages: 1) protein ubiquitination, 2) sorting of ubiquitinated cargoes on the vacuole membrane, 3) internalization of sorted cargoes, 4) degradation within the lysosome. We have identified two distinct vacuole membrane anchored E3 ligases to initiate the pathway. However, downstream machinery and the detailed molecular mechanisms of this process still remain to be elucidated. We have invented several new tools that will enable us for an in-depth study of this degradation process and its potential roles in lysosomal membrane quality control.
- Identify new components that participate in the lysosomal membrane regulation;
- How do E3 ligases recognize vacuole membrane substrates?
- Characterize mammalian lysosomal regulation and quality control.