Ubiquitin-dependent lysosomal membrane protein sorting and degradation.

As an essential organelle in the cell, the lysosome is responsible for digestion and recycling of intracellular components, storage of nutrients, and pH homeostasis. The lysosome is enclosed by a special membrane to maintain its integrity, and nutrients are transported across the membrane by numerous transporters. Despite their importance in maintaining nutrient homeostasis and regulating signaling pathways, little is known about how lysosomal membrane protein lifetimes are regulated. We identified a yeast vacuolar amino acid transporter, Ypq1, that is selectively sorted and degraded in the vacuolar lumen following lysine withdrawal. This selective degradation process requires a vacuole anchored ubiquitin ligase (VAcUL-1) complex composed of Rsp5 and Ssh4. We propose that after ubiquitination, Ypq1 is selectively sorted into an intermediate compartment. The ESCRT machinery is then recruited to sort the ubiquitinated Ypq1 into intraluminal vesicles (ILVs). Finally, the compartment fuses with the vacuole and delivers ILVs into the lumen for degradation.