A conserved ubiquitin- and ESCRT-dependent pathway to regulate human lysosomal membrane proteins

Abstract The lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate lysosomal membrane proteins is poorly understood. In this study, we developed a cycloheximide chase assay to measure the half-lives of ~30 human lysosomal membrane proteins, and identified RNF152 as a short-lived protein. The degradation of RNF152 depends on ubiquitin and the endosomal sorting complexes required for transport (ESCRT) machinery. Ubiquitinated RNF152 is sorted and internalized by the ESCRT machinery into the lysosomal lumen for degradation. Strikingly, when expressed in budding yeast, human RNF152 is also degraded by the vacuole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a conserved mechanism to down-regulate lysosome membrane proteins.