A conserved ubiquitin- And ESCRT-dependent pathway internalizes human lysosomal membrane proteins for degradation

Abstract

The lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate its membrane proteins is poorly under stood. In this study, we performed a cycloheximide (CHX) chase assay to measure the half- lives of approximately 30 human lysosomal membrane proteins (LMPs) and identified RNF152 and LAPTM4A as short-lived membrane proteins. The degradation of both proteins is ubiquitin dependent. RNF152 is a transmembrane E3 ligase that ubiquitinates itself, whereas LAPTM4A uses its carboxyl-terminal PY motifs to recruit NEDD4-1 for ubiquitina- tion. After ubiquitination, they are internalized into the lysosome lumen by the endosomal sorting complexes required for transport (ESCRT) machinery for degradation. Strikingly, when ectopically expressed in budding yeast, human RNF152 is still degraded by the vacu ole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a con-served mechanism to down-regulate lysosome membrane proteins. Copyright: