An Essential Role of Hrs/Vps27 in Endosomal Cholesterol Trafficking

SummaryThe endosomal sorting complex required for transport (ESCRT) plays a crucial role in the degradation of ubiquitinated endosomal membrane proteins. Here, we report that Hrs, a key protein of the ESCRT-0 complex, is required for the transport of low-density lipoprotein-derived cholesterol from endosomes to the endoplasmic reticulum. This function of Hrs in cholesterol transport is distinct from its previously defined role in lysosomal sorting and downregulation of membrane receptors via the ESCRT pathway. In line with this, knocking down other ESCRT proteins does not cause prominent endosomal cholesterol accumulation. Importantly, the localization and biochemical properties of key cholesterol-sorting proteins, NPC1 and NPC2, appear to be unchanged upon Hrs knockdown. Our data identify Hrs as a regulator of endosomal cholesterol trafficking and provide additional insights into the budding of intralumenal vesicles.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A function of Hrs/VPS27 in endosomal cholesterol transport is discovered ► Hrs/VPS27 depletion causes endosomal accumulation of LDL-derived cholesterol ► Niemann Pick C 1 and 2 proteins appear to be unaffected upon Hrs/Vps27 knockdown