Abstract
The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, also known as SCARB2) reveals a large cavity that traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. The detection of cholesterol within the LIMP-2 structure and the formation of cholesterol−like inclusions in LIMP-2 knockout mice suggested the possibility that LIMP2 transports cholesterol in lysosomes. We present results of molecular modeling, crosslinking studies, microscale thermophoresis and cell-based assays that support a role of LIMP-2 in cholesterol transport. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Depletion of LIMP-2 alters SREBP-2-mediated cholesterol regulation, as well as LDL-receptor levels. Our data indicate that LIMP-2 operates in parallel with Niemann Pick (NPC)-proteins, mediating a slower mode of lysosomal cholesterol export.
Highlights
The intracellular transport of cholesterol is subject to tight regulation
Twenty-four simulations were initiated with cholesterol in the bulk solution and fifteen with cholesterol docked within the LIMP-2 cavity
NPC1 polymorphisms were shown to lead to a lysosomal cholesterol accumulation, the lifespan of patients bearing these mutations varied with the age of onset
Summary
The intracellular transport of cholesterol is subject to tight regulation. The structure of the lysosomal integral membrane protein type 2 (LIMP-2, known as SCARB2) reveals a large cavity that traverses the molecule and resembles the cavity in SR-B1 that mediates lipid transfer. We show that the cavity in the luminal domain of LIMP-2 can bind and deliver exogenous cholesterol to the lysosomal membrane and later to lipid droplets. Cholesterol is an important membrane component of higher eukaryotes, regulating barrier function, membrane fluidity, integral membrane protein operation, membrane traffic and transmembrane signaling processes[4]. It plays a major role in vascular diseases, diabetes, cancer and several monogenic disorders[5]. Like LIMP-2, the ectodomain of SR-B1 displays an intramolecular tunnel that is thought to deliver cholesterol from bound lipoproteins to the plasma membrane[15]. We provide multiple lines of evidence that LIMP2 participates in lipid transport from lysosomes by transporting cholesterol (and possibly other lipid species) through its luminal cavity to the lysosomal membrane
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