Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export

Nature Communications
Saskia HeybrockDante Neculai

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.

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Citations

Feb 13, 2020·Cell Discovery·Willa Wen-You Yim, Noboru Mizushima
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Methods Mentioned

BETA
microscale thermophoresis
Confocal microscopy
immunoprecipitation
transfection
PCR
Fluorescence
flow cytometry
scraping
glycosylation
FCS

Software Mentioned

CHARMM36
Volocity
NIS
Visual Molecular Dynamics volmap
CGenFF
SETTLE
LINCS
MODELLER
ImageJ
MDS

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