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Nat Commun. 2019 Aug 6;10(1):3521. doi: 10.1038/s41467-019-11425-0.

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

Author information

1
Biochemisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany.
2
Faculty of Medicine, Anatomy and Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland.
3
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
4
Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
5
Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada.
6
Department of Biochemistry, University of Toronto, Toronto, M5S 1A8, Canada.
7
Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, New York, USA.
8
Cell Biology Program, Hospital for Sick Children, Toronto, M5G 1X8, Canada.
9
Department of Physiology, University of Toronto, Toronto, M5S 1A8, Canada.
10
Princes Margaret Cancer Centre, Toronto, ON, Canada.
11
Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, Leuven, Belgium.
12
Faculty of Chemistry, Biochemistry III, University of Bielefeld, 33615, Bielefeld, Germany.
13
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
14
Institut für Biochemie und Molekulare Zellbiologie, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg-Eppendorf, Germany.
15
Institut für Anatomie, Christian-Albrechts-Universität Kiel, Kiel, Germany.
16
Department of Biochemistry, University of Toronto, Toronto, M5S 1A8, Canada. sergio.grinstein@sickkids.ca.
17
Cell Biology Program, Hospital for Sick Children, Toronto, M5G 1X8, Canada. sergio.grinstein@sickkids.ca.
18
Faculty of Medicine, Anatomy and Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland. elina.ikonen@helsinki.fi.
19
Minerva Foundation Institute for Medical Research, Helsinki, Finland. elina.ikonen@helsinki.fi.
20
Biochemisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany. psaftig@biochem.uni-kiel.de.
21
Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China. dneculai@zju.edu.cn.

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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