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.

Details

Title
Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export
Author
Heybrock, Saskia 1 ; Kanerva, Kristiina 2   VIAFID ORCID Logo  ; Meng, Ying 3 ; Ing, Chris 4   VIAFID ORCID Logo  ; Liang, Anna 4 ; Zi-Jian Xiong 5 ; Weng, Xialian 3 ; Young Ah Kim 6 ; Collins, Richard 7 ; Trimble, William 8   VIAFID ORCID Logo  ; Pomès, Régis 4   VIAFID ORCID Logo  ; Privé, Gilbert G 9   VIAFID ORCID Logo  ; Annaert, Wim 10   VIAFID ORCID Logo  ; Schwake, Michael 11 ; Heeren, Joerg 12   VIAFID ORCID Logo  ; Lüllmann-Rauch, Renate 13 ; Grinstein, Sergio 14 ; Ikonen, Elina 2   VIAFID ORCID Logo  ; Saftig, Paul 1 ; Neculai, Dante 3   VIAFID ORCID Logo 

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; Minerva Foundation Institute for Medical Research, Helsinki, Finland 
3  Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China 
4  Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada 
5  Department of Biochemistry, University of Toronto, Toronto, Canada 
6  Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, New York, USA 
7  Cell Biology Program, Hospital for Sick Children, Toronto, Canada 
8  Department of Biochemistry, University of Toronto, Toronto, Canada; Cell Biology Program, Hospital for Sick Children, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada 
9  Department of Biochemistry, University of Toronto, Toronto, Canada; Princes Margaret Cancer Centre, Toronto, ON, Canada 
10  Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, Leuven, Belgium 
11  Faculty of Chemistry, Biochemistry III, University of Bielefeld, Bielefeld, Germany; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 
12  Institut für Biochemie und Molekulare Zellbiologie, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg-Eppendorf, Germany 
13  Institut für Anatomie, Christian-Albrechts-Universität Kiel, Kiel, Germany 
14  Department of Biochemistry, University of Toronto, Toronto, Canada; Cell Biology Program, Hospital for Sick Children, Toronto, Canada 
Pages
1-12
Publication year
2019
Publication date
Aug 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11425-0
ProQuest document ID
2268790333
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.