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

Saskia Heybrock, Kristiina Kanerva, Ying Meng, Chris Ing, Anna Liang, Zi-Jian Xiong, Xialian Weng, Young Ah Kim, Richard Collins, William Trimble, Régis Pomès, Gilbert G. Privé, Wim Annaert, Michael Schwake, Joerg Heeren, Renate Lüllmann-Rauch, Sergio Grinstein (), Elina Ikonen (), Paul Saftig () and Dante Neculai ()
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Saskia Heybrock: Christian-Albrechts-Universität Kiel
Kristiina Kanerva: University of Helsinki
Ying Meng: Zhejiang University School of Medicine
Chris Ing: Research Institute, The Hospital for Sick Children
Anna Liang: Research Institute, The Hospital for Sick Children
Zi-Jian Xiong: University of Toronto
Xialian Weng: Zhejiang University School of Medicine
Young Ah Kim: City University of New York
Richard Collins: Hospital for Sick Children
William Trimble: University of Toronto
Régis Pomès: Research Institute, The Hospital for Sick Children
Gilbert G. Privé: University of Toronto
Wim Annaert: VIB-Center for Brain and Disease Research
Michael Schwake: University of Bielefeld
Joerg Heeren: Universitätsklinikum Hamburg-Eppendorf
Renate Lüllmann-Rauch: Christian-Albrechts-Universität Kiel
Sergio Grinstein: University of Toronto
Elina Ikonen: University of Helsinki
Paul Saftig: Christian-Albrechts-Universität Kiel
Dante Neculai: Zhejiang University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11425-0

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