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

• Published in: Nature communications Vol. 10; no. 1; pp. 3521 - 12
• Main Authors: Heybrock, Saskia, Kanerva, Kristiina, Meng, Ying, Ing, Chris, Liang, Anna, Xiong, Zi-Jian, Weng, Xialian, Ah Kim, Young, Collins, Richard, Trimble, William, Pomès, Régis, Privé, Gilbert G., Annaert, Wim, Schwake, Michael, Heeren, Joerg, Lüllmann-Rauch, Renate, Grinstein, Sergio, Ikonen, Elina, Saftig, Paul, Neculai, Dante
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 14/28; 14/34; 14/35; 14/63; 631/45/287/1197; 631/80/642/1624; 64; 64/60; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; CD36 Antigens - genetics; CD36 Antigens - metabolism; CHO Cells; Cholesterol; Cholesterol, LDL - metabolism; Cricetulus; Crosslinking; Depletion; Exports; Fibroblasts; Gene Knockout Techniques; HeLa Cells; Humanities and Social Sciences; Humans; Inclusions; Integral membrane proteins; Integrals; Intracellular Signaling Peptides and Proteins; Lipid Droplets - metabolism; Lipids; Low density lipoprotein; Lysosomal Membrane Proteins - genetics; Lysosomal Membrane Proteins - metabolism; Lysosomes; Lysosomes - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Molecular modelling; multidisciplinary; Niemann-Pick C1 Protein; Protein Domains; Proteins; Receptors, Scavenger - genetics; Receptors, Scavenger - metabolism; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Sterol regulatory element-binding protein; Thermophoresis; Transport
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11425-0

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. Cholesterol transport is tightly regulated in the cell and in lysosomes is regulated by NPC1/2. Here, Heybrock et al. use molecular modeling, knockout mice and cell based studies to show that LIMP-2 also mediates lysosomal cholesterol transport.