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

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http://hdl.handle.net/10138/306337

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Heybrock , S , Kanerva , K , Meng , Y , Ing , C , Liang , A , Xiong , Z-J , Weng , X , Kim , Y A , Collins , R , Trimble , W , Pomes , R , Prive , G G , Annaert , W , Schwake , M , Heeren , J , Lullmann-Rauch , R , Grinstein , S , Ikonen , E , Saftig , P & Neculai , D 2019 , ' Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export ' , Nature Communications , vol. 10 , 3521 . https://doi.org/10.1038/s41467-019-11425-0

Title: Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export
Author: Heybrock, Saskia; Kanerva, Kristiina; Meng, Ying; Ing, Chris; Liang, Anna; Xiong, Zi-Jian; Weng, Xialian; Kim, Young Ah; Collins, Richard; Trimble, William; Pomes, Regis; Prive, Gilbert G.; Annaert, Wim; Schwake, Michael; Heeren, Joerg; Lullmann-Rauch, Renate; Grinstein, Sergio; Ikonen, Elina; Saftig, Paul; Neculai, Dante
Contributor: University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
Date: 2019-08-06
Language: eng
Number of pages: 12
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/306337
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.
Subject: MOLECULAR-DYNAMICS
DENSITY-LIPOPROTEIN
TRANSPORT
RECEPTOR
MECHANISMS
NPC1
CELL
TRAFFICKING
DEGRADATION
DEFICIENCY
3111 Biomedicine
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