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Nature communications
08 06, 2019;10 (1): 3521.

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, Dante Neculai
Author Information
  1. Saskia Heybrock: Biochemisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany.
  2. Kristiina Kanerva: Faculty of Medicine, Anatomy and Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland. ORCID
  3. Ying Meng: Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
  4. Chris Ing: Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada. ORCID
  5. Anna Liang: Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada.
  6. Zi-Jian Xiong: Department of Biochemistry, University of Toronto, Toronto, M5S 1A8, Canada.
  7. Xialian Weng: Department of Cell Biology, and Department of Pathology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
  8. Young Ah Kim: Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, New York, USA.
  9. Richard Collins: Cell Biology Program, Hospital for Sick Children, Toronto, M5G 1X8, Canada.
  10. William Trimble: Department of Biochemistry, University of Toronto, Toronto, M5S 1A8, Canada. ORCID
  11. Régis Pomès: Program in Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada. ORCID
  12. Gilbert G Privé: Department of Biochemistry, University of Toronto, Toronto, M5S 1A8, Canada. ORCID
  13. Wim Annaert: Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, Leuven, Belgium. ORCID
  14. Michael Schwake: Faculty of Chemistry, Biochemistry III, University of Bielefeld, 33615, Bielefeld, Germany.
  15. Joerg Heeren: Institut für Biochemie und Molekulare Zellbiologie, Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg-Eppendorf, Germany. ORCID
  16. Renate Lüllmann-Rauch: Institut für Anatomie, Christian-Albrechts-Universität Kiel, Kiel, Germany.
  17. Sergio Grinstein: Department of Biochemistry, University of Toronto, Toronto, M5S 1A8, Canada. sergio.grinstein@sickkids.ca.
  18. Elina Ikonen: Faculty of Medicine, Anatomy and Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland. elina.ikonen@helsinki.fi. ORCID
  19. Paul Saftig: Biochemisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany. psaftig@biochem.uni-kiel.de.
  20. Dante Neculai: 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. ORCID
PMID: 31387993 DOI: 10.1038/s41467-019-11425-0

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 cholesterollike 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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Grants

  1. /CIHR

MeSH Term

Animals
CD36 Antigens
CHO Cells
Carrier Proteins
Cholesterol, LDL
Cricetulus
Fibroblasts
Gene Knockout Techniques
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
Lipid Droplets
Lysosomal Membrane Proteins
Lysosomes
Membrane Glycoproteins
Mice
Niemann-Pick C1 Protein
Protein Domains
RNA, Small Interfering
Receptors, Scavenger

Chemicals

CD36 Antigens
Carrier Proteins
Cholesterol, LDL
Intracellular Signaling Peptides and Proteins
Lysosomal Membrane Proteins
Membrane Glycoproteins
NPC1 protein, human
Niemann-Pick C1 Protein
RNA, Small Interfering
Receptors, Scavenger
SCARB2 protein, human
Scarb2 protein, mouse
Journal Article Research Support, Non-U.S. Gov't

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