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

Author

Listed:
  • Saskia Heybrock

    (Christian-Albrechts-Universität Kiel)

  • Kristiina Kanerva

    (University of Helsinki
    Minerva Foundation Institute for Medical Research)

  • Ying Meng

    (Zhejiang University School of Medicine)

  • Chris Ing

    (Research Institute, The Hospital for Sick Children
    University of Toronto)

  • Anna Liang

    (Research Institute, The Hospital for Sick Children
    University of Toronto)

  • 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
    Hospital for Sick Children
    University of Toronto)

  • Régis Pomès

    (Research Institute, The Hospital for Sick Children
    University of Toronto)

  • Gilbert G. Privé

    (University of Toronto
    Princes Margaret Cancer Centre)

  • Wim Annaert

    (VIB-Center for Brain and Disease Research)

  • Michael Schwake

    (University of Bielefeld
    Northwestern University Feinberg School of Medicine)

  • Joerg Heeren

    (Universitätsklinikum Hamburg-Eppendorf)

  • Renate Lüllmann-Rauch

    (Christian-Albrechts-Universität Kiel)

  • Sergio Grinstein

    (University of Toronto
    Hospital for Sick Children)

  • Elina Ikonen

    (University of Helsinki
    Minerva Foundation Institute for Medical Research)

  • Paul Saftig

    (Christian-Albrechts-Universität Kiel)

  • Dante Neculai

    (Zhejiang University School of Medicine)

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.

Suggested Citation

  • 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 Annaer, 2019. "Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11425-0
    DOI: 10.1038/s41467-019-11425-0
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    Cited by:

    1. Peter H. Dixon & Adam P. Levine & Inês Cebola & Melanie M. Y. Chan & Aliya S. Amin & Anshul Aich & Monika Mozere & Hannah Maude & Alice L. Mitchell & Jun Zhang & Jenny Chambers & Argyro Syngelaki & Je, 2022. "GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Feng Wang & Yang Gao & Situ Xue & Luyao Zhao & Huimin Jiang & Tingting Zhang & Yunxuan Li & Chenxi Zhao & Fan Wu & Tana Siqin & Ying Liu & Jie Wu & Yechao Yan & Jian Yuan & Jian-dong Jiang & Ke Li, 2023. "SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Fangquan Chen & Hu Tang & Changfeng Li & Rui Kang & Daolin Tang & Jiao Liu, 2025. "CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    4. Jan Philipp Dobert & Jan-Hannes Schäfer & Thomas Dal Maso & Priyadarshini Ravindran & Dustin J. E. Huard & Eileen Socher & Lisa A. Schildmeyer & Raquel L. Lieberman & Wim Versées & Arne Moeller & Frie, 2025. "Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2," Nature Communications, Nature, vol. 16(1), pages 1-14, December.

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