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Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport

Nature Cell Biology volume 1, pages 113–118 (1999)Cite this article

Abstract

The fate of free cholesterol released after endocytosis of low-density lipoproteins remains obscure. Here we report that late endosomes have a pivotal role in intracellular cholesterol transport. We find that in the genetic disease Niemann–Pick type C (NPC), and in drug-treated cells that mimic NPC, cholesterol accumulates in late endosomes and sorting of the lysosomal enzyme receptor is impaired. Our results show that the characteristic network of lysobisphosphatidic acid-rich membranes contained within multivesicular late endosomes regulates cholesterol transport, presumably by acting as a collection and distribution device. The results also suggest that similar endosomal defects accompany the anti-phospholipid syndrome and NPC.

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Figure 1: Cholesterol accumulates in late endosomes of NPC fibroblasts.
Figure 2: IGF2/MPR is redistributed to late endosomes in NPC fibroblasts.
Figure 3: U18666A causes cholesterol accumulation in late endosomes.
Figure 4: Zn2+ causes cholesterol accumulation in late endosomes of cells expressing ZnT2.
Figure 5: IGF2/MPR is redistributed to late endosomes after treatment with U18666A or Zn2+.
Figure 6: Antibodies against LBPA cause cholesterol accumulation in late endosomes.

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Acknowledgements

We thank R. Gagescu, G. van der Goot, F. Perez, and M. Rojo for critical reading of the manuscript. This work was supported by the Swiss National Science Foundation (J.G.), the NHMRC of Australia (R.G.P.) and by the International Human Frontier Science Program (J.G., R.G.P., T.K).

Correspondence and requests for materials should be addressed to J.G.

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Authors and Affiliations

  1. Department of Biochemistry, Sciences II, University of Geneva, 30 quai E. Ansermet, Geneva 4, 1211, Switzerland

    Toshihide Kobayashi, Marie-Hélène Beuchat, Sonia Frias & Jean Gruenberg

  2. Center for Molecular and Cellular Biology and Department of Physiology and Pharmacology University of Queensland, Center for Microscopy and Microanalysis, University of Queensland, Queensland 4072, Australia

    Margaret Lindsay & Robert G. Parton

  3. Howard Hughes Medical Institute and Department of Biochemistry Box 357370, University of Washington, Seattle, Washington, 98195-7370, USA

    Richard D. Palmiter

  4. Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Sciences, Bunkyo-ku, Tokyo 113, Japan

    Hitoshi Sakuraba

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  1. Toshihide Kobayashi
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Correspondence to Jean Gruenberg.

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Kobayashi, T., Beuchat, MH., Lindsay, M. et al. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat Cell Biol 1, 113–118 (1999). https://doi.org/10.1038/10084

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