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A lipid associated with the antiphospholipid syndrome regulates endosome structure and function

Nature volume 392, pages 193–197 (1998)Cite this article

Abstract

Little is known about the structure and function of membrane domains in the vacuolar apparatus of animal cells. A unique feature of late endosomes, which are part of the pathway that leads to lysosomes, is that they contain a complex system of poorly characterized internal membranes in their lumen. These endosomes are therefore known as multivesicular or multilamellar organelles1,2. Some proteins distribute preferentially within these internal membranes, whereas others are exclusively localized to the organelle's limiting membrane3. The composition and function of this membrane system are poorly understood. Here we show that these internal membranes contain large amounts of a unique lipid, and thus form specialized domains within endosomes. These specialized domains are involved in sorting the multifunctional receptor4 for insulin-like growth factor 2 and ligands bearing mannose-6-phosphate, in particular lysosomal enzymes. We also show that this unique lipid is a specific antigen for human antibodies associated with the antiphospholipid syndrome5,6. These antibodies may act intracellularly by altering the protein-sorting functions of endosomes.

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Figure 1: The 6C4 antigen is localized in late endosomes.
Figure 2: LBPA is enriched in late-endosome fractions and is the 6C4 antigen.
Figure 3: Electron microscopy.
Figure 4: The ingested anti-LBPA antibody causes IGF2/MPR redistribution and alter late endosome ultrastructure.
Figure 5: Sera from patients with antiphospholipid syndrome recognize LBPA.

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Acknowledgements

We thank M.-H. Beuchat for technical assistance; G. Griffiths for his help and support in the analysis of the monoclonal antibodies, H. Hardersen for preparing monoclonal antibodies; J. Deshusses for help in LBPA identification; M. Lindsay for help with electron microscopy; and G. van der Goot, U. Schiebler and F. Perez for reading the manuscript. This work was supported by grants from the Swiss National Science Foundation (to J.G.), the NHMRC of Australia (to R.G.P.), and the International Human Frontier Science Program (to J.G., R.G.P. and T.K.)

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Authors and Affiliations

  1. Department of Biochemsitry, Sciences II, 30 quai E. Ansermet, 1211-Geneva-4, Switzerland

    Toshihide Kobayashi, Karen S. Fang & Jean Gruenberg

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

    Espen Stang & Robert G. Parton

  3. Division of Angiology and Haemostasis, University Hospital of Geneva, 1211-Geneva-14, Switzerland

    Philippe de Moerloose

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  1. Toshihide Kobayashi
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Correspondence to Jean Gruenberg.

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Kobayashi, T., Stang, E., Fang, K. et al. A lipid associated with the antiphospholipid syndrome regulates endosome structure and function. Nature 392, 193–197 (1998). https://doi.org/10.1038/32440

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