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

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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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References

  1. Mellman, I. Endocytosis and molecular sorting. Annu. Rev. Cell Dev. Biol. 12, 575–626 (1996).

    Article  CAS  Google Scholar 

  2. Gruenberg, J. & Maxfield, F. Membrane transport in the endocytic pathway. Curr. Opin. Cell Biol. 7, 552–563 (1995).

    Article  CAS  Google Scholar 

  3. Griffiths, G., Hoflack, B., Simons, K., Mellman, I. & Kornfeld, S. The mannose-6-phosphate receptor and the biogenesis of lysosomes. Cell 52, 329–341 (1988).

    Article  CAS  Google Scholar 

  4. Kornfeld, S. Structure and function of the mannose-6-phosphate/insulin-like growth factor II receptors. Annu. Rev. Biochem. 61, 307–330 (1992).

    Article  CAS  Google Scholar 

  5. McNeil, H. P., Chesterman, C. N. & Krilis, S. A. Immunology and clinical importance of antiphospholipid antibodies. Adv. Immunol. 49, 193–280 (1991).

    Article  CAS  Google Scholar 

  6. Asherson, R. A., Cervera, R., Piette, J.-C. & Shoenfeld, Y. (eds) The antiphospholipid syndrome 1–339 (CRC Boca Raton, New York, London, Tokyo, (1996)).

  7. Chavrier, P., Parton, R. G., Hauri, H. P., Simons, K. & Zerial, M. Localisation of low molecular weight GTP binding proteins to exocytic and endocytic compartments. Cell 62, 317–329 (1990).

    Article  CAS  Google Scholar 

  8. Acharya, U. et al. The formation of Golgi stacks from vesiculated Golgi membranes requires two distinct fusion events. Cell 82, 895–904 (1995).

    Article  CAS  Google Scholar 

  9. Rabouille, C., Levine, T. P., Peters, J.-M. & Warren, G. An NSF-like ATPase, p97, and NSF mediate cisternal regrowth from mitotic Golgi fragments. Cell 82, 905–914 (1995).

    Article  CAS  Google Scholar 

  10. Cosson, P. & Letourneur, F. Coatomer (COPI)-coated vesicles: role in intracellular transport and protein sorting. Curr. Opin. Cell Biol. 9, 484–487 (1997).

    Article  CAS  Google Scholar 

  11. Gorvel, J. P., Chavrier, P., Zerial, M. & Gruenberg, J. Rab 5 controls early endosome fusion in vitro. Cell 64, 915–925 (1991).

    Article  CAS  Google Scholar 

  12. Brotherus, J., Renkonen, O., Herrmann, J. & Fisher, W. Novel stereochemical configuration in lysobisphosphatidic acid of cultured BHK cells. Chem. Phys. Lipids 13, 178–182 (1974).

    Article  CAS  Google Scholar 

  13. Wherrett, J. R. & Huterer, S. Enrichment of bis(monoacylglycero)phosphate in lysosomes from rat liver. J. Biol. Chem. 247, 4114–4120 (1972).

    CAS  PubMed  Google Scholar 

  14. Aniento, F., Emans, N., Griffiths, G. & Gruenberg, J. Cytoplasmic dynein-dependent vesicular transport from early to late endosomes. J. Cell Biol. 123, 1373–1388 (1993).

    Article  CAS  Google Scholar 

  15. Reaves, B., Horn, M. & Banting, G. TGN38/41 recycles between the cell surface and the TGN: brefeldin A affects its rate of return to the TGN. Mol. Biol. Cell 4, 93–105 (1993).

    Article  CAS  Google Scholar 

  16. Khamashta, M. A., Gharavi, A. E. & Wilson, W. A. (eds) New Orleans 7th Int. Symp. on Antiphospholipid Antibodies: Proceedings and Abstracts. Lupus 5, 343–558 (1996).

    Article  Google Scholar 

  17. Alarcon-Segovia, D. & Cabral, A. R. The antiphospholipid/cofactor syndromes. J. Rheumatol. 23, 1319–1322 (1996).

    CAS  PubMed  Google Scholar 

  18. Hörkkö, S. et al. Antiphosphoslipid antibodies are directed against epitopes of oxidized phospholipids. J. Clin. Invest. 98, 815–825 (1996).

    Article  Google Scholar 

  19. Ludwig,, Le Borgne, R. & Hoflack, B. Roles for mannose-6-phosphate receptors in lysosomal sorting, IGF-II binding and clathrin coat assembly. Trends Cell Biol. 5, 202–205 (1995).

    Article  CAS  Google Scholar 

  20. Wang, Z. Q., Fung, M. R., Barlow, D. P. & Wagner, E. F. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature 372, 464–467 (1994).

    Article  ADS  CAS  Google Scholar 

  21. Volpert, O., Jackson, D., Bouck, N. & Linzer, D. I. The insulin-like growth factor II/mannose 6-phosphate receptor is required for proliferin-induced angiogenesis. Endocrinology 137, 3871–3876 (1996).

    Article  CAS  Google Scholar 

  22. Groskopf, J. C., Syu, L. J., Saltiel, A. R. & Linzer, D. I. Proliferin induces endothelial cell chemotaxis throgh a G protein-coupled, mitogen-activated protein kinase-dependent pathway. Endocrinology 138, 2835–2840 (1997).

    Article  CAS  Google Scholar 

  23. Gruenberg, J., Griffiths, G. & Howell, K. E. Characterisation of the early endosome and putative endocytic carrier vesicles in vivo and with an assay of vesicle fusion in vitro. J. Cell Biol. 108, 1301–1316 (1989).

    Article  CAS  Google Scholar 

  24. Joutti, A. The stereoconfiguration of newly formed molecules of bis(monoacylglycerol)phosphate in BHK cells. Biochim. Biophys. Acta 575, 10–15 (1979).

    Article  CAS  Google Scholar 

  25. Somerharju, P. & Renkonen, O. Glycerophospho-(N-acyl)-ethanolamine lipids in degenerating BHK cells. Biochim. Biophys. Acta 573, 83–89 (1979).

    Article  CAS  Google Scholar 

  26. Umeda, M., Igarashi, K., Nam, K. S. & Inoue, K. Effective production of monoclonal antibodies against phosphatidylserine: stereo-specific recognition of phosphatidylserine by monoclonal antibody. J. Immunol. 143, 2273–2279 (1989).

    CAS  PubMed  Google Scholar 

  27. Reber, G., Tremblet, C., Bernard, C., Mermillod, B. & de Moerloose, P. Anticardiolipin antibodies and thrombosis: buffer's influence on the detection and quantitation of anticardiolipin antibody measured by ELISA. Thromb. Res. 57, 215–226 (1990).

    Article  CAS  Google Scholar 

  28. Karasawa, K., Satoh, N., Nakagawa, Y., Setaka, M. & Nojima, S. Specific binding of antibodies to platelet activating factor (PAF) as demonstrated by thin-layer chromatography/immunostaining. Lipids 26, 1122–1125 (1991).

    Article  CAS  Google Scholar 

  29. Gu, F., Aniento, F., Parton, R. & Gruenberg, J. Functional dissection of COP-I subunits in the biogenesis of multivesicular endosomes. J. Cell Biol. 139, 1183–1195 (1997).

    Article  CAS  Google Scholar 

  30. Griffiths, G., McDowell, A., Back, R. & Dubochet, J. On the preparation of cryosections for immunocytochemistry. J. Ultrastruct. Res. 89, 65–78 (1984).

    Article  CAS  Google Scholar 

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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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  2. Espen Stang
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  4. Philippe de Moerloose
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  5. Robert G. Parton
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  6. Jean Gruenberg
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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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