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Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes

Nature Cell Biology volume 7, pages 808–816 (2005)Cite this article

Abstract

Phosphatidylserine (PS) exposure is normally associated with apoptosis and the removal of dying cells. We observed that PS is exposed constitutively at high levels on T lymphocytes that express low levels of the transmembrane tyrosine phosphatase CD45RB. CD45 was shown to be a negative regulator of PS translocation in response to various signals, including activation of the ATP receptor P2X7. Changes in PS distribution were shown to modulate several membrane activities: Ca2+ and Na+ uptake through the P2X7 cation channel itself; P2X7-stimulated shedding of the homing receptor CD62L; and reversal of activity of the multidrug transporter P-glycoprotein. The data identify a role for PS distribution changes in signal transduction, rapidly modulating the activities of several membrane proteins. This seems to be an all-or-none effect, coordinating the activity of most or all the molecules of a target protein in each cell. The data also suggest a new approach to circumventing multidrug resistance.

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Figure 1: PS translocation by T cells is inversely related to the level of CD45RB.
Figure 2: P2X7-dependent PS translocation in cells from mice expressing different levels of CD45.
Figure 3: PS exposure stimulates CD62L shedding and T-cell migration.
Figure 4: Ca2+ uptake and PS translocation in cells stimulated with the P2X7 agonist BzATP.
Figure 5: P2X7-stimulated Ca2+ uptake is independent of PS translocation in lymphocytes expressing the P2X7-P allele.
Figure 6: P2X7 stimulation inhibits P-glycoprotein activity.
Figure 7: PS translocation inhibits P-glycoprotein-dependent drug export.
Figure 8: Schematic showing the role for changes in membrane PS distribution as a signal transduction mechanism regulating cellular responses.

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Acknowledgements

We thank M. Merkenschlager for valuable suggestions, S. Jarmin, D. Scott and G. Morgan for technical support, and G. Gilbert (VA Boston Healthcare System) for the gift of fluorescently labelled lactadherin. We are grateful to the Medical Research Council, the Jenner Institute and the Biotechnology and Biological Sciences Research Council for financial support.

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Authors and Affiliations

  1. MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, Du Cane Rd, London, W12 0NN, UK

    James I. Elliott, Carol Wooding, Kenneth Linton & Christopher F. Higgins

  2. Department of Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Rd, London, W12 0NN, UK

    Federica M. Marelli-Berg

  3. Department of Biomedical Science, Institute of Molecular Physiology, Addison Bldg, Western Bank, University of Sheffield, S10 2TN, UK

    Annmarie Surprenant

  4. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, CB2 4AT, Cambridge, UK

    Joanne C. Cooper & Denis R. Alexander

  5. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Robin L. Cassady-Cain

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Correspondence to James I. Elliott.

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The MRC have patented the concept of stimulating phosphatidylserine distribution as a means of overcoming multidrug resistance.

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Elliott, J., Surprenant, A., Marelli-Berg, F. et al. Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat Cell Biol 7, 808–816 (2005). https://doi.org/10.1038/ncb1279

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