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Membrane rafts in immunoreceptor signaling - reality vs. artefacts

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Host: Helga Schneider,

Membrane (lipid) rafts, microdomains enriched in glycosphingolipids, cholesterol, glycosylphosphatidylinositol-anchored proteins, Src-family kinases, several transmembrane adaptor proteins and G-proteins and markedly resistant to solubilization by certain detergents, appear to play important roles in early phases of immunoreceptor signaling, but also in regulation of a number of other receptors. Biological importance and even the very existence of rafts has been repeatedly questioned, as they are difficult to visualize by current microscopic techniques and most information on them comes from biochemical studies in detergent lysates.

For a long time there has been a discussion on the relevance of the detergent-resistant membrane microdomains (DRMs) to the native membrane rafts. Ideally, the DRMs should closely correspond to the native membrane microdomains before solubilization. However, this ideal situation may be more or less far from reality, because the detergent may induce various types of artefacts.

We believe that many of such problems are due to the use of Triton-X100 in most studies. Even at low temperatures, this detergent actually gradually dissolves DRMs and does not yield stable products. On the other hand, Brij-98 is much better in this respect – the properties and composition of DRMs obtained when using it are almost independent of temperature and detergent concentration.

Our data indicate that under these conditions leukocyte membranes yield a mixture of DRMs, differing in their protein composition, buoyant density and sensitivity to cholesterol depletion. These different types of DRMs appear to correspond to functionally different native membrane microdomains.

We believe that the current skepticism concerning the usefulness of DRMs is exaggerated and the biochemical approach should be rehabilitated. Under optimal conditions, DRMs may actually be as useful as various detergent-resistant multi-subunit receptor complexes.

Relevant recent papers from our laboratory:

Draber P, Vonkova I, Stepanek O, Hrdinka M, Kucova M, Skopcova T, Otahal P, Angelisova P, Horejsi V, Yeung M, Weiss A, Brdicka T. SCIMP : transmembrane adaptor protein involved in MHCII signaling. Mol Cell Biol. 2011 Sep 19. [Epub ahead of print]

Hrdinka M, Dráber P, Stepanek O, Ormsby T, Otahal P, Angelisova P, Brdicka T, Paces J, Horejsi V, Drbal K. PRR7 is a transmembrane adaptor protein expressed in activated T cells involved in regulation of T cell receptor signaling and apoptosis. J Biol Chem. 2011;286(22):19617-29.

Otahal P, Pata S, Angelisová P, Horejsi V, Brdicka T. The effects of membrane compartmentalization of csk on TCR signaling. Biochim Biophys Acta. 2011;1813(2):367-76.

Otahal P, Angelisova P, Hrdinka M, Brdicka T, Novak P, Drbal K, Horejsi V. A new type of membrane raft-like microdomains and their possible involvement in TCR signaling. J Immunol. 2010;184(7):3689-96.

This talk is part of the Immunology in Pathology series.

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