Abstract
The 'lipid raft' hypothesis has been a contentious topic over the past 5 years, with much of the immunology community divided into 'believers' and 'nonbelievers'. The disagreement is due mainly to the inability to observe these membrane domains directly and to the widespread use of experimental approaches of dubious utility. As a lipid raft 'dilettante' who has dabbled in the area over the years, I view the lipid raft model with some skepticism and disinterest because of that confusion. Although progress in the field has helped clarify some of the issues, more work is still needed to formally confirm the lipid raft hypothesis and to reestablish the scientific credibility of this area.
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References
Yu, J., Fischman, D.A. & Steck, T.L. Selective solubilization of proteins and phospholipids from red blood cell membranes by nonionic detergents. J. Supramol. Struct. 1, 233–248 (1973).
Ben-Ze'ev, A., Duerr, A., Solomon, F. & Penman, S. The outer boundary of the cytoskeleton: a lamina derived from plasma membrane proteins. Cell 17, 859–865 (1979).
Hooper, N.M. & Turner, A.J. Ectoenzymes of the kidney microvillar membrane. Differential solubilization by detergents can predict a glycosyl-phosphatidylinositol membrane anchor. Biochem. J. 250, 865–869 (1988).
van Meer, G. & Simons, K. Viruses budding from either the apical or the basolateral plasma membrane domain of MDCK cells have unique phospholipid compositions. EMBO J. 1, 847–852 (1982).
Brown, D.A. & Rose, J.K. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68, 533–544 (1992).
Brown, D.A., Crise, B. & Rose, J.K. Mechanism of membrane anchoring affects polarized expression of two proteins in MDCK cells. Science 245, 1499–1501 (1989).
Hanada, K., Nishijima, M., Akamatsu, Y. & Pagano, R.E. Both sphingolipids and cholesterol participate in the detergent insolubility of alkaline phosphatase, a glycosylphosphatidylinositol-anchored protein, in mammalian membranes. J. Biol. Chem. 270, 6254–6260 (1995).
Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).
Radhakrishnan, A. & McConnell, H.M. Condensed complexes of cholesterol and phospholipids. Biophys. J. 77, 1507–1517 (1999).
Brown, D.A. & London, E. Structure and origin of ordered lipid domains in biological membranes. J. Membr. Biol. 164, 103–114 (1998).
Shenoy-Scaria, A.M., Dietzen, D.J., Kwong, J., Link, D.C. & Lublin, D.M. Cysteine3 of Src family protein tyrosine kinase determines palmitoylation and localization in caveolae. J. Cell Biol. 126, 353–363 (1994).
Stefanova, I., Horejsi, V., Ansotegui, I.J., Knapp, W. & Stockinger, H. GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science 254, 1016–1019 (1991).
Zhang, W., Trible, R.P. & Samelson, L.E. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239–246 (1998).
Geppert, T.D. & Lipsky, P.E. Association of various T cell-surface molecules with the cytoskeleton. Effect of cross-linking and activation. J. Immunol. 146, 3298–3305 (1991).
Rozdzial, M.M., Malissen, B. & Finkel, T.H. Tyrosine-phosphorylated T cell receptor zeta chain associates with the actin cytoskeleton upon activation of mature T lymphocytes. Immunity 3, 623–633 (1995).
Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283, 680–682 (1999).
Pierce, S.K. To cluster or not to cluster: FRETting over rafts. Nat. Cell Biol. 6, 180–181 (2004).
Giocondi, M.C., Vie, V., Lesniewska, E., Goudonnet, J.P. & Le Grimellec, C. In situ imaging of detergent-resistant membranes by atomic force microscopy. J. Struct. Biol. 131, 38–43 (2000).
Pizzo, P. et al. Lipid rafts and T cell receptor signaling: a critical re-evaluation. Eur. J. Immunol. 32, 3082–3091 (2002).
Hao, M., Mukherjee, S. & Maxfield, F.R. Cholesterol depletion induces large scale domain segregation in living cell membranes. Proc. Natl. Acad. Sci. USA 98, 13072–13077 (2001).
Ahmed, S.N., Brown, D.A. & London, E. On the origin of sphingolipid/cholesterol-rich detergent-insoluble cell membranes: physiological concentrations of cholesterol and sphingolipid induce formation of a detergent-insoluble, liquid-ordered lipid phase in model membranes. Biochemistry 36, 10944–10953 (1997).
Maxfield, F.R. & Mayor, S. Cell surface dynamics of GPI-anchored proteins. Adv. Exp. Med. Biol. 419, 355–364 (1997).
Zacharias, D.A., Violin, J.D., Newton, A.C. & Tsien, R.Y. Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296, 913–916 (2002).
Kenworthy, A.K. & Edidin, M. Distribution of a glycosylphosphatidylinositol-anchored protein at the apical surface of MDCK cells examined at a resolution of <100 A using imaging fluorescence resonance energy transfer. J. Cell Biol. 142, 69–84 (1998).
Hancock, J.F. Lipid rafts: contentious only from simplistic standpoints. Nat. Rev. Mol. Cell. Biol. 7, 456–462 (2006).
Sharma, P. et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116, 577–589 (2004).
Varma, R. & Mayor, S. GPI-anchored proteins are organized in submicron domains at the cell surface. Nature 394, 798–801 (1998).
Prior, I.A., Muncke, C., Parton, R.G. & Hancock, J.F. Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J. Cell Biol. 160, 165–170 (2003).
Kawasaki, K., Yin, J.J., Subczynski, W.K., Hyde, J.S. & Kusumi, A. Pulse EPR detection of lipid exchange between protein-rich raft and bulk domains in the membrane: methodology development and its application to studies of influenza viral membrane. Biophys. J. 80, 738–748 (2001).
Kusumi, A., Koyama-Honda, I. & Suzuki, K. Molecular dynamics and interactions for creation of stimulation-induced stabilized rafts from small unstable steady-state rafts. Traffic 5, 213–230 (2004).
Kenworthy, A.K., Petranova, N. & Edidin, M. High-resolution FRET microscopy of cholera toxin B-subunit and GPI-anchored proteins in cell plasma membranes. Mol. Biol. Cell 11, 1645–1655 (2000).
Housden, H.R. et al. Investigation of the kinetics and order of tyrosine phosphorylation in the T-cell receptor ζ chain by the protein tyrosine kinase Lck. Eur. J. Biochem. FEBS 270, 2369–2376 (2003).
Amarasinghe, G.K. & Rosen, M.K. Acidic region tyrosines provide access points for allosteric activation of the autoinhibited Vav1 Dbl homology domain. Biochemistry 44, 15257–15268 (2005).
Bu, J.Y., Shaw, A.S. & Chan, A.C. Analysis of the interaction of ZAP-70 and syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance. Proc. Natl. Acad. Sci. USA 92, 5106–5110 (1995).
Almeida, P.F., Pokorny, A. & Hinderliter, A. Thermodynamics of membrane domains. Biochim. Biophys. Acta 1720, 1–13 (2005).
Gaus, K., Chklovskaia, E., Fazekas de St Groth, B., Jessup, W. & Harder, T. Condensation of the plasma membrane at the site of T lymphocyte activation. J. Cell Biol. 171, 121–131 (2005).
Douglass, A.D. & Vale, R.D. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Cell 121, 937–950 (2005).
Larson, D.R., Gosse, J.A., Holowka, D.A., Baird, B.A. & Webb, W.W. Temporally resolved interactions between antigen-stimulated IgE receptors and Lyn kinase on living cells. J. Cell Biol. 171, 527–536 (2005).
Burack, W.R., Lee, K.H., Holdorf, A.D., Dustin, M.L. & Shaw, A.S. Cutting edge: quantitative imaging of raft accumulation in the immunological synapse. J. Immunol. 169, 2837–2841 (2002).
Pike, L.J. Rafts defined. J. Lipid Res. 47, 1597–1598 (2006).
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Shaw, A. Lipid rafts: now you see them, now you don't. Nat Immunol 7, 1139–1142 (2006). https://doi.org/10.1038/ni1405
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DOI: https://doi.org/10.1038/ni1405
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