Chapter 1 Lipid Rafts and Caveolae Organization
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The advent and almost universal acceptance of the Singer fluid-mosaic model over 30 years ago (Singer and Nicolson, 1972) led to the concept that membrane lipids spontaneously form a bilayer structure composed of randomly assembled lipids wherein proteins are inserted. In this view, lipids do not contribute to organizing proteins within the membrane. However, subsequent studies from many laboratories indicate that within model and biological membrane bilayers both lipids and proteins are non-randomly organized across (reviewed in Thompson et al., 1974; Schroeder and Nemecz, 1990; Schroeder et al., 1996) and within the lateral plane (reviewed in Thompson et al., 1974; Edidin, 1990; Schroeder et al., 1991a; Anderson, 1993; Bretscher and Munro, 1993; Glaser, 1993; Lisanti et al., 1995; Smart et al., 1995; Schroeder et al., 1996; Brown and London, 1998b; Hooper, 1999; Edidin, 2001; Schroeder et al., 2001a; Anderson and Jacobson, 2002; Lin and Tian, 2003). It is now believed that lipids such as cholesterol and sphingolipids spontaneously form cholesterol-rich, sphingolipid-rich lipid domains (reviewed in Bretscher and Munro, 1993; Brown, 1998; Brown and London, 1998b) (Fig. 1). Although cholesterol is not required for sphingolipids to form phase-segregated domains, cholesterol stabilizes such domains (reviewed in Bretscher and Munro, 1993; Brown, 1998; Brown and London, 1998b). Thus, by spontaneously organizing into domains, lipids such as cholesterol have been postulated to provide the driving force for selective recruitment and organization of proteins into domains (reviewed in Bretscher and Munro, 1993; Brown, 1998; Brown and London, 1998b). Cholesterol-rich microdomains, termed lipid rafts (reviewed in Marx, 2001), are present in almost all cell plasma membranes studied (Fig. 1), while caveolae, a specialized subclass of flask-shaped lipid rafts (Fig. 1), are present only in cells expressing caveolin protein (reviewed in Masserini and Ravasi, 2001). The literature contains more than 2000 publications from the past decade that ascribe a growing variety of functions to plasma membrane caveolae/lipid rafts. Many signaling pathways (reviewed in Lavie and Liscovitch, 2000) are organized in non-caveolar lipid rafts (Fig. 1) that individually appear to be relatively short lived, but that exhibit a stable overall pattern (reviewed in Edidin, 2001). Diverse plasma membrane processes such as diffusional cholesterol uptake/efflux to HDL (Fig. 1), SRB1-facilitated cholesterol uptake/efflux to HDL (Fig. 1), SRB1-facilitated selective cholesteryl ester uptake from HDL (Fig. 1), receptor-effector coupling (insulin receptor), cell signaling (eNOS), immune function, transcytosis, and cell recognition appear organized within cholesterol-rich microdomains such as caveolae (reviewed in Lavie and Liscovitch, 2000). Caveolae, in contrast to other lipid rafts, appear to be much more stable and longer lived (reviewed in Sheets et al., 1997; Pralle et al., 2000; Edidin, 2001; Anderson and Jacobson, 2002). While HDL-mediated cholesterol uptake/efflux via caveolae/lipid rafts is very rapid (reviewed in Smart and van der Westhuyzen, 1998), the mechanism(s) whereby cholesterol moves in and out of these highly cholesterol-rich domains is only beginning to be understood ("?" in Fig. 1). Growing evidence also indicates that many potential bioterror agents, including bacterial (anthrax toxin, cholera toxin, Shiga toxin, enterohemorrhagic E. coli Shiga-like toxin, NSP4 enterotoxic peptides) and plant (ricin) toxins (Sandvig and van Deurs, 1999; Abrami et al., 2003), viruses (Ebola, Marburg, Echovirus, influenza) (Scheiffele et al., 1997; Marsh and Pelchen-Matthews, 2000; Bavari et al., 2002; Empig and Goldsmith, 2002; Marjomaki et al., 2002; Sieczkarski and Whittaker, 2002), and parasites (malaria) (reviewed in Shin and Abraham, 2002), utilize lipid rafts/caveolae as cell entry portals (Norkin, 2001). With the exception of cholera toxin (binds GM1 in caveolae), however, the mechanisms whereby other toxins such as the rotaviral and retroviral enterotoxic peptides (Huang et al., 2001, 2004; Swaggerty et al., 2004) and other organisms are recruited to or influence lipid rafts/caveolae are only beginning to be resolved. The importance of cholesterol to the structure and protein organization of plasma membrane caveolae/lipid rafts is evidenced by the fact that cholesterol depletion or disruption abolishes many functions associated with caveolae/lipid rafts (reviewed in Smart and van der Westhuyzen, 1998). Nevertheless, very little is known regarding the lipid composition, distribution, and structure of caveolae/lipid rafts either in vitro or in intact cells. Part of the problem is that the majority of biochemical studies of caveolae/lipid rafts utilize detergents to isolate these microdomains from whole cells and, in a few cases, from purified plasma membranes. Interpretation of plasma membrane caveolar/lipid raft lipid composition and structure from whole cell detergent-based preparations is complicated by the presence of lipid domains from intracellular membranes (reviewed in Pike et al., 2002; Eckert et al., 2003). Even when they are isolated from purified plasma membranes, it is not possible to directly correlate the properties of detergent-resistant membrane domains with those of caveolae/lipid rafts isolated without detergents or in the physiologically intact membrane of living cells (reviewed in Pike et al., 2002; Eckert et al., 2003). For example, estimates of the amount of plasma membrane composed of caveolae/lipid rafts range from a few percent (determined by non-detergent isolation) to a majority (determined from detergent-resistant isolation) of membrane lipids, depending on the amount of detergent, type of detergent, and conditions used (Brown, 1998; Masserini and Ravasi, 2001). Finally, there is considerable discussion regarding the size of lipid rafts/caveolae, which, depending on the specific marker (GPI-anchor
