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Host‐cell lipid rafts: a safe door for micro‐organisms?

Host‐cell lipid rafts: a safe door for micro‐organisms? Biol. Cell (2010) 102, 391–407 (Printed in Great Britain) doi:10.1042/BC20090138 Review Host-cell lipid rafts: a safe door for micro-organisms? 1 1,2 Flavia ´ Sarmento Vieira*† ,GladysCorrea*† ˆ , Marcelo Einicker-Lamas‡ and Robson Coutinho-Silva* *Laboratorio ´ de Imunofisiologia, Universidade Federal do Rio de Janeiro, Instituto de Biof´ısica Carlos Chagas Filho, CCS, Rio de Janeiro, RJ, Brazil, †Pos-graduac ´ ¸ ao ˜ em Ciencias ˆ Biologicas ´ (Biof´ısica), Universidade Federal do Rio de Janeiro, Instituto de Biof´ısica Carlos Chagas Filho, CCS, Rio de Janeiro, RJ, Brazil, and ‡Laboratorio ´ de F´ısico-Qu´ımica Biologica, ´ Universidade Federal do Rio de Janeiro, Instituto de Biof´ısica, Carlos Chagas Filho, CCS, Rio de Janeiro, RJ, Brazil The lipid raft hypothesis proposed that these microdomains are small (10–200 nM), highly dynamic and enriched in cholesterol, glycosphingolipids and signalling phospholipids, which compartmentalize cellular processes. These membrane regions play crucial roles in signal transduction, phagocytosis and secretion, as well as pathogen adhesion/interaction. Throughout evolution, many pathogens have developed mechanisms to escape from the host immune system, some of which are based on the host membrane microdomain machinery. Thus lipid rafts might be exploited by pathogens as signalling and entry platforms. In this review, we summarize the role of lipid rafts as players in the overall invasion process used by different pathogens to escape from the host immune system. lipids, proteins (receptord, kinases, etc.), which inter- Introduction acts upon different stimuli triggering different cell Lipid rafts: a heterogeneous membrane responses. microdomain Since it was first described as a simple barrier bet- Over the last decade, several works have provided ween extra and intracellular compartments, differ- evidence that the plasma membrane is really more ent plasma membrane structural and composition mosaic than fluid (Pike, 2003; Engelman, 2005). It models have been proposed (Pike, 2009). Among was shown that lipids are not randomly distributed, these different models, the ‘fluid mosaic’ model leading to the proposal of a new model for under- proposed by Singer and Nicolson (1972) helps standing the biological membrane architecture (Pike, to provide answers about the different roles of the 2003; Garcıa-Marcos et al., 2006). The new model plasma membrane in cell biology, including trans- suggests that the plasma membrane is patchy, with port processes, cell protection, cell–cell contact and, segregated portions that are distinct in structure and function and that can also vary in thickness and com- principally, cell signalling. The plasma membrane position. From the first reports in the 1950s provided harbours many molecules involved in different cell by Palade (1953) and Yamada (1955) showing stable signalling cascades, such as glycero- and sphingo- flask-like invaginations of the plasma membrane, to the current view of multiple membrane domains al- These authors contributed equally to this work. lowing different protein–lipid and protein–protein To whom correspondence should be addressed (email gladys@biof.ufrj.br). Key words: cell signalling, lipid raft, membrane microdomain, parasite–host interactions that compartmentalize and temporarily cell interaction, pathogen. order the membrane moiety, many different reports Abbreviations used: AFM, atomic force microscopy; APC, antigen-presenting cell; DAMP, damage-associated molecular pattern; DRM, detergent-resistant still bring some controversy to the theme. membrane; ER, endoplasmic reticulum; EV-1, echovirus type 1; FRET, fluorescence resonance energy transfer; gp, glycoprotein; GPI, glycosylphosphatidylinositol; HCV, hepatitis C virus; HGF-R, hepatocyte growth factor receptor; Hsp, heat-shock protein; LPG, lipophosphoglycan; LPS, lipopolysaccharide; MLV, murine leukaemia virus; PAMP, pathogen-associated Fluid mosaic: A term used by Singer and Nicolson since 1972 to describe (C) molecular pattern; PIP , phosphatidylinositol 4,5-bisphosphate; PrP , the structural features of biological membranes. The plasma membrane was (cellular) prion protein; SARS-CoV, severe acute respiratory syndrome considered fluid because its components, such as lipids and membrane coronavirus; SV40, simian virus 40; T3SS, type 3 secretion system; TCR, T-cell proteins, move laterally or sideways throughout the membrane. receptor; TLR, Toll-like receptor. www.biolcell.org | Volume 102 (7) | Pages 391–407 391 F.S. Vieira and others The concept of lipid microdomains arose in the Figure 1 Membrane microdomains 1980s in the reports of Van Meer and Simons (1983) (a) A classical lipid-raft scheme. Membrane microdomains are and Klausner and colleagues (1980). It is now widely enriched with cholesterol and sphingolipids and also possess accepted that lipid rafts are not pre-existing do- associated proteins such as GPI-anchored protein. (b) A cave- mains in which proteins dynamically partition, but olin-rich lipid-raft scheme. The membrane microdomain can form invaginations called caveolae. Caveolin is a marker pro- rather that the formation and disassembly of raft tein of caveolae structure. domains is a dynamic process (see, for example, Plowman et al., 2005). Later, rafts were visually observed by Simons and Ikonen (1997), who de- scribed them as lipid rafts, imagining these micro- domains as floating islands in the membrane (Triantafilou et al., 2002; Luo et al., 2008). Further studies provided evidence that lipid rafts are mainly composed of cholesterol, (glyco)sphingolipids and (glycero)phospholipids, with a high degree of satur- ation in their fatty-acid chains (Figure 1a). The tight interaction between these components provides the basis of their packing and rigidity, which leads to a phase separation (Simons and Ikonen, 1997). This tight-packing organization of lipid rafts con- fers their resistance to solubilization by non-ionic detergents, which allows their separation and isol- ation from the rest of the plasma membrane us- ing sucrose-density gradients (Brown and Rose, 1992). The development of this method is widely used for the isolation and analysis of lipid rafts and their associated proteins in different cell types (Triantafilou et al., 2002; Bouillon et al., 2003; Chazal and Gerlier, 2003; Laughlin et al., 2004; Tortelote et al., 2004; Vacca et al., 2004; Olsson and Sundler, 2006). However, new considerations this method, as discussed by Lai (2003). Another effi- about the term ‘detergent-resistant membranes’ cient tool used to study lipid rafts is cholesterol deple- (DRMs) had already been reviewed. DRM no longer tion, by the use of cholesterol-removing and -binding defines the bona fide rafts (Lai, 2003), because this agents, such as cyclodextrins and filipin (Schnitzer technique can create several artifacts, such as the loss et al., 1994; Luker et al., 2000). This method is based of membrane components during extraction (Edidin, on the theory that cholesterol acts as a dynamic ‘glue’, 2003). However, many proteins functionally involved holding lipid rafts together, and its removal from the with microdomains had already been described via Lipid raft: A cholesterol- and sphingolipid-enriched microdomain or platform found in cell membranes. Sphingolipids: A class of lipids derived from the aliphatic amino alcohol sphingosine. These compounds play important roles in signal transmission and cell recognition. Sucrose-gradient centrifugation: A type of centrifugation often used to purify enveloped viruses and also to separate cell organelles. This method is also used to purify lipid rafts. DRM: Detergent-resistant membrane was a denomination used for an important early indication that rafts may exist in cells through the observation that cell membranes are not fully solubilized by non-ionic detergents, such as Triton X-100, at low temperatures. Cyclodextrins: Cyclodextrins (cycloamyloses) belong to a family of cyclic oligosaccharides. Methyl-β-cyclodextrin is employed for the cholesterol removal of cell membrane. Filipin: Filipin was isolated from the fungus Streptomyces filipinensis. Often used in cellular biology as an inhibitor of the raft/caveolae endocytosis pathway in mammalian cells. C  C 392 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review membrane results in the dispersion of raft-associated The techniques of AFM and confocal microscopy in lipids and proteins (Manes ˜ et al., 2003; Hawkes combination with inhibitors of cholesterol synthesis and Mak, 2006). Considering that cholesterol is and an agent that chelates cholesterol were allied in a relatively rigid molecule, it was postulated that the study of lipid rafts in this context, as well as the cholesterol-rich microdomains have a slower mobility pursuit of flotillin-1 and the ganglioside G ,which M1 in the membrane than non-raft regions (Shaw, 2006). are known markers of microdomains. Nowadays, more accurate methods are employed The lipid raft size in vivo has been estimated to in order to improve the research into lipid rafts. be 25–700 nm by using FRET and single-molecule- Fluorescent biosensors that are capable of tracking tracking microscopy. The size, arrangement and signalling events in live cells are powerful tools movement of lipid rafts are dynamic and can be to aid the understanding of dynamic cellular sig- found in localized cellular structures, such as filipodia nalling (Gao and Zhang, 2008). The proposals re- and cell adhesion points (Chazal and Gerlier, 2003; garding microdomains postulated in the late 1990s Hawkes and Mak, 2006). It is accepted that mem- can be now supported by, for example, FRET (fluor- brane rafts in basal conditions are small regions of escence resonance energy transfer) microscopy and the lipid membranes, which tend to cluster after cer- AFM (atomic force microscopy). Given the import- tain stimuli to form larger structures that are also ance of the Akt pathway in cell proliferation and sur- called platforms (Liu and Anderson, 1995; Holo- vival, and thus its involvement in cancer, this path- painen et al., 1998; Kusumi et al., 2004; Bollinger way has been increasingly studied. Gao and Zhang et al., 2005; Rao and Mayor, 2005). It is important (2008) developed a genetically encodable Akt activ- to mention that the assembly of those small regions ity reporter and analysed the spatiotemporal dynam- (pre-rafts) seems to be dependent on the presence of ics of Akt activity within plasma membrane mi- ceramide (Liu and Anderson, 1995; Bollinger et al., crodomains by FRET. Using this tool, it was ob- 2005). In addition to the lipid components, a variety served that Akt activity is differentially regulated of cell receptors and signalling proteins are known to between raft and non-raft regions of the plasma mem- be associated with membrane rafts. They include the brane (Gao and Zhang, 2008). In addition, AFM GPI (glycosylphosphatidylinositol)-anchored pro- has been described as an essential tool to follow teins, kinases and adaptor molecules that act as in- the motion of lipid-raft microdomains and proteins termediate transducers for many receptors, including that might be interacting with them (Henderson TCRs (T-cell receptors) and BCRs (B-cell receptors) et al., 2004). Several works have demonstrated the (Montixi et al., 1998; Cheng et al., 1999; Chazal and importance of AFM in experimental approaches to Gerlier, 2003; Hawkes and Mak, 2006). study lipid rafts. Poole et al. (2004), studying MDCK The role of lipid rafts in different cell types has (Madin–Darby canine kidney) cell microvilli, sugges- been the subject of numerous studies, and their ted that lipid rafts might be involved in the main- physiological significance for cell biology has re- tenance of these structures. These authors used a cently become clear. These membrane regions play an combination of AFM and laser-scanning confocal important role in a variety of cellular functions, in- microscopy in order to attest their hypothesis. cluding polarization, signal transduction, endocyt- Cecchi et al. (2009) interestingly observed an increase osis, secretion, cell–cell and cell–pathogen adhes- in specific amyloid ligands when raft components, ion (Manes ˜ et al., 1999; Martin-Belmonte et al., such as cholesterol, are depleted. This group sugges- 2000; Harris et al., 2001; Grimmer et al., 2002; ted that cholesterol can reduce membrane modifica- Ha et al., 2003; Pierini et al., 2003; Jacobson et al., tions triggered by amyloid residues at the lipid-raft 2007). One of the most widely appreciated roles of level, possibly involving physicochemical features. lipid rafts is the recruitment and concentration of FRET: Fluorescence (or Forster) ¨ resonance energy transfer is a mechanism involving energy transfer between two fluorophores. AFM: Atomic force microscopy is a very high-resolution type of scanning probe microscopy, with a nanometre resolution. Ceramides: A family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane. GPI anchor: Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during post-translational modification. www.biolcell.org | Volume 102 (7) | Pages 391–407 393 F.S. Vieira and others molecules involved in cellular signalling. The forma- transduction and tumour suppression (Razani et al., tion of a molecular cluster and their signal transduc- 2002; Duncan et al., 2002; Manes ˜ et al., 2003; tion machinery in membrane rafts leads to enhanced Cohen et al., 2004; Tortelote et al., 2004). The signalling efficiency (Triantafilou et al., 2002). protein caveolin-1 has itself been implicated in Anderson et al. (2000) reported that MHC class signal transduction, because of its direct interaction II molecules are located in lipid rafts of murine and with a multitude of signalling molecules through the human B-cell lines. Such a localization seems to be caveolin-scaffolding domain. In addition, caveolin-1 critical for T-cell activation. The binding of TCRs to has been shown to be phosphorylated on tyrosine MHC class II molecules of APCs (antigen-presenting residues during some signalling events (Mastick and cells) occurs in lipid rafts. The raft aggregation pro- Saltiel, 1997; Okamoto et al., 1998; Ushio-Fukai motes tyrosine phosphorylation and recruitment of et al., 2001; Duncan et al., 2002). signalling proteins, but excludes certain proteins, Vesicular transport is one of the most important such as the tyrosine phosphatases CD45 and CD43, roles of caveolae, including endocytosis when cave- which leads to the formation of a supramolecular ac- olae are, indeed, functional endocytic vesicles (Lajoie tivation cluster (Monks et al., 1998). However, in vivo, and Nabi, 2007), and promotes transcytosis of specific TCR does not constitutively reside in membrane lipid macromolecules in endothelial cells (Minshall et al., rafts. After T-cell activation, the TCR moves into the 2003). Previous studies proposed that, as well as ca- rafts (Monks et al., 1998; Anderson et al., 2000; Luo veolae, caveolins also have an important involvement et al., 2008). This characteristic was also observed for in signal transduction, principally due to its scaffold other molecules that migrate to the lipid rafts after domain, which acts as a harbour for different cytoso- specific stimulation in several physiological events. lic proteins involved in different signalling cascades There is a specific subtype of microdomain called (Sargiacomo et al., 1993; Lisanti et al., 1994; Razani caveolae. These structures are small membrane- et al., 2002; Cohen et al., 2004). surface invaginations, which were initially described as cave-like invaginations of the plasma membrane, Pathogens and rafts: interacting to survive 50–100 nm in size and found in many cell types (Fig- It is well known that intracellular parasites have ure 1b). Although they were identified by electron many mechanisms to avoid the host defence response. microscopy more than 50 years ago as an invagin- The inhibition of lysosomal fusion, a classical escape ation in the plasma membrane with a flask-shape mechanism, was observed after infection by Mycobac- morphology that can be singular or found in detached terium, Chlamydia, Toxoplasma (Coutinho-Silva et al., 2009) and Trypanosoma cruzi (Hall and Joiner, 1993), grape-like clusters, caveolin caveolae have remained for example. Another way that pathogens can pro- enigmatic structures (Palade, 1953; Yamada, 1955; long their survival inside the host is by prevention of Razani et al., 2002; Lajoie et al., 2009). Forty years after the description of caveolae, their structure host-cell apoptosis and by the modulation of reactive could be more closely studied upon the discovery of oxygen and nitrogen species generation (Coutinho- caveolin, the signature protein present in calveolae Silva et al., 2009). (Rothberg et al., 1992). It has been suggested that ca- An interesting manner that allows pathogens to veolae can be stabilized by caveolin and, additionally, evade the immune system is through membrane may further become immobilized by filamin, which microdomains. As signalling for the innate and binds to caveolin, as well as to the actin cytoskeleton adaptative immune responses is initiated in rafts, (Stahlhut and van Deurs, 2000; Hommelgaard some pathogens have evolved mechanisms to subvert et al., 2005). Since that time, caveolae have been this signalling by co-opting raft-associated pathways implicated and demonstrated to be important in (Manes ˜ et al., 2003). Different pathogens, such as a variety of cellular functions, including endocytic viruses, bacteria and protozoa, can use the host-cell processes, cholesterol and lipid homoeostasis, signal lipid rafts to secure their entrance and maintenance Caveola: A special type of lipid raft, comprising small (50–100 nanometre) invaginations of the plasma membrane, found in many vertebrate cell types. Caveolins: A family of proteins involved in receptor-independent endocytosis. The caveolin gene family has three members in vertebrates, caveolin-1, -2 and -3. Pathogens: The term pathogen is most commonly used to refer to infectious organisms. These include bacteria, viruses, protozoa and fungi. C  C 394 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review Figure 2 Pathogen–raft interaction Several pathogens can directly interact with different target cells through membrane microdomains in different manners. It is known that the entry via lipid rafts can avoid lysosomal fusion and therefore allow pathogen survival. In addition, parasites might modulate signalling pathways, including lipid-raft-associated protein kinases [Srfk (Src family kinases)]. Especially viruses, which do not have their own protein synthesis machinery, target the ER after subverting the lysosomal pathway. Lys, lysosome; PV, parasitophorous vacuole. inside target cells (Figure 2). The benefit provided by entry into the cell. Many animal viruses exploit the by interaction with lipid rafts can vary from one endocytic machinery of their host cell for infection, pathogen to another. The list of pathogens that hijack and lipid rafts are often a site for entry, assembly rafts also includes the non-classical infectious agent, and budding of microbial pathogens, as confirmed the scrapie PrP (prion protein). Here, we provide an by biochemical approaches and microscopy evidence update of how different pathogens modulate host im- (Kovbasnjuk et al., 2001; Suomalainen, 2002; Lu mune response by using their lipid rafts. et al., 2008). For non-enveloped viruses, after the attachment to cell-surface receptors, the bound capsids are intern- How do different pathogens interact with alized, mostly by invagination of the plasma mem- the host via lipid rafts? brane and intracytoplasmic vesiculation. The involve- Viruses: exploiting lipid rafts ment of lipid rafts in mediating this process has been Different viruses have evolved strategies to subvert described for several viruses, as reviewed by Chazal raft-associated signalling, enabling their efficient rep- and Gerlier (2003). The most thoroughly studied of lication in immune cells, and at the same time block- these is SV40 (simian virus 40). SV40 initiates in- ing the immune response that is elicited by the target fection by binding to the MHC class I molecules cells (Hawkes and Mak, 2006). (Stang et al., 1997; Anderson et al., 1998; Duncan et al., 2002; Chazal and Gerlier, 2003). SV40 dir- (a) Entry ectly associates with caveolae, leading to a loss of Virus entry into a host cell involves the binding of the actin stress fibres and the appearance of actin tails virus to one or more cell-surface receptors, followed Budding: In virology, budding is a form of viral shedding by which enveloped viruses acquire their external envelope from the host-cell membrane, which bulges outwards and encloses the virion. www.biolcell.org | Volume 102 (7) | Pages 391–407 395 F.S. Vieira and others emanating from the virus containing caveolae bis virus), as well as other alphaviruses, depends on (Duncan et al., 2002; Pelkmans et al., 2002). the presence of cholesterol and sphingolipid in the Moreover, caveolae transport SV40 particles to the target membrane (Bron et al., 1993; Lu et al., 1999; ER (endoplasmic reticulum), where the virus is dis- Smit et al., 1999; Chazal and Gerlier, 2003), which assembled (Norkin et al., 2002; Chazal and Gerlier, are known to be abundant in lipid rafts (Pike, 2003). 2003). Other enveloped viruses enter the host cell using a Both the polyoma virus and EV-1 (echovirus type 1) pH-independent fusion process, as found for HIV. also directly associate with caveolae (Richterovae ´ t al., The HIV-1 Env is composed of two associated gly- 2001; Marjomaki et al., 2002). The polyoma virus coprotein subunits, gp120 and gp41. The external associates with caveolin-1 after entry, a possible as- gp120 is responsible for the attachment to the cel- sociation with ‘caveosomes’ and trafficking to the lular receptors and co-receptors (chemokine receptor ER (Richterova et al., 2001). EV-1 is internalized family member CCR5 and/or CXCR4), whereas the into caveolae using the integrin α2β1 as cellular transmembrane protein gp41 is responsible for the receptor. Studies have shown that EV-1, α2β1integ- fusion of viral envelope with the plasma membrane rin and caveolin-1 were internalized together in vesi- of the target CD4 T-cells (Popik et al., 2002). Rafts cular structures and accumulated in a perinuclear are proposed to be the specific cell membrane regions compartment (Marjomaki et al., 2002). Interestingly, in which these clustering events occur. It is import- it was shown (Richterova´ et al., 2001; Marjomaki ant to point out that the entry of HIV-1 through rafts et al., 2002) that the entry of the virus does not oc- may direct the virus complex into a favourable com- cur by endocytosis through the classic clathrin-coated partment for a productive infection (Fantini et al., vesicles. However, these authors observed that virus 2002; Chazal and Gerlier, 2003; Manes ˜ et al., 2003; particles had merged with caveolin-1, and incuba- Luo et al., 2008). A recent study showed that HIV tion with methyl-β-cyclodextrin inhibited the virus entry into macrophages is sensitive to membrane cho- entry. lesterol depletion, which favours the hypothesis for Enveloped viruses also use rafts during the intern- a role of macrophage lipid rafts in the HIV-1 entry alization and fusion process. The entry of enveloped process (Carter et al., 2009). virus involves virus attachment, followed by close ap- The cellular receptor for the MLV, CAT1 (cationic position of the virus and plasma membranes. Then amino acid transporter 1), is physically associated the two membranes fuse to deliver the virus’ gen- with caveolin in membrane rafts, and the disruption omic RNA into the host cells, which requires con- of rafts inhibits the early step of MLV infection, sug- version of the virus-encoded envelope glycoprotein gesting that the localization of the receptor within (Env) from its native state to its fusion-activated rafts is crucial for the virus entry (Lu and Silver, 2000). form (Fantini et al., 2002; Chazal and Gerlier, 2003; It was already demonstrated that the penetration of Manes ˜ et al., 2003). The glycoproteins of several vir- filoviruses, such as Ebola virus and Marburg virus, is uses, including influenza virus, HIV, MLV (murine inhibited after cholesterol depletion of the host cell, leukaemia virus), measles virus and Ebola virus, are and, after internalization, viral proteins co-localized associated with host-cell membrane rafts (Scheiffele with caveolin (Bavari et al., 2002; Empig and et al., 1997; Manie et al., 2000; Vincent et al., 2000; Goldsmith, 2002; Chazal and Gerlier, 2003). Pickl et al., 2001; Bavari et al., 2002). Additionally, there is biochemical evidence showing that choles- (b) Assembly terol and possibly cholesterol-rich lipid rafts are re- The late stages of the viral life cycle are the assembly quired for efficient porcine pseudorabies virus entry of viral components into virions, maturation into (Desplanques et al., 2008). Another recent study re- infectious particles, and, in the case of enveloped ported that the SARS-CoV (severe acute respiratory viruses, release from the cell via a budding process syndrome coronavirus) receptor is located in lipid (Ivanchenko et al., 2009). Assembly and budding are rafts and the productive entry of the SARS-CoV the last, but critical, steps in the virus life cycle for pseudovirus into the host cell requires the presence the survival of the virus and its disease-producing of intact and functional lipid rafts (Lu et al., 2008). ability in the host (Chen et al., 2008; Wang et al., Fusion of SFV (Semliki Forest virus) and SIN (Sind- 2009). An explanation as to why viruses use lipid rafts C  C 396 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review is that these structures offer an efficient system for disrupt cellular and/or humoral immune responses to concentrating all the virus proteins that are required the virus (Vanderplasschen et al., 1998; Peterlin and for the assembly of new virions, as reviewed by Nayak Trono, 2003). et al. (2004). The lipid composition of the influenza virus HIV-1 is enclosed in a lipid envelope enriched family is due to affinity of the haemagglutinin in cholesterol and sphingolipids, suggesting spe- and neuraminidase glycoproteins for these lipids, cific membrane localization for assembly (Aloia et al., and some authors suggest that the influenza virus 1993; Campbell et al., 2001; Raulin, 2002). Recent buds from raft domains (Chazal and Gerlier, 2003; studies have reported that rafts represent a necessary Nayak et al., 2004). step during HIV-1 assembly. With similar methods of Several reports suggest that HIV-1 buds from lipid both assembly and budding within membrane rafts, rafts (Campbell et al., 2001; Fantini et al., 2002). many other viruses, including influenza virus, measles HIV incorporates raft-associated complement regu- virus, Ebola virus and possibly Sendai virus, also use latory proteins, which remain functionally active on lipid rafts as assembly platforms (Luo et al., 2008). the surface of the virus and down-regulate the com- In this regard, it was also suggested that the RSV plement cascade (Manes ˜ et al., 2003; Peterlin and (respiratory syncytial virus) assembled within lipid Trono, 2003). rafts where viral proteins co-localize with caveolin-1 After budding from the host cell, viruses are re- (Brown et al., 2002a, 2002b). leased into the surrounding medium to infect other Although rafts are involved in virus assembly, cells. The mechanism of this bud completion is as yet we have to keep in mind that only a fraction of unclear and a number of both viral and host factors viral proteins are found associated with rafts; this may affect this process (Nayak et al., 2004; Luo et al., could be due to the poor biochemical characteriza- 2008). tion of raft subsets or to the transient nature of the association. Bacteria: taking advantage of host-cell membrane microdomains (c) Budding Studies have been suggested that several bacteria in- Whereas non-enveloped viruses are released from teract with host lipid rafts to enter and survive in- the infected cell by disruption of the plasma mem- side the cell (Manes ˜ et al., 2003; Hawkes and Mak, brane, enveloped viruses contain a host-cell-derived 2006). The mechanisms that underlie this interaction lipid bilayer, which is acquired during budding are starting to be unravelled. Activation of secretion, (Garoff et al., 1998; Chazal and Gerlier, 2003). Mem- binding, perforation of the host-cell membrane and brane lipids are not randomly incorporated into the signalling to trigger bacterial phagocytosis are in- viral envelope. In addition, some authors suggest volved with components of membrane microdomains that viral glycoproteins determine the site of virus (Lafont and van der Goot, 2005). It was found that assembly and budding (Garoff and Simons 1974; the polarity of epithelial cells and the involvement Allison et al., 1995; Vennema et al., 1996; Bruss, of CD55 are important in the interaction of bacteria 2004). On the other hand, in polarized epithelial with lipid rafts (Peiffer et al., 1998). Two advantages cells, the viral glycoproteins contain sorting signals in bacteria invasion were postulated: (1) avoidance of or motifs and are directed to the specific site where as- the intracellular degradative pathway and (2) trig- sembly and budding will occur (Nayak et al., 2004). gering of the cell signalling cascades that lead to Lipid rafts function as microdomains for concentrat- membrane ruffling and cytoskeleton rearrangement ing viral glycoproteins and may serve as a platform (Manes ˜ et al., 2003). for virus budding. The structures have the ability to The avoidance of the host immune pathway regulate budding; however, the mechanism by which after phagocytosis was developed by several micro- the lipid raft can favour the budding and/or fission organisms, mainly bacterial cells. Subversion of process is as yet unknown (Nayak et al., 2004; Luo phagosome fusion with lysosome and presentation et al., 2008). The budding of new virions from the raft to immune system was observed in pathogens such allows the exclusion or inclusion of specific host-cell as Mycobacterium and Chlamydia. Gatfield and Pieters membrane proteins in the virus particle, which could (2000) showed for the first time the relevant role of www.biolcell.org | Volume 102 (7) | Pages 391–407 397 F.S. Vieira and others cholesterol for mycobacteria entry into macrophages. into macropinosomes containing Brucella. In con- In addition, some bacteria hidden inside the cell took trast, the lysosomal glycoprotein LAMP-1 (lysosome- advantage of host lipids to generate phagosomes and associated membrane protein 1) and the host-cell survive inside them, such as Brucella spp. and Legion- transmembrane protein CD44 were excluded from ella pneumophila (Naroeni and Porte, 2002; Watarai these macropinosomes (Watarai et al., 2002). Inter- et al., 2001, 2002). Besides, these parasites can hi- estingly, it had already been demonstrated that Bru- jack rafts, altering host-cell signalling, for example cella abortus infection is related with PrP (cellular Shigella flexneri (Lafont et al., 2002). The interaction PrP), one of the lipid raft-associated molecules on the between pathogens and the host cell can also mod- plasma membrane of different cell types. In addition, ulate other host features, such as cytoskeletal dy- Watarai et al. (2002, 2004) postulated that the sig- namics. In the case of S. flexneri, cholesterol removal nal transduction induced by the interaction between decreased the binding of an effector protein, called bacterial Hsp60 (heat-shock protein 60) and PrP on IpaB, with host CD44, which is known to be in- macrophages contributes to the establishment of B. volved in cytoskeleton-dependent signalling events abortus infection. Coxiella burnetti, the causative agent (Hirao et al., 1996). of human acute and chronic Q fever, can be found in Seveau et al. (2004) demonstrated for the first time cholesterol-rich vacuoles with lipid-raft proteins, and that the cell adhesion molecule, E-cadherin, and also can modulate the cholesterol metabolism from HGF-R (hepatocyte growth factor receptor) require the host cell (Howe and Heinzen, 2006). The im- host lipid rafts to mediate Listeria monocytogenes entry. portance of cholesterol in C. burnetti infection can be It had already been reported by the same group that, directly associated with its pathophysiology (Howe in L. monocytogenes, two major proteins, internalin and and Heinzen, 2006). InIB, mediate bacterial invasion into host It was also suggested that pathogens and particles and bind to E-cadherin and HGF-R respectively that bind to lipid-raft components may trigger (Cossart et al., 2003). the macrophage autophagic machinery (Amer et al., Salmonella, Shigella and the entheropathogenic 2005). L. pneumophila and a uropathogenic E. coli can Escherichia coli have a common requirement for a T3SS stimulate autophagosome formation, which contains (type III secretion system), which is a multicompon- both lipid rafts and autophagy-involved cell mo- ent molecular syringe that allows the translocation of lecules. In addition, it was observed that internaliza- so-called effector proteins from bacterial cytoplasm, tion of pathogen and the autophagy stimulation are through the inner and outer bacterial membrane, as cholesterol sensitive and the pathogens harbouring well as the host plasma membrane, directly into cyto- in autophagosomes could avoid immediate killing plasm (van der Goot et al., 2004; Lafont and van (Amer et al., 2005). Components of lipid rafts do der Goot, 2005). Activation of this system requires not appear to be essential for assembly of autophago- contact with the host cell, and has effector proteins, somes, but instead may affect a signal transduction named SipB and SipC for Salmonella, IpaB and IpaC pathway dedicated to host recognition of microbes, for Shigella and PopB and PopC for Pseudomonas. as suggested by Amer et al. (2005). Hayward et al. (2005) showed a new requirement for The specific subtype of microdomain, caveolae, also cholesterol, for which the main binding determin- appeared to be directly involved in the interaction ant was SipB/IpaB to host cells, and Lafont and van with bacteria (Duncan et al., 2002), such as Chlamydia der Goot (2005) suggest that this must occur down- trachomatis (Norkin et al., 2001), E. coli (Shin et al., stream of the T3SS activation. 2000) and Campylobacter jejuni (Wooldridge et al., The pathogenic bacterium Brucella, which causes 1996). Among the Chlamydiae, depending on the brucellosis, can avoid bactericidal activity of mac- serovar, or the species, one or both of the caveolin rophages triggering the cAMP/PKA (protein kinase proteins (1 or 2) may play important roles in the de- A) pathway. This process occurs immediately after velopmental cycles (Stuart et al., 2003; Webley et al., the first contact with the target cell (Jimenez de 2004). Bagues et al., 2005). Lipid-raft-associated molecules, Porphyromonas gingivalis capitalizes on the lipid- such as GPI-anchored proteins, G gangliosides raft structure to down-modulate innate defence M1 and cholesterol, were found selectively incorporated mechanisms. Remarkably, this novel mechanism C  C 398 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review employs host-cell signalling pathways through lipids, was labelled with DilC16 (1,1 -dihexadecyl- cross-talk between TLR2 (Toll-like receptor-2)/ 3,3,3 ,3 -tetramethylindocarbocyanine), a marker for chemokine receptor 4 to attenuate the protective lipid rafts, and DiO (3,3 -dilinoleyloxacarbocyanine), and bactericidal response to P. gingivalis infection a marker for non-raft membrane domains, which sug- (Darveau, 2009). gests that both contribute to the formation of the Campylobacter enteritis, regardless of its own in- vacuole membrane (Ronneb ¨ aumer ¨ et al., 2008). This vasiveness, promotes the translocation of the non- report points to an alternative method of fungal in- invasive bacteria E. coli across the intestinal epithe- fection in host cells that is raft-independent. lium via a lipid-raft-mediated transcellular process (Kalischuk et al., 2009). Furthermore, bacterial toxins, such as cholera toxin, listeriolysin O and anthrax toxin, also tar- Protozoa: hiding with lipid rafts get lipid domains (Orlandi and Fishman, 1998; The protozoan invasion in the host cell occurs during Coconnier et al., 2000; Abrami et al., 2003). More specific stages of the pathogen life cycle. Intracellular recently, several pathogenic bacteria have been asso- entrance of these parasites does not depend on the ciated with lipid rafts, such as Francisella tularensis endocytic machinery of the host cell, as in the case (Tamilselvam and Daefler, 2008), Helicobacter pylori of bacteria and viruses. This can be explained due to (Lai et al., 2008), P.s gingivalis (Hajishengallis et al., the protozoan’s larger size (5–10 μm). As shown for 2006; Wang and Hajishengallis, 2008) and M. tuber- other pathogens, the exploitation of host membrane culosis (Shin et al., 2008), which are members of an microdomains by protozoa constitutes a crucial step ever increasing list as the years progress. Recently, for its maintenance, survival and modulation of host Caserta et al. (2008) described evidence for the first immune response (Manes ˜ et al., 2003). time that Clostridium perfringens enterotoxin acts in- Members of the Apicomplexa group, such as Tox- dependently of lipid microdomains. oplasma gondii and Plasmodium falciparum, the aeti- ological agents of toxoplasmosis and malaria disease Fungi: signalling modulation through host rafts respectively, are obligatory intracellular parasites and The involvement of fungal infection with lipid rafts actively enter their target cells (Aikawa et al., 1978; is not yet well explored; however, for mycopatho- Suss-Toby et al., 1996). Previous studies related that gens, a modulation in host-cell signalling pathways these parasites can interact with lipid rafts during has been reported, as described below. The invasion the infection process, because parasitophorous va- process of Candida albicans or Paracoccidioides brasi- cuole membranes contain host raft lipids and pro- liensis had already been associated with activation teins (Aikawa et al., 1978; Mordue et al., 1999; Lauer of host-cell tyrosine kinases (Belanger et al., 2002; et al., 2000). This event shows that parasites might Monteiro da Silva et al., 2007). The manipulation hijack or recruit these microdomains during infec- of signalling pathways, which involve the host-cell tion. Furthermore, GPI-anchored proteins, such as kinases, can lead to an efficient way to enter, prolifer- CD55 and CD59, that are major inhibitors of mem- ate and exit the host cell during the infectious cycle brane complement, are progressively depleted from (Munter ¨ et al., 2006). Recently, Maza et al. (2008) the infected cell surface (Haldar et al., 2002). It was investigated yeast forms of P. brasiliensis in the con- further demonstrated that host raft cholesterol is im- text of kinase signalling. It was observed that this portant to vacuolar parasites because, when choles- pathogen promotes the aggregation of lipid rafts in terol was depleted from Plasmodium-infected eryth- epithelial cells, which is an important step to fungal rocytes, the expulsion of non-infective parasites adhesion and Src kinase family activation. Thereby, occurred (Lauer et al., 2000). In addition, cholesterol for the first time, it was shown that a pathogenic depletion from red blood cells prevents P. falciparum fungus can interact with host-cell membrane rafts infection (Samuel et al., 2001). Theileria parva,an- to establish infection. Encephalitozoon cuniculi,ami- other member of Apicomplexa, also interacts with crosporidiam parasite that affects the nervous system, host-cell rafts, with further regulation of host pro- as well as the respiratory and digestive tracts, resides tein kinases (Dobbelaere et al., 2000; Baumgartner in a parasitophorous vacuole surrounded by host-cell et al., 2003). www.biolcell.org | Volume 102 (7) | Pages 391–407 399 F.S. Vieira and others Studies indicated that raft association might not enter, survive and proliferate inside macrophages be sufficient to shuttle membrane molecules past (Alexander and Russell, 1992). Leishmania donovani the moving junctions (tight constrictions formed is responsible for the visceral leishmaniasis (Parson between parasite and host cell), for example, caveolin- et al., 1983), which is characterized by defective cell- 1 is excluded from the T. gondii parasitophorous vacu- mediated immunity (Basak et al., 1992; Saha et al., ole (Mordue et al., 1999; Coppens and Joiner, 2003). 1995; Sen et al., 2001). L. donovani LPG (lipophos- Flotillin-2, a raft protein anchored in plasma mem- phoglycan) requires intact membrane rafts to control brane by acylation, was also discarded from its para- host-cell functions. It was reported that LPG associ- sitophorous vacuole (Charron and Sibley, 2004). It ates with membrane rafts in the host cell and exerts was demonstrated during T. gondii infection that se- its actions on host-cell actin and phagosomal matur- lective portioning at the host–parasite interface is a ation through subversion of raft function (Winberg highly complex process and that the raft interaction et al., 2009). Macrophages infected with Leishmania can benefit the parasite inclusion into parasitophor- are unable to present, even processing-independent ous vacuoles (Charron and Sibley, 2004). On the other peptide sequences, to T-cells, and this event is not hand, it was observed that the association with mem- due to MHC expression (Prina et al., 1993). In this brane microdomains is not necessary to direct inser- context, lipid rafts are also involved in the interaction tion of host-cell membrane molecules into T. gondii between MHC and APC (Poloso and Roche, 2004). parasitophorous vacuole (Charron and Sibley, 2004). L. donovani can affect antigen presentation of mac- Murphy et al. (2007) related that different remodel- rophages due to the increase in membrane fluidity, ling and sorting may occur in distinct endo-vacuoles. which leads to a lipid-raft disruption. Although the In this case, primaquine was used to disturb red blood number of MHC complexes in infected cell surfaces cell membranes and induce detergent-free vesicles, was sufficient, there was no possibility of forming an which are enriched in cholesterol, raft proteins (flotil- aggregate and stimulating T-cells (Chakraborty et al., lin and stomatin) and PIP (phosphatidylinositol 4,5- 2005). bisphosphate). However, PIP was abrogated of Plas- Host evolution: the other side of lipid modium parasitophorous vacuoles and another lipid rafts was found, PS (phosphatidylserine). So, interestingly, Over millions of years, hosts and pathogens co- erythrocyte raft lipid recruited to the site of invasion evolved to improve their mechanisms of parasite can be remodelled by malaria parasites to establish elimination and maintenance of the infection respect- blood-stage infection. Protein and lipid distribution ively. As described above, pathogens can take advant- in the erythrocyte membrane may be more ordered age of lipid rafts for their own benefit. In the same than previously expected (Murphy et al., 2007). way, the host membrane microdomains can trigger It is known that there is a unique relationship and enhance the immune response against micro- between cholesterol and caveolae (caveolins), which organisms. is involved in cholesterol homoeostasis. Therefore, Studies of lipid rafts of mammals have described caveolae become sensitive to cholesterol depletion the interaction between TLRs and rafts. This fam- and a cross-link between cholesterol and caveolin ily of receptors, which might be activated by has been demonstrated (Murata et al., 1995; Razani PAMPs (pathogen-associated molecular patterns), et al., 2002). Cholesterol also appeared to be im- such as gram-negative bacteria LPS (lipopolysacchar- portant in the infection by the trypanosomatide, ide), is important to pathogen recognition. However, Leishmania (Pucadyil et al., 2004). This parasite can Flotillin: Flotillins belong to a family of lipid-raft-associated integral membrane proteins. Flotillin members are ubiquitously expressed and located to non-caveolar microdomains on the cell plasma membrane. Two flotillin members have been described, flotillin-1 and flotillin-2. Stomatin: Stomatin is a 32 kDa integral and lipid-raft-associated membrane protein that was first characterized in human red blood cells. Stomatin might play a fundamental role in the control of the surface expression of membrane proteins. TLRs: Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes. PAMPs: Pathogen-associated molecular patterns are the molecules associated with groups of pathogens, which are recognized by cells of the innate immune system. PAMPs are recognized by TLRs. C  C 400 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review only a few members constitutively co-localize with Bannas et al., 2005; Vial and Evans, 2005; Garc´ıa- membrane microdomains (Triantafilou et al., 2002). Marcos et al., 2006; Barth et al., 2007; Norambuena Besides, other TLRs can migrate to this specific re- et al., 2008). Recently, we observed that the disrup- gion after activation. In the macrophage-like cell line tion of lipid rafts can reduce P2X -activated pore RAW 264.7, for example, LPS stimulation induces formation on dendritic cells and macrophages from translocation of CD14, ERK-2 (extracellular-signal- humans and mice (F.S. Vieira and R. Coutinho-Silva, regulated kinase 2) and p38 to lipid rafts, but other unpublished data). Thus it is possible to suggest proteins also involved in the LPS signalling response that the integrated signals from P2 receptors and do not migrate within these microdomains (Trianta- TLRs located on rafts might explain the synergic ef- filou et al., 2007; Olsson and Sundler, 2006). In ad- fects of these sensors on stimulation of the immune dition, Cuschieri et al. (2006) observed that when response (Hu et al., 1998; Perregaux et al., 2000; the human monocytic cell line THP-1 was stimu- Garcıa-Marcos et al., 2009) (Figure 3). lated with LPS, there was a mobilization of TLR4 and HSP70 into the lipid raft. Taken together, these Lipid rafts as targets for chemotherapy: examples show the importance of the aggregation two sides of the coin of specific receptor molecules within lipid rafts fa- Nowadays, several groups are studying and develop- cilitating the LPS signalling to favour the clearance ing new treatment strategies for less harmful chemo- of intracellular pathogens (Triantafilou et al., 2002). therapeutic agents, especially those against viral in- Other molecules are able to induce receptor migra- fections. One of these strategies could be to block tion into lipid rafts, for example, DAMPs (damage- HIV-1 entry and its replication using natural dietary associated molecular patterns). Extracellular ATP is a and plant-derived compounds that target lipid rafts, nucleotide which works as an important DAMP (Di principally due to its affinity for cholesterol (Verma, Virgilio, 2005). P2 purinergic receptors, a family of 2009). Sakamoto et al. (2005) showed that a second- nucleotide receptors, are involved with inflammatory ary fungal metabolite (NA255) acts as a new anti- responses (Burnstock and Knight, 2004; Bours et al., HCV (hepatitis C virus) replication inhibitor that 2006; Burnstock, 2009) and the clearance of intracel- targets host lipid rafts, suggesting that the inhibi- lular pathogens (Coutinho-Silva et al., 2007, 2009). tion of sphingolipid metabolism may provide a new Several motifs in P2X receptors have been identified therapeutic strategy for treatment of HCV infection. that are homologous with those known to be involved In addition, a novel therapeutic strategy, consider- in protein–protein interactions and LPS binding. It ing the biochemistry of raft–pathogen interaction, was suggested that the C-terminal region of the P2X called glycolipidomimetics, was proposed by Ta¨ıeb receptor may directly associate with proteins and/or et al. (2004). lipids that are important for regulating macrophage New concepts in the chemotherapy field interest- function (Denlinger et al., 2001). In addition, the ac- ingly reported the ability to specifically deliver thera- tivation of P2X receptors can induce ceramide gen- peutic agents or drugs to selected cell types, thus eration and accumulation in macrophages (Raymond minimizing systemic toxicity. This is the principal and Le Strunff, 2006), which is a sphingolipid im- goal of nanoparticle-based drug-delivery approaches. plicated to be involved with the formation of larger It was reported by Partlow et al. (2008) that the pre- rafts, so called signalling platforms (Gulbins et al., dominant mechanism of direct delivery of lipophilic 2004). substances to the target cell plasma membrane acts Previous studies have already related that specific via lipid mixing and subsequent intracellular traf- P2X and P2Y receptors can also be recruited towards ficking through lipid-raft-dependent processes. membrane microdomain regions (Vacca et al., 2004; DAMPs: Damage-associated molecular pattern molecules can initiate and perpetuate the immune response in the non-infectious inflammatory response. They serve as a start signal. P2X receptors: A family of cation-permeable ligand-gated ion channels that open in response to the binding of ATP. P2Y receptors: P2Y receptors are a family of purinergic receptors, and are G-protein-coupled receptors stimulated by nucleotides, such as ATP, ADP, UTP, UDP and UDP-glucose. www.biolcell.org | Volume 102 (7) | Pages 391–407 401 F.S. Vieira and others Figure 3 P2X receptor and TLR interaction with lipid rafts (a)P2X receptor (P2X R) and/or TLR activation, by ATP or PAMPs respectively, in non-raft membrane regions. (b) These 7 7 receptors, when stimulated, migrate to lipid-raft domains. In addition, the P2X R is involved with inflammatory immune response, as well as TLRs which are related to the initial signal to the immune response. Thus it is suggested that the action of both receptors, together within lipid rafts, can lead to a more intense immune response. MyD88, myeloid differentiation primary response gene Final considerations forms enriched in ceramide (Liu and Anderson, 1995; Initially, the special regions of plasma membrane, so- Holopainen et al., 1998; Bollinger et al., 2005; called lipid rafts, were identified by their relative res- Plowman et al., 2005). This fusion of small pre-rafts istance to detergent extraction, namely DRM. How- may be induced in different cell types upon infec- ever, several articles still refer to membrane microdo- tion by different pathogens. Thus the association of mains as a DRM; this denomination should be used a protein with lipid rafts during cell infection may carefully, considering that this separation method is be a unique event concerning this protein and rafts, not completely reliable in unveiling these structures. which may mean that this association never occurs There is an ongoing controversy regarding the nature naturally. So upon the parasite adhesion, this protein is directed to the raft. Similarly, cholesterol is known and function of lipid rafts, because different exper- to be involved in many different cellular functions, imental approaches have yielded different results. and not only the assembly and maintenance of lipid Meanwhile, these substantial experimental data in rafts, which leads us to propose that other cellular the literature have provided not only biochemical but processes, rather than the disruption or disturbance also microscopical evidence for the close relationship of lipid rafts, may explain how some pathogens enter between different pathogens and lipid rafts. Another and survive within their hosts. important consideration is the now widely accepted Taken together, the explanations above show us view that lipid rafts may not be pre-existing do- that each pathogen has developed its own strategies mains, but dynamic membrane regions that can fuse to maintain virulence and disseminate the disease. to each other to form larger rafts or signalling plat- Signalling platforms: Lipid rafts have been demonstrated to be aggregated in response to different stimuli. In addition, they play an important role in transmembrane signalling. C  C 402 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review At present, lipid rafts have emerged as a safe entrance Aloia, R.C., Tian, H. and Jensen, F.C. (1993) Lipid composition and fluidity of the human immunodeficiency virus envelope and host door to pathogens. Furthermore, host-cell raft lipids cell plasma membranes. Proc. Natl. Acad. Sci. U.S.A. 90, were seen to be recruited to the invasion loci which 5181–5185 Amer, A.O., Byrne, B.G. and Swanson, M.S. (2005) Macrophages may be remodelled by parasites to help in the estab- rapidly transfer pathogens from lipid raft vacuoles to lishment of the infection. There are at least two major autophagosomes. Autophagy 1, 53–58 Anderson, H.A., Chen, Y. and Norkin, L.C. (1998) MHC class I mechanisms involving the host lipid raft by which molecules are enriched in caveolae but do not enter with simian parasites gain entry to the host cytoplasm and are virus 40. J. Gen. Virol. 79, 1469–1477 Anderson, H.A., Hiltbold, E.M. and Roche, P.A. (2000) Concentration able to survive: (i) the avoidance of lysosomal fusion of MHC class II molecules in lipid rafts facilitates antigen and posterior degradation; and (ii) the modulation of presentation. Nat. Immunol. 1, 156–162 Bannas, P., Adriouch, S., Kahl, S., Braasch, F., Haag, F. and host-cell signalling pathways to its own benefits. Koch-Nolte, F. (2005) Activity and specificity of toxin-related Each year the number of reports implicating new mouse T cell ecto-ADP-ribosyltransferase ART2.2 depends on its association with lipid rafts. Blood 105, 3663–3670 pathogens and their interactions with lipid rafts rap- Barth, K., Weinhold, K., Guenther, A., Young, M.T., Schnittler, H. and idly increases. New methods and techniques are also Kasper, M. (2007) Caveolin-1 influences P2X receptor expression helping the researchers to identify, in a more precise and localization in mouse lung alveolar epithelial cells. FEBS J. 274, 3021–3033 way, the interaction of pathogens and lipid rafts. In Basak, S.K., Saha, B., Bhattacharya, A. and Roy, S. (1992) this regard, biophysical approaches have been increas- Immunobiological studies on experimental visceral leishmaniasis. II. Adherent cell-mediated down-regulation of delayed-type ingly employed to better understand the aspects that hypersensitivity response and up-regulation of B cell activation. are not yet fully elucidated regarding microdomains Eur. J. Immunol. 22, 2041–2045 Baumgartner, M., Angelisova, ´ P., Setterblad, N., Mooney, N., Werling, and pathogen association. In parallel, development of D., Horejs´ı, V. and Langsley, G. (2003) Constitutive exclusion of new drus targeting host lipid rafts has been extens- Csk from Hck-positive membrane microdomains permits Src kinase-dependent proliferation of Theileria-transformed B ively studied, especially for viruses. However, many lymphocytes. Blood 101, 1874–1881 questions about the immune evasion and infection Bavari, S., Bosio, C.M., Wiegand, E., Ruthel, G., Will, A.B., Geisbert, T.W., Hevey, M., Schmaljohn, C., Schmaljohn, A. and Aman, M.J. control yet remain to be answered and further studies (2002) Lipid raft microdomains: a gateway for compartmentalized are necessary to minimize the historical controversy trafficking of Ebola and Marburg viruses. J. Exp. Med. 195, about the nature and cell biology of the membrane 593–602 Belanger, P.H., Johnston, D.A., Fratti, R.A., Zhang, M. and lipid rafts. Filler, S.G. (2002) Endocytosis of Candida albicans by vascular endothelial cells is associated with tyrosine phosphorylation of specific host cell proteins. Cell. Microbiol. 4, 805–812 Funding Bollinger, C.R., Teichgraber ¨ , V. and Gulbins, E. (2005) This work was supported by the Conselho Nacional de Ceramide-enriched membrane domains. Biochim. Biophys. 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Cytol. 1, 445–458 Received 14 September 2009/9 February 2010; accepted 10 February 2010 Published on the Internet 6 April 2010, doi:10.1042/BC20090138 www.biolcell.org | Volume 102 (7) | Pages 391–407 407 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biology of the Cell Pubmed Central

Host‐cell lipid rafts: a safe door for micro‐organisms?

Biology of the Cell , Volume 102 (7) – Jan 3, 2012

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Abstract

Biol. Cell (2010) 102, 391–407 (Printed in Great Britain) doi:10.1042/BC20090138 Review Host-cell lipid rafts: a safe door for micro-organisms? 1 1,2 Flavia ´ Sarmento Vieira*† ,GladysCorrea*† ˆ , Marcelo Einicker-Lamas‡ and Robson Coutinho-Silva* *Laboratorio ´ de Imunofisiologia, Universidade Federal do Rio de Janeiro, Instituto de Biof´ısica Carlos Chagas Filho, CCS, Rio de Janeiro, RJ, Brazil, †Pos-graduac ´ ¸ ao ˜ em Ciencias ˆ Biologicas ´ (Biof´ısica), Universidade Federal do Rio de Janeiro, Instituto de Biof´ısica Carlos Chagas Filho, CCS, Rio de Janeiro, RJ, Brazil, and ‡Laboratorio ´ de F´ısico-Qu´ımica Biologica, ´ Universidade Federal do Rio de Janeiro, Instituto de Biof´ısica, Carlos Chagas Filho, CCS, Rio de Janeiro, RJ, Brazil The lipid raft hypothesis proposed that these microdomains are small (10–200 nM), highly dynamic and enriched in cholesterol, glycosphingolipids and signalling phospholipids, which compartmentalize cellular processes. These membrane regions play crucial roles in signal transduction, phagocytosis and secretion, as well as pathogen adhesion/interaction. Throughout evolution, many pathogens have developed mechanisms to escape from the host immune system, some of which are based on the host membrane microdomain machinery. Thus lipid rafts might be exploited by pathogens as signalling and entry platforms. In this review, we summarize the role of lipid rafts as players in the overall invasion process used by different pathogens to escape from the host immune system. lipids, proteins (receptord, kinases, etc.), which inter- Introduction acts upon different stimuli triggering different cell Lipid rafts: a heterogeneous membrane responses. microdomain Since it was first described as a simple barrier bet- Over the last decade, several works have provided ween extra and intracellular compartments, differ- evidence that the plasma membrane is really more ent plasma membrane structural and composition mosaic than fluid (Pike, 2003; Engelman, 2005). It models have been proposed (Pike, 2009). Among was shown that lipids are not randomly distributed, these different models, the ‘fluid mosaic’ model leading to the proposal of a new model for under- proposed by Singer and Nicolson (1972) helps standing the biological membrane architecture (Pike, to provide answers about the different roles of the 2003; Garcıa-Marcos et al., 2006). The new model plasma membrane in cell biology, including trans- suggests that the plasma membrane is patchy, with port processes, cell protection, cell–cell contact and, segregated portions that are distinct in structure and function and that can also vary in thickness and com- principally, cell signalling. The plasma membrane position. From the first reports in the 1950s provided harbours many molecules involved in different cell by Palade (1953) and Yamada (1955) showing stable signalling cascades, such as glycero- and sphingo- flask-like invaginations of the plasma membrane, to the current view of multiple membrane domains al- These authors contributed equally to this work. lowing different protein–lipid and protein–protein To whom correspondence should be addressed (email gladys@biof.ufrj.br). Key words: cell signalling, lipid raft, membrane microdomain, parasite–host interactions that compartmentalize and temporarily cell interaction, pathogen. order the membrane moiety, many different reports Abbreviations used: AFM, atomic force microscopy; APC, antigen-presenting cell; DAMP, damage-associated molecular pattern; DRM, detergent-resistant still bring some controversy to the theme. membrane; ER, endoplasmic reticulum; EV-1, echovirus type 1; FRET, fluorescence resonance energy transfer; gp, glycoprotein; GPI, glycosylphosphatidylinositol; HCV, hepatitis C virus; HGF-R, hepatocyte growth factor receptor; Hsp, heat-shock protein; LPG, lipophosphoglycan; LPS, lipopolysaccharide; MLV, murine leukaemia virus; PAMP, pathogen-associated Fluid mosaic: A term used by Singer and Nicolson since 1972 to describe (C) molecular pattern; PIP , phosphatidylinositol 4,5-bisphosphate; PrP , the structural features of biological membranes. The plasma membrane was (cellular) prion protein; SARS-CoV, severe acute respiratory syndrome considered fluid because its components, such as lipids and membrane coronavirus; SV40, simian virus 40; T3SS, type 3 secretion system; TCR, T-cell proteins, move laterally or sideways throughout the membrane. receptor; TLR, Toll-like receptor. www.biolcell.org | Volume 102 (7) | Pages 391–407 391 F.S. Vieira and others The concept of lipid microdomains arose in the Figure 1 Membrane microdomains 1980s in the reports of Van Meer and Simons (1983) (a) A classical lipid-raft scheme. Membrane microdomains are and Klausner and colleagues (1980). It is now widely enriched with cholesterol and sphingolipids and also possess accepted that lipid rafts are not pre-existing do- associated proteins such as GPI-anchored protein. (b) A cave- mains in which proteins dynamically partition, but olin-rich lipid-raft scheme. The membrane microdomain can form invaginations called caveolae. Caveolin is a marker pro- rather that the formation and disassembly of raft tein of caveolae structure. domains is a dynamic process (see, for example, Plowman et al., 2005). Later, rafts were visually observed by Simons and Ikonen (1997), who de- scribed them as lipid rafts, imagining these micro- domains as floating islands in the membrane (Triantafilou et al., 2002; Luo et al., 2008). Further studies provided evidence that lipid rafts are mainly composed of cholesterol, (glyco)sphingolipids and (glycero)phospholipids, with a high degree of satur- ation in their fatty-acid chains (Figure 1a). The tight interaction between these components provides the basis of their packing and rigidity, which leads to a phase separation (Simons and Ikonen, 1997). This tight-packing organization of lipid rafts con- fers their resistance to solubilization by non-ionic detergents, which allows their separation and isol- ation from the rest of the plasma membrane us- ing sucrose-density gradients (Brown and Rose, 1992). The development of this method is widely used for the isolation and analysis of lipid rafts and their associated proteins in different cell types (Triantafilou et al., 2002; Bouillon et al., 2003; Chazal and Gerlier, 2003; Laughlin et al., 2004; Tortelote et al., 2004; Vacca et al., 2004; Olsson and Sundler, 2006). However, new considerations this method, as discussed by Lai (2003). Another effi- about the term ‘detergent-resistant membranes’ cient tool used to study lipid rafts is cholesterol deple- (DRMs) had already been reviewed. DRM no longer tion, by the use of cholesterol-removing and -binding defines the bona fide rafts (Lai, 2003), because this agents, such as cyclodextrins and filipin (Schnitzer technique can create several artifacts, such as the loss et al., 1994; Luker et al., 2000). This method is based of membrane components during extraction (Edidin, on the theory that cholesterol acts as a dynamic ‘glue’, 2003). However, many proteins functionally involved holding lipid rafts together, and its removal from the with microdomains had already been described via Lipid raft: A cholesterol- and sphingolipid-enriched microdomain or platform found in cell membranes. Sphingolipids: A class of lipids derived from the aliphatic amino alcohol sphingosine. These compounds play important roles in signal transmission and cell recognition. Sucrose-gradient centrifugation: A type of centrifugation often used to purify enveloped viruses and also to separate cell organelles. This method is also used to purify lipid rafts. DRM: Detergent-resistant membrane was a denomination used for an important early indication that rafts may exist in cells through the observation that cell membranes are not fully solubilized by non-ionic detergents, such as Triton X-100, at low temperatures. Cyclodextrins: Cyclodextrins (cycloamyloses) belong to a family of cyclic oligosaccharides. Methyl-β-cyclodextrin is employed for the cholesterol removal of cell membrane. Filipin: Filipin was isolated from the fungus Streptomyces filipinensis. Often used in cellular biology as an inhibitor of the raft/caveolae endocytosis pathway in mammalian cells. C  C 392 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review membrane results in the dispersion of raft-associated The techniques of AFM and confocal microscopy in lipids and proteins (Manes ˜ et al., 2003; Hawkes combination with inhibitors of cholesterol synthesis and Mak, 2006). Considering that cholesterol is and an agent that chelates cholesterol were allied in a relatively rigid molecule, it was postulated that the study of lipid rafts in this context, as well as the cholesterol-rich microdomains have a slower mobility pursuit of flotillin-1 and the ganglioside G ,which M1 in the membrane than non-raft regions (Shaw, 2006). are known markers of microdomains. Nowadays, more accurate methods are employed The lipid raft size in vivo has been estimated to in order to improve the research into lipid rafts. be 25–700 nm by using FRET and single-molecule- Fluorescent biosensors that are capable of tracking tracking microscopy. The size, arrangement and signalling events in live cells are powerful tools movement of lipid rafts are dynamic and can be to aid the understanding of dynamic cellular sig- found in localized cellular structures, such as filipodia nalling (Gao and Zhang, 2008). The proposals re- and cell adhesion points (Chazal and Gerlier, 2003; garding microdomains postulated in the late 1990s Hawkes and Mak, 2006). It is accepted that mem- can be now supported by, for example, FRET (fluor- brane rafts in basal conditions are small regions of escence resonance energy transfer) microscopy and the lipid membranes, which tend to cluster after cer- AFM (atomic force microscopy). Given the import- tain stimuli to form larger structures that are also ance of the Akt pathway in cell proliferation and sur- called platforms (Liu and Anderson, 1995; Holo- vival, and thus its involvement in cancer, this path- painen et al., 1998; Kusumi et al., 2004; Bollinger way has been increasingly studied. Gao and Zhang et al., 2005; Rao and Mayor, 2005). It is important (2008) developed a genetically encodable Akt activ- to mention that the assembly of those small regions ity reporter and analysed the spatiotemporal dynam- (pre-rafts) seems to be dependent on the presence of ics of Akt activity within plasma membrane mi- ceramide (Liu and Anderson, 1995; Bollinger et al., crodomains by FRET. Using this tool, it was ob- 2005). In addition to the lipid components, a variety served that Akt activity is differentially regulated of cell receptors and signalling proteins are known to between raft and non-raft regions of the plasma mem- be associated with membrane rafts. They include the brane (Gao and Zhang, 2008). In addition, AFM GPI (glycosylphosphatidylinositol)-anchored pro- has been described as an essential tool to follow teins, kinases and adaptor molecules that act as in- the motion of lipid-raft microdomains and proteins termediate transducers for many receptors, including that might be interacting with them (Henderson TCRs (T-cell receptors) and BCRs (B-cell receptors) et al., 2004). Several works have demonstrated the (Montixi et al., 1998; Cheng et al., 1999; Chazal and importance of AFM in experimental approaches to Gerlier, 2003; Hawkes and Mak, 2006). study lipid rafts. Poole et al. (2004), studying MDCK The role of lipid rafts in different cell types has (Madin–Darby canine kidney) cell microvilli, sugges- been the subject of numerous studies, and their ted that lipid rafts might be involved in the main- physiological significance for cell biology has re- tenance of these structures. These authors used a cently become clear. These membrane regions play an combination of AFM and laser-scanning confocal important role in a variety of cellular functions, in- microscopy in order to attest their hypothesis. cluding polarization, signal transduction, endocyt- Cecchi et al. (2009) interestingly observed an increase osis, secretion, cell–cell and cell–pathogen adhes- in specific amyloid ligands when raft components, ion (Manes ˜ et al., 1999; Martin-Belmonte et al., such as cholesterol, are depleted. This group sugges- 2000; Harris et al., 2001; Grimmer et al., 2002; ted that cholesterol can reduce membrane modifica- Ha et al., 2003; Pierini et al., 2003; Jacobson et al., tions triggered by amyloid residues at the lipid-raft 2007). One of the most widely appreciated roles of level, possibly involving physicochemical features. lipid rafts is the recruitment and concentration of FRET: Fluorescence (or Forster) ¨ resonance energy transfer is a mechanism involving energy transfer between two fluorophores. AFM: Atomic force microscopy is a very high-resolution type of scanning probe microscopy, with a nanometre resolution. Ceramides: A family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane. GPI anchor: Glycosylphosphatidylinositol is a glycolipid that can be attached to the C-terminus of a protein during post-translational modification. www.biolcell.org | Volume 102 (7) | Pages 391–407 393 F.S. Vieira and others molecules involved in cellular signalling. The forma- transduction and tumour suppression (Razani et al., tion of a molecular cluster and their signal transduc- 2002; Duncan et al., 2002; Manes ˜ et al., 2003; tion machinery in membrane rafts leads to enhanced Cohen et al., 2004; Tortelote et al., 2004). The signalling efficiency (Triantafilou et al., 2002). protein caveolin-1 has itself been implicated in Anderson et al. (2000) reported that MHC class signal transduction, because of its direct interaction II molecules are located in lipid rafts of murine and with a multitude of signalling molecules through the human B-cell lines. Such a localization seems to be caveolin-scaffolding domain. In addition, caveolin-1 critical for T-cell activation. The binding of TCRs to has been shown to be phosphorylated on tyrosine MHC class II molecules of APCs (antigen-presenting residues during some signalling events (Mastick and cells) occurs in lipid rafts. The raft aggregation pro- Saltiel, 1997; Okamoto et al., 1998; Ushio-Fukai motes tyrosine phosphorylation and recruitment of et al., 2001; Duncan et al., 2002). signalling proteins, but excludes certain proteins, Vesicular transport is one of the most important such as the tyrosine phosphatases CD45 and CD43, roles of caveolae, including endocytosis when cave- which leads to the formation of a supramolecular ac- olae are, indeed, functional endocytic vesicles (Lajoie tivation cluster (Monks et al., 1998). However, in vivo, and Nabi, 2007), and promotes transcytosis of specific TCR does not constitutively reside in membrane lipid macromolecules in endothelial cells (Minshall et al., rafts. After T-cell activation, the TCR moves into the 2003). Previous studies proposed that, as well as ca- rafts (Monks et al., 1998; Anderson et al., 2000; Luo veolae, caveolins also have an important involvement et al., 2008). This characteristic was also observed for in signal transduction, principally due to its scaffold other molecules that migrate to the lipid rafts after domain, which acts as a harbour for different cytoso- specific stimulation in several physiological events. lic proteins involved in different signalling cascades There is a specific subtype of microdomain called (Sargiacomo et al., 1993; Lisanti et al., 1994; Razani caveolae. These structures are small membrane- et al., 2002; Cohen et al., 2004). surface invaginations, which were initially described as cave-like invaginations of the plasma membrane, Pathogens and rafts: interacting to survive 50–100 nm in size and found in many cell types (Fig- It is well known that intracellular parasites have ure 1b). Although they were identified by electron many mechanisms to avoid the host defence response. microscopy more than 50 years ago as an invagin- The inhibition of lysosomal fusion, a classical escape ation in the plasma membrane with a flask-shape mechanism, was observed after infection by Mycobac- morphology that can be singular or found in detached terium, Chlamydia, Toxoplasma (Coutinho-Silva et al., 2009) and Trypanosoma cruzi (Hall and Joiner, 1993), grape-like clusters, caveolin caveolae have remained for example. Another way that pathogens can pro- enigmatic structures (Palade, 1953; Yamada, 1955; long their survival inside the host is by prevention of Razani et al., 2002; Lajoie et al., 2009). Forty years after the description of caveolae, their structure host-cell apoptosis and by the modulation of reactive could be more closely studied upon the discovery of oxygen and nitrogen species generation (Coutinho- caveolin, the signature protein present in calveolae Silva et al., 2009). (Rothberg et al., 1992). It has been suggested that ca- An interesting manner that allows pathogens to veolae can be stabilized by caveolin and, additionally, evade the immune system is through membrane may further become immobilized by filamin, which microdomains. As signalling for the innate and binds to caveolin, as well as to the actin cytoskeleton adaptative immune responses is initiated in rafts, (Stahlhut and van Deurs, 2000; Hommelgaard some pathogens have evolved mechanisms to subvert et al., 2005). Since that time, caveolae have been this signalling by co-opting raft-associated pathways implicated and demonstrated to be important in (Manes ˜ et al., 2003). Different pathogens, such as a variety of cellular functions, including endocytic viruses, bacteria and protozoa, can use the host-cell processes, cholesterol and lipid homoeostasis, signal lipid rafts to secure their entrance and maintenance Caveola: A special type of lipid raft, comprising small (50–100 nanometre) invaginations of the plasma membrane, found in many vertebrate cell types. Caveolins: A family of proteins involved in receptor-independent endocytosis. The caveolin gene family has three members in vertebrates, caveolin-1, -2 and -3. Pathogens: The term pathogen is most commonly used to refer to infectious organisms. These include bacteria, viruses, protozoa and fungi. C  C 394 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review Figure 2 Pathogen–raft interaction Several pathogens can directly interact with different target cells through membrane microdomains in different manners. It is known that the entry via lipid rafts can avoid lysosomal fusion and therefore allow pathogen survival. In addition, parasites might modulate signalling pathways, including lipid-raft-associated protein kinases [Srfk (Src family kinases)]. Especially viruses, which do not have their own protein synthesis machinery, target the ER after subverting the lysosomal pathway. Lys, lysosome; PV, parasitophorous vacuole. inside target cells (Figure 2). The benefit provided by entry into the cell. Many animal viruses exploit the by interaction with lipid rafts can vary from one endocytic machinery of their host cell for infection, pathogen to another. The list of pathogens that hijack and lipid rafts are often a site for entry, assembly rafts also includes the non-classical infectious agent, and budding of microbial pathogens, as confirmed the scrapie PrP (prion protein). Here, we provide an by biochemical approaches and microscopy evidence update of how different pathogens modulate host im- (Kovbasnjuk et al., 2001; Suomalainen, 2002; Lu mune response by using their lipid rafts. et al., 2008). For non-enveloped viruses, after the attachment to cell-surface receptors, the bound capsids are intern- How do different pathogens interact with alized, mostly by invagination of the plasma mem- the host via lipid rafts? brane and intracytoplasmic vesiculation. The involve- Viruses: exploiting lipid rafts ment of lipid rafts in mediating this process has been Different viruses have evolved strategies to subvert described for several viruses, as reviewed by Chazal raft-associated signalling, enabling their efficient rep- and Gerlier (2003). The most thoroughly studied of lication in immune cells, and at the same time block- these is SV40 (simian virus 40). SV40 initiates in- ing the immune response that is elicited by the target fection by binding to the MHC class I molecules cells (Hawkes and Mak, 2006). (Stang et al., 1997; Anderson et al., 1998; Duncan et al., 2002; Chazal and Gerlier, 2003). SV40 dir- (a) Entry ectly associates with caveolae, leading to a loss of Virus entry into a host cell involves the binding of the actin stress fibres and the appearance of actin tails virus to one or more cell-surface receptors, followed Budding: In virology, budding is a form of viral shedding by which enveloped viruses acquire their external envelope from the host-cell membrane, which bulges outwards and encloses the virion. www.biolcell.org | Volume 102 (7) | Pages 391–407 395 F.S. Vieira and others emanating from the virus containing caveolae bis virus), as well as other alphaviruses, depends on (Duncan et al., 2002; Pelkmans et al., 2002). the presence of cholesterol and sphingolipid in the Moreover, caveolae transport SV40 particles to the target membrane (Bron et al., 1993; Lu et al., 1999; ER (endoplasmic reticulum), where the virus is dis- Smit et al., 1999; Chazal and Gerlier, 2003), which assembled (Norkin et al., 2002; Chazal and Gerlier, are known to be abundant in lipid rafts (Pike, 2003). 2003). Other enveloped viruses enter the host cell using a Both the polyoma virus and EV-1 (echovirus type 1) pH-independent fusion process, as found for HIV. also directly associate with caveolae (Richterovae ´ t al., The HIV-1 Env is composed of two associated gly- 2001; Marjomaki et al., 2002). The polyoma virus coprotein subunits, gp120 and gp41. The external associates with caveolin-1 after entry, a possible as- gp120 is responsible for the attachment to the cel- sociation with ‘caveosomes’ and trafficking to the lular receptors and co-receptors (chemokine receptor ER (Richterova et al., 2001). EV-1 is internalized family member CCR5 and/or CXCR4), whereas the into caveolae using the integrin α2β1 as cellular transmembrane protein gp41 is responsible for the receptor. Studies have shown that EV-1, α2β1integ- fusion of viral envelope with the plasma membrane rin and caveolin-1 were internalized together in vesi- of the target CD4 T-cells (Popik et al., 2002). Rafts cular structures and accumulated in a perinuclear are proposed to be the specific cell membrane regions compartment (Marjomaki et al., 2002). Interestingly, in which these clustering events occur. It is import- it was shown (Richterova´ et al., 2001; Marjomaki ant to point out that the entry of HIV-1 through rafts et al., 2002) that the entry of the virus does not oc- may direct the virus complex into a favourable com- cur by endocytosis through the classic clathrin-coated partment for a productive infection (Fantini et al., vesicles. However, these authors observed that virus 2002; Chazal and Gerlier, 2003; Manes ˜ et al., 2003; particles had merged with caveolin-1, and incuba- Luo et al., 2008). A recent study showed that HIV tion with methyl-β-cyclodextrin inhibited the virus entry into macrophages is sensitive to membrane cho- entry. lesterol depletion, which favours the hypothesis for Enveloped viruses also use rafts during the intern- a role of macrophage lipid rafts in the HIV-1 entry alization and fusion process. The entry of enveloped process (Carter et al., 2009). virus involves virus attachment, followed by close ap- The cellular receptor for the MLV, CAT1 (cationic position of the virus and plasma membranes. Then amino acid transporter 1), is physically associated the two membranes fuse to deliver the virus’ gen- with caveolin in membrane rafts, and the disruption omic RNA into the host cells, which requires con- of rafts inhibits the early step of MLV infection, sug- version of the virus-encoded envelope glycoprotein gesting that the localization of the receptor within (Env) from its native state to its fusion-activated rafts is crucial for the virus entry (Lu and Silver, 2000). form (Fantini et al., 2002; Chazal and Gerlier, 2003; It was already demonstrated that the penetration of Manes ˜ et al., 2003). The glycoproteins of several vir- filoviruses, such as Ebola virus and Marburg virus, is uses, including influenza virus, HIV, MLV (murine inhibited after cholesterol depletion of the host cell, leukaemia virus), measles virus and Ebola virus, are and, after internalization, viral proteins co-localized associated with host-cell membrane rafts (Scheiffele with caveolin (Bavari et al., 2002; Empig and et al., 1997; Manie et al., 2000; Vincent et al., 2000; Goldsmith, 2002; Chazal and Gerlier, 2003). Pickl et al., 2001; Bavari et al., 2002). Additionally, there is biochemical evidence showing that choles- (b) Assembly terol and possibly cholesterol-rich lipid rafts are re- The late stages of the viral life cycle are the assembly quired for efficient porcine pseudorabies virus entry of viral components into virions, maturation into (Desplanques et al., 2008). Another recent study re- infectious particles, and, in the case of enveloped ported that the SARS-CoV (severe acute respiratory viruses, release from the cell via a budding process syndrome coronavirus) receptor is located in lipid (Ivanchenko et al., 2009). Assembly and budding are rafts and the productive entry of the SARS-CoV the last, but critical, steps in the virus life cycle for pseudovirus into the host cell requires the presence the survival of the virus and its disease-producing of intact and functional lipid rafts (Lu et al., 2008). ability in the host (Chen et al., 2008; Wang et al., Fusion of SFV (Semliki Forest virus) and SIN (Sind- 2009). An explanation as to why viruses use lipid rafts C  C 396 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review is that these structures offer an efficient system for disrupt cellular and/or humoral immune responses to concentrating all the virus proteins that are required the virus (Vanderplasschen et al., 1998; Peterlin and for the assembly of new virions, as reviewed by Nayak Trono, 2003). et al. (2004). The lipid composition of the influenza virus HIV-1 is enclosed in a lipid envelope enriched family is due to affinity of the haemagglutinin in cholesterol and sphingolipids, suggesting spe- and neuraminidase glycoproteins for these lipids, cific membrane localization for assembly (Aloia et al., and some authors suggest that the influenza virus 1993; Campbell et al., 2001; Raulin, 2002). Recent buds from raft domains (Chazal and Gerlier, 2003; studies have reported that rafts represent a necessary Nayak et al., 2004). step during HIV-1 assembly. With similar methods of Several reports suggest that HIV-1 buds from lipid both assembly and budding within membrane rafts, rafts (Campbell et al., 2001; Fantini et al., 2002). many other viruses, including influenza virus, measles HIV incorporates raft-associated complement regu- virus, Ebola virus and possibly Sendai virus, also use latory proteins, which remain functionally active on lipid rafts as assembly platforms (Luo et al., 2008). the surface of the virus and down-regulate the com- In this regard, it was also suggested that the RSV plement cascade (Manes ˜ et al., 2003; Peterlin and (respiratory syncytial virus) assembled within lipid Trono, 2003). rafts where viral proteins co-localize with caveolin-1 After budding from the host cell, viruses are re- (Brown et al., 2002a, 2002b). leased into the surrounding medium to infect other Although rafts are involved in virus assembly, cells. The mechanism of this bud completion is as yet we have to keep in mind that only a fraction of unclear and a number of both viral and host factors viral proteins are found associated with rafts; this may affect this process (Nayak et al., 2004; Luo et al., could be due to the poor biochemical characteriza- 2008). tion of raft subsets or to the transient nature of the association. Bacteria: taking advantage of host-cell membrane microdomains (c) Budding Studies have been suggested that several bacteria in- Whereas non-enveloped viruses are released from teract with host lipid rafts to enter and survive in- the infected cell by disruption of the plasma mem- side the cell (Manes ˜ et al., 2003; Hawkes and Mak, brane, enveloped viruses contain a host-cell-derived 2006). The mechanisms that underlie this interaction lipid bilayer, which is acquired during budding are starting to be unravelled. Activation of secretion, (Garoff et al., 1998; Chazal and Gerlier, 2003). Mem- binding, perforation of the host-cell membrane and brane lipids are not randomly incorporated into the signalling to trigger bacterial phagocytosis are in- viral envelope. In addition, some authors suggest volved with components of membrane microdomains that viral glycoproteins determine the site of virus (Lafont and van der Goot, 2005). It was found that assembly and budding (Garoff and Simons 1974; the polarity of epithelial cells and the involvement Allison et al., 1995; Vennema et al., 1996; Bruss, of CD55 are important in the interaction of bacteria 2004). On the other hand, in polarized epithelial with lipid rafts (Peiffer et al., 1998). Two advantages cells, the viral glycoproteins contain sorting signals in bacteria invasion were postulated: (1) avoidance of or motifs and are directed to the specific site where as- the intracellular degradative pathway and (2) trig- sembly and budding will occur (Nayak et al., 2004). gering of the cell signalling cascades that lead to Lipid rafts function as microdomains for concentrat- membrane ruffling and cytoskeleton rearrangement ing viral glycoproteins and may serve as a platform (Manes ˜ et al., 2003). for virus budding. The structures have the ability to The avoidance of the host immune pathway regulate budding; however, the mechanism by which after phagocytosis was developed by several micro- the lipid raft can favour the budding and/or fission organisms, mainly bacterial cells. Subversion of process is as yet unknown (Nayak et al., 2004; Luo phagosome fusion with lysosome and presentation et al., 2008). The budding of new virions from the raft to immune system was observed in pathogens such allows the exclusion or inclusion of specific host-cell as Mycobacterium and Chlamydia. Gatfield and Pieters membrane proteins in the virus particle, which could (2000) showed for the first time the relevant role of www.biolcell.org | Volume 102 (7) | Pages 391–407 397 F.S. Vieira and others cholesterol for mycobacteria entry into macrophages. into macropinosomes containing Brucella. In con- In addition, some bacteria hidden inside the cell took trast, the lysosomal glycoprotein LAMP-1 (lysosome- advantage of host lipids to generate phagosomes and associated membrane protein 1) and the host-cell survive inside them, such as Brucella spp. and Legion- transmembrane protein CD44 were excluded from ella pneumophila (Naroeni and Porte, 2002; Watarai these macropinosomes (Watarai et al., 2002). Inter- et al., 2001, 2002). Besides, these parasites can hi- estingly, it had already been demonstrated that Bru- jack rafts, altering host-cell signalling, for example cella abortus infection is related with PrP (cellular Shigella flexneri (Lafont et al., 2002). The interaction PrP), one of the lipid raft-associated molecules on the between pathogens and the host cell can also mod- plasma membrane of different cell types. In addition, ulate other host features, such as cytoskeletal dy- Watarai et al. (2002, 2004) postulated that the sig- namics. In the case of S. flexneri, cholesterol removal nal transduction induced by the interaction between decreased the binding of an effector protein, called bacterial Hsp60 (heat-shock protein 60) and PrP on IpaB, with host CD44, which is known to be in- macrophages contributes to the establishment of B. volved in cytoskeleton-dependent signalling events abortus infection. Coxiella burnetti, the causative agent (Hirao et al., 1996). of human acute and chronic Q fever, can be found in Seveau et al. (2004) demonstrated for the first time cholesterol-rich vacuoles with lipid-raft proteins, and that the cell adhesion molecule, E-cadherin, and also can modulate the cholesterol metabolism from HGF-R (hepatocyte growth factor receptor) require the host cell (Howe and Heinzen, 2006). The im- host lipid rafts to mediate Listeria monocytogenes entry. portance of cholesterol in C. burnetti infection can be It had already been reported by the same group that, directly associated with its pathophysiology (Howe in L. monocytogenes, two major proteins, internalin and and Heinzen, 2006). InIB, mediate bacterial invasion into host It was also suggested that pathogens and particles and bind to E-cadherin and HGF-R respectively that bind to lipid-raft components may trigger (Cossart et al., 2003). the macrophage autophagic machinery (Amer et al., Salmonella, Shigella and the entheropathogenic 2005). L. pneumophila and a uropathogenic E. coli can Escherichia coli have a common requirement for a T3SS stimulate autophagosome formation, which contains (type III secretion system), which is a multicompon- both lipid rafts and autophagy-involved cell mo- ent molecular syringe that allows the translocation of lecules. In addition, it was observed that internaliza- so-called effector proteins from bacterial cytoplasm, tion of pathogen and the autophagy stimulation are through the inner and outer bacterial membrane, as cholesterol sensitive and the pathogens harbouring well as the host plasma membrane, directly into cyto- in autophagosomes could avoid immediate killing plasm (van der Goot et al., 2004; Lafont and van (Amer et al., 2005). Components of lipid rafts do der Goot, 2005). Activation of this system requires not appear to be essential for assembly of autophago- contact with the host cell, and has effector proteins, somes, but instead may affect a signal transduction named SipB and SipC for Salmonella, IpaB and IpaC pathway dedicated to host recognition of microbes, for Shigella and PopB and PopC for Pseudomonas. as suggested by Amer et al. (2005). Hayward et al. (2005) showed a new requirement for The specific subtype of microdomain, caveolae, also cholesterol, for which the main binding determin- appeared to be directly involved in the interaction ant was SipB/IpaB to host cells, and Lafont and van with bacteria (Duncan et al., 2002), such as Chlamydia der Goot (2005) suggest that this must occur down- trachomatis (Norkin et al., 2001), E. coli (Shin et al., stream of the T3SS activation. 2000) and Campylobacter jejuni (Wooldridge et al., The pathogenic bacterium Brucella, which causes 1996). Among the Chlamydiae, depending on the brucellosis, can avoid bactericidal activity of mac- serovar, or the species, one or both of the caveolin rophages triggering the cAMP/PKA (protein kinase proteins (1 or 2) may play important roles in the de- A) pathway. This process occurs immediately after velopmental cycles (Stuart et al., 2003; Webley et al., the first contact with the target cell (Jimenez de 2004). Bagues et al., 2005). Lipid-raft-associated molecules, Porphyromonas gingivalis capitalizes on the lipid- such as GPI-anchored proteins, G gangliosides raft structure to down-modulate innate defence M1 and cholesterol, were found selectively incorporated mechanisms. Remarkably, this novel mechanism C  C 398 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review employs host-cell signalling pathways through lipids, was labelled with DilC16 (1,1 -dihexadecyl- cross-talk between TLR2 (Toll-like receptor-2)/ 3,3,3 ,3 -tetramethylindocarbocyanine), a marker for chemokine receptor 4 to attenuate the protective lipid rafts, and DiO (3,3 -dilinoleyloxacarbocyanine), and bactericidal response to P. gingivalis infection a marker for non-raft membrane domains, which sug- (Darveau, 2009). gests that both contribute to the formation of the Campylobacter enteritis, regardless of its own in- vacuole membrane (Ronneb ¨ aumer ¨ et al., 2008). This vasiveness, promotes the translocation of the non- report points to an alternative method of fungal in- invasive bacteria E. coli across the intestinal epithe- fection in host cells that is raft-independent. lium via a lipid-raft-mediated transcellular process (Kalischuk et al., 2009). Furthermore, bacterial toxins, such as cholera toxin, listeriolysin O and anthrax toxin, also tar- Protozoa: hiding with lipid rafts get lipid domains (Orlandi and Fishman, 1998; The protozoan invasion in the host cell occurs during Coconnier et al., 2000; Abrami et al., 2003). More specific stages of the pathogen life cycle. Intracellular recently, several pathogenic bacteria have been asso- entrance of these parasites does not depend on the ciated with lipid rafts, such as Francisella tularensis endocytic machinery of the host cell, as in the case (Tamilselvam and Daefler, 2008), Helicobacter pylori of bacteria and viruses. This can be explained due to (Lai et al., 2008), P.s gingivalis (Hajishengallis et al., the protozoan’s larger size (5–10 μm). As shown for 2006; Wang and Hajishengallis, 2008) and M. tuber- other pathogens, the exploitation of host membrane culosis (Shin et al., 2008), which are members of an microdomains by protozoa constitutes a crucial step ever increasing list as the years progress. Recently, for its maintenance, survival and modulation of host Caserta et al. (2008) described evidence for the first immune response (Manes ˜ et al., 2003). time that Clostridium perfringens enterotoxin acts in- Members of the Apicomplexa group, such as Tox- dependently of lipid microdomains. oplasma gondii and Plasmodium falciparum, the aeti- ological agents of toxoplasmosis and malaria disease Fungi: signalling modulation through host rafts respectively, are obligatory intracellular parasites and The involvement of fungal infection with lipid rafts actively enter their target cells (Aikawa et al., 1978; is not yet well explored; however, for mycopatho- Suss-Toby et al., 1996). Previous studies related that gens, a modulation in host-cell signalling pathways these parasites can interact with lipid rafts during has been reported, as described below. The invasion the infection process, because parasitophorous va- process of Candida albicans or Paracoccidioides brasi- cuole membranes contain host raft lipids and pro- liensis had already been associated with activation teins (Aikawa et al., 1978; Mordue et al., 1999; Lauer of host-cell tyrosine kinases (Belanger et al., 2002; et al., 2000). This event shows that parasites might Monteiro da Silva et al., 2007). The manipulation hijack or recruit these microdomains during infec- of signalling pathways, which involve the host-cell tion. Furthermore, GPI-anchored proteins, such as kinases, can lead to an efficient way to enter, prolifer- CD55 and CD59, that are major inhibitors of mem- ate and exit the host cell during the infectious cycle brane complement, are progressively depleted from (Munter ¨ et al., 2006). Recently, Maza et al. (2008) the infected cell surface (Haldar et al., 2002). It was investigated yeast forms of P. brasiliensis in the con- further demonstrated that host raft cholesterol is im- text of kinase signalling. It was observed that this portant to vacuolar parasites because, when choles- pathogen promotes the aggregation of lipid rafts in terol was depleted from Plasmodium-infected eryth- epithelial cells, which is an important step to fungal rocytes, the expulsion of non-infective parasites adhesion and Src kinase family activation. Thereby, occurred (Lauer et al., 2000). In addition, cholesterol for the first time, it was shown that a pathogenic depletion from red blood cells prevents P. falciparum fungus can interact with host-cell membrane rafts infection (Samuel et al., 2001). Theileria parva,an- to establish infection. Encephalitozoon cuniculi,ami- other member of Apicomplexa, also interacts with crosporidiam parasite that affects the nervous system, host-cell rafts, with further regulation of host pro- as well as the respiratory and digestive tracts, resides tein kinases (Dobbelaere et al., 2000; Baumgartner in a parasitophorous vacuole surrounded by host-cell et al., 2003). www.biolcell.org | Volume 102 (7) | Pages 391–407 399 F.S. Vieira and others Studies indicated that raft association might not enter, survive and proliferate inside macrophages be sufficient to shuttle membrane molecules past (Alexander and Russell, 1992). Leishmania donovani the moving junctions (tight constrictions formed is responsible for the visceral leishmaniasis (Parson between parasite and host cell), for example, caveolin- et al., 1983), which is characterized by defective cell- 1 is excluded from the T. gondii parasitophorous vacu- mediated immunity (Basak et al., 1992; Saha et al., ole (Mordue et al., 1999; Coppens and Joiner, 2003). 1995; Sen et al., 2001). L. donovani LPG (lipophos- Flotillin-2, a raft protein anchored in plasma mem- phoglycan) requires intact membrane rafts to control brane by acylation, was also discarded from its para- host-cell functions. It was reported that LPG associ- sitophorous vacuole (Charron and Sibley, 2004). It ates with membrane rafts in the host cell and exerts was demonstrated during T. gondii infection that se- its actions on host-cell actin and phagosomal matur- lective portioning at the host–parasite interface is a ation through subversion of raft function (Winberg highly complex process and that the raft interaction et al., 2009). Macrophages infected with Leishmania can benefit the parasite inclusion into parasitophor- are unable to present, even processing-independent ous vacuoles (Charron and Sibley, 2004). On the other peptide sequences, to T-cells, and this event is not hand, it was observed that the association with mem- due to MHC expression (Prina et al., 1993). In this brane microdomains is not necessary to direct inser- context, lipid rafts are also involved in the interaction tion of host-cell membrane molecules into T. gondii between MHC and APC (Poloso and Roche, 2004). parasitophorous vacuole (Charron and Sibley, 2004). L. donovani can affect antigen presentation of mac- Murphy et al. (2007) related that different remodel- rophages due to the increase in membrane fluidity, ling and sorting may occur in distinct endo-vacuoles. which leads to a lipid-raft disruption. Although the In this case, primaquine was used to disturb red blood number of MHC complexes in infected cell surfaces cell membranes and induce detergent-free vesicles, was sufficient, there was no possibility of forming an which are enriched in cholesterol, raft proteins (flotil- aggregate and stimulating T-cells (Chakraborty et al., lin and stomatin) and PIP (phosphatidylinositol 4,5- 2005). bisphosphate). However, PIP was abrogated of Plas- Host evolution: the other side of lipid modium parasitophorous vacuoles and another lipid rafts was found, PS (phosphatidylserine). So, interestingly, Over millions of years, hosts and pathogens co- erythrocyte raft lipid recruited to the site of invasion evolved to improve their mechanisms of parasite can be remodelled by malaria parasites to establish elimination and maintenance of the infection respect- blood-stage infection. Protein and lipid distribution ively. As described above, pathogens can take advant- in the erythrocyte membrane may be more ordered age of lipid rafts for their own benefit. In the same than previously expected (Murphy et al., 2007). way, the host membrane microdomains can trigger It is known that there is a unique relationship and enhance the immune response against micro- between cholesterol and caveolae (caveolins), which organisms. is involved in cholesterol homoeostasis. Therefore, Studies of lipid rafts of mammals have described caveolae become sensitive to cholesterol depletion the interaction between TLRs and rafts. This fam- and a cross-link between cholesterol and caveolin ily of receptors, which might be activated by has been demonstrated (Murata et al., 1995; Razani PAMPs (pathogen-associated molecular patterns), et al., 2002). Cholesterol also appeared to be im- such as gram-negative bacteria LPS (lipopolysacchar- portant in the infection by the trypanosomatide, ide), is important to pathogen recognition. However, Leishmania (Pucadyil et al., 2004). This parasite can Flotillin: Flotillins belong to a family of lipid-raft-associated integral membrane proteins. Flotillin members are ubiquitously expressed and located to non-caveolar microdomains on the cell plasma membrane. Two flotillin members have been described, flotillin-1 and flotillin-2. Stomatin: Stomatin is a 32 kDa integral and lipid-raft-associated membrane protein that was first characterized in human red blood cells. Stomatin might play a fundamental role in the control of the surface expression of membrane proteins. TLRs: Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single membrane-spanning non-catalytic receptors that recognize structurally conserved molecules derived from microbes. PAMPs: Pathogen-associated molecular patterns are the molecules associated with groups of pathogens, which are recognized by cells of the innate immune system. PAMPs are recognized by TLRs. C  C 400 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review only a few members constitutively co-localize with Bannas et al., 2005; Vial and Evans, 2005; Garc´ıa- membrane microdomains (Triantafilou et al., 2002). Marcos et al., 2006; Barth et al., 2007; Norambuena Besides, other TLRs can migrate to this specific re- et al., 2008). Recently, we observed that the disrup- gion after activation. In the macrophage-like cell line tion of lipid rafts can reduce P2X -activated pore RAW 264.7, for example, LPS stimulation induces formation on dendritic cells and macrophages from translocation of CD14, ERK-2 (extracellular-signal- humans and mice (F.S. Vieira and R. Coutinho-Silva, regulated kinase 2) and p38 to lipid rafts, but other unpublished data). Thus it is possible to suggest proteins also involved in the LPS signalling response that the integrated signals from P2 receptors and do not migrate within these microdomains (Trianta- TLRs located on rafts might explain the synergic ef- filou et al., 2007; Olsson and Sundler, 2006). In ad- fects of these sensors on stimulation of the immune dition, Cuschieri et al. (2006) observed that when response (Hu et al., 1998; Perregaux et al., 2000; the human monocytic cell line THP-1 was stimu- Garcıa-Marcos et al., 2009) (Figure 3). lated with LPS, there was a mobilization of TLR4 and HSP70 into the lipid raft. Taken together, these Lipid rafts as targets for chemotherapy: examples show the importance of the aggregation two sides of the coin of specific receptor molecules within lipid rafts fa- Nowadays, several groups are studying and develop- cilitating the LPS signalling to favour the clearance ing new treatment strategies for less harmful chemo- of intracellular pathogens (Triantafilou et al., 2002). therapeutic agents, especially those against viral in- Other molecules are able to induce receptor migra- fections. One of these strategies could be to block tion into lipid rafts, for example, DAMPs (damage- HIV-1 entry and its replication using natural dietary associated molecular patterns). Extracellular ATP is a and plant-derived compounds that target lipid rafts, nucleotide which works as an important DAMP (Di principally due to its affinity for cholesterol (Verma, Virgilio, 2005). P2 purinergic receptors, a family of 2009). Sakamoto et al. (2005) showed that a second- nucleotide receptors, are involved with inflammatory ary fungal metabolite (NA255) acts as a new anti- responses (Burnstock and Knight, 2004; Bours et al., HCV (hepatitis C virus) replication inhibitor that 2006; Burnstock, 2009) and the clearance of intracel- targets host lipid rafts, suggesting that the inhibi- lular pathogens (Coutinho-Silva et al., 2007, 2009). tion of sphingolipid metabolism may provide a new Several motifs in P2X receptors have been identified therapeutic strategy for treatment of HCV infection. that are homologous with those known to be involved In addition, a novel therapeutic strategy, consider- in protein–protein interactions and LPS binding. It ing the biochemistry of raft–pathogen interaction, was suggested that the C-terminal region of the P2X called glycolipidomimetics, was proposed by Ta¨ıeb receptor may directly associate with proteins and/or et al. (2004). lipids that are important for regulating macrophage New concepts in the chemotherapy field interest- function (Denlinger et al., 2001). In addition, the ac- ingly reported the ability to specifically deliver thera- tivation of P2X receptors can induce ceramide gen- peutic agents or drugs to selected cell types, thus eration and accumulation in macrophages (Raymond minimizing systemic toxicity. This is the principal and Le Strunff, 2006), which is a sphingolipid im- goal of nanoparticle-based drug-delivery approaches. plicated to be involved with the formation of larger It was reported by Partlow et al. (2008) that the pre- rafts, so called signalling platforms (Gulbins et al., dominant mechanism of direct delivery of lipophilic 2004). substances to the target cell plasma membrane acts Previous studies have already related that specific via lipid mixing and subsequent intracellular traf- P2X and P2Y receptors can also be recruited towards ficking through lipid-raft-dependent processes. membrane microdomain regions (Vacca et al., 2004; DAMPs: Damage-associated molecular pattern molecules can initiate and perpetuate the immune response in the non-infectious inflammatory response. They serve as a start signal. P2X receptors: A family of cation-permeable ligand-gated ion channels that open in response to the binding of ATP. P2Y receptors: P2Y receptors are a family of purinergic receptors, and are G-protein-coupled receptors stimulated by nucleotides, such as ATP, ADP, UTP, UDP and UDP-glucose. www.biolcell.org | Volume 102 (7) | Pages 391–407 401 F.S. Vieira and others Figure 3 P2X receptor and TLR interaction with lipid rafts (a)P2X receptor (P2X R) and/or TLR activation, by ATP or PAMPs respectively, in non-raft membrane regions. (b) These 7 7 receptors, when stimulated, migrate to lipid-raft domains. In addition, the P2X R is involved with inflammatory immune response, as well as TLRs which are related to the initial signal to the immune response. Thus it is suggested that the action of both receptors, together within lipid rafts, can lead to a more intense immune response. MyD88, myeloid differentiation primary response gene Final considerations forms enriched in ceramide (Liu and Anderson, 1995; Initially, the special regions of plasma membrane, so- Holopainen et al., 1998; Bollinger et al., 2005; called lipid rafts, were identified by their relative res- Plowman et al., 2005). This fusion of small pre-rafts istance to detergent extraction, namely DRM. How- may be induced in different cell types upon infec- ever, several articles still refer to membrane microdo- tion by different pathogens. Thus the association of mains as a DRM; this denomination should be used a protein with lipid rafts during cell infection may carefully, considering that this separation method is be a unique event concerning this protein and rafts, not completely reliable in unveiling these structures. which may mean that this association never occurs There is an ongoing controversy regarding the nature naturally. So upon the parasite adhesion, this protein is directed to the raft. Similarly, cholesterol is known and function of lipid rafts, because different exper- to be involved in many different cellular functions, imental approaches have yielded different results. and not only the assembly and maintenance of lipid Meanwhile, these substantial experimental data in rafts, which leads us to propose that other cellular the literature have provided not only biochemical but processes, rather than the disruption or disturbance also microscopical evidence for the close relationship of lipid rafts, may explain how some pathogens enter between different pathogens and lipid rafts. Another and survive within their hosts. important consideration is the now widely accepted Taken together, the explanations above show us view that lipid rafts may not be pre-existing do- that each pathogen has developed its own strategies mains, but dynamic membrane regions that can fuse to maintain virulence and disseminate the disease. to each other to form larger rafts or signalling plat- Signalling platforms: Lipid rafts have been demonstrated to be aggregated in response to different stimuli. In addition, they play an important role in transmembrane signalling. C  C 402 The Authors Journal compilation 2010 Portland Press Limited Host-cell lipid rafts Review At present, lipid rafts have emerged as a safe entrance Aloia, R.C., Tian, H. and Jensen, F.C. (1993) Lipid composition and fluidity of the human immunodeficiency virus envelope and host door to pathogens. Furthermore, host-cell raft lipids cell plasma membranes. Proc. Natl. Acad. Sci. U.S.A. 90, were seen to be recruited to the invasion loci which 5181–5185 Amer, A.O., Byrne, B.G. and Swanson, M.S. (2005) Macrophages may be remodelled by parasites to help in the estab- rapidly transfer pathogens from lipid raft vacuoles to lishment of the infection. There are at least two major autophagosomes. Autophagy 1, 53–58 Anderson, H.A., Chen, Y. and Norkin, L.C. (1998) MHC class I mechanisms involving the host lipid raft by which molecules are enriched in caveolae but do not enter with simian parasites gain entry to the host cytoplasm and are virus 40. J. Gen. Virol. 79, 1469–1477 Anderson, H.A., Hiltbold, E.M. and Roche, P.A. (2000) Concentration able to survive: (i) the avoidance of lysosomal fusion of MHC class II molecules in lipid rafts facilitates antigen and posterior degradation; and (ii) the modulation of presentation. Nat. Immunol. 1, 156–162 Bannas, P., Adriouch, S., Kahl, S., Braasch, F., Haag, F. and host-cell signalling pathways to its own benefits. Koch-Nolte, F. (2005) Activity and specificity of toxin-related Each year the number of reports implicating new mouse T cell ecto-ADP-ribosyltransferase ART2.2 depends on its association with lipid rafts. Blood 105, 3663–3670 pathogens and their interactions with lipid rafts rap- Barth, K., Weinhold, K., Guenther, A., Young, M.T., Schnittler, H. and idly increases. New methods and techniques are also Kasper, M. (2007) Caveolin-1 influences P2X receptor expression helping the researchers to identify, in a more precise and localization in mouse lung alveolar epithelial cells. FEBS J. 274, 3021–3033 way, the interaction of pathogens and lipid rafts. In Basak, S.K., Saha, B., Bhattacharya, A. and Roy, S. (1992) this regard, biophysical approaches have been increas- Immunobiological studies on experimental visceral leishmaniasis. II. Adherent cell-mediated down-regulation of delayed-type ingly employed to better understand the aspects that hypersensitivity response and up-regulation of B cell activation. are not yet fully elucidated regarding microdomains Eur. J. Immunol. 22, 2041–2045 Baumgartner, M., Angelisova, ´ P., Setterblad, N., Mooney, N., Werling, and pathogen association. In parallel, development of D., Horejs´ı, V. and Langsley, G. (2003) Constitutive exclusion of new drus targeting host lipid rafts has been extens- Csk from Hck-positive membrane microdomains permits Src kinase-dependent proliferation of Theileria-transformed B ively studied, especially for viruses. However, many lymphocytes. 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Cytol. 1, 445–458 Received 14 September 2009/9 February 2010; accepted 10 February 2010 Published on the Internet 6 April 2010, doi:10.1042/BC20090138 www.biolcell.org | Volume 102 (7) | Pages 391–407 407

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Published: Jan 3, 2012

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