Lipid-Mediated Endocytosis

Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Lipid-Mediated Endocytosis Helge Ewers1 and Ari Helenius2 1Laboratorium fu¨r Physikalische Chemie, ETH Zurich, 8093 Zurich, Switzerland 2Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland Correspondence: [email protected] Receptor-mediated endocytosis is used by a number of viruses and toxins to gain entry into cells. Some have evolved to use specific lipids in the plasma membrane as their receptors. They include bacterial toxins such as Shiga and Cholera toxin and viruses such as mouse polyoma virus and simian virus 40. Through multivalent binding to glycosphingolipids, they induce lipid clustering and changes in membrane properties. Internalization occurs by unusual endocytic mechanisms involving lipid rafts, induction of membrane curvature, trans-bilayer coupling, and activation of signaling pathways. Once delivered to early endo- somes, they follow diverse intracellular routes to the lumen of the ER, from which they penetrate into the cytosol. The role of the lipid receptors is central in these well-studied processes. ndocytosis is a general term for the inter- receptors for endocytic uptake. They exploit Enalization of particles, solutes, fluid, and these receptors and the endocytic machinery membrane components by invagination of of the cell for infection and intoxication. The the plasma membrane (PM) and internaliza- endocytic processes and intracellular trafficking tion of membrane vesicles. It plays a central routes differ in many respects from those used role in the life of eukaryotic cells by mediat- by most other cargo. ing important aspects in the communication In a typical animal cell, several different between the cell and the outside world, and mechanisms of endocytosis operate side by by serving as a sensitive regulator of cell dy- side. The most important for the present dis- namics and homeostasis (Collinet et al. 2010). cussion are the clathrin-mediated and various The endocytosed cargo includes nutrients, re- lipid raft-dependent pathways because they are ceptor-ligand complexes, lipids, antigens, the main pathways taken by lipid-bound membrane proteins, toxins, and pathogens, to ligands. The clathrin-mediated pathway is con- name a few. tinuously ongoing, whereas the others are li- In this article, we limit our discussion to a gand-induced and involve signaling pathways special form of endocytosis; the internalization that engage tyrosine kinases and other cytosolic of viruses and bacterial toxins that use neutral signaling factors (Sandvig et al. 2008; Mercer and acidic glycosphingolipids (SP05/SP06) as et al. 2010). Editor: Kai Simons Additional Perspectives on The Biology of Lipids available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004721 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004721 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press H. Ewers and A. Helenius GLYCOSPHINGOLIPIDS the formation of lipid domains with reduced fluidity and tight packing (Tsamaloukas et al. Glycosphingolipids are synthesized in the Golgi 2006; Sonnino et al. 2007). This process has apparatus and enriched in the outer bilayer leaf- been studied extensively in artificial membranes let of the plasma membrane (PM). They have that have a lipid composition similar to that of bulky hydrophilic head groups composed of the PM (McConnell and Vrljic 2003; Feigenson an oligosaccharide with up to seven monosac- 2007; Blanchette et al. 2008). charide units. Gangliosides (SP0601) constitute a subgroup of acidic glycosphingolipids (SP06) with one or more terminal sialic acids. The total ganglioside content of the plasma membrane LIGANDS THAT BIND TO GLYCOSPHINGOLIPIDS: BACTERIAL (PM) can reach up to 1%–2%, with individual TOXINS AND VIRUSES gangliosides in the range of 0.01%–0.1% (Levis et al. 1976; Ortegren et al. 2004; Sonnino et al. Endocytosed ligands known to bind to glyco- 2006). The glycosphingolipids are enriched in sphingolipids include certain bacterial toxins, the apical domain of polarized cells (Crespo viruses, lectins, and antibodies (Schengrund et al. 2008), and they are especially abundant 2003). Unlike other toxins and viruses that use in neurons (Sonnino et al. 2006). cell surface proteins as their receptors, those The larger the oligosaccharide, the more that bind to glycosphingolipids are special likely gangliosides are to cluster in membrane because they are usually transported to the regions of positive curvature (Sonnino et al. endoplasmic reticulum (ER) from where they 2007). The preference for membrane curvature penetrate into the cytosol. Once in the cytosol, may be the reason, why gangliosides can be the bacterial toxins and plant lectins manifest detected in the neck region of caveolae (Parton their toxicity by interfering with critical cell 1994). Exogenously added gangliosides enter functions such as protein translation and regu- caveolae (Fra et al. 1995; Pitto et al. 2000), and lation of membrane traffic (Sandvig et al. 2010). are endocytosed through these (Choudhury The viruses take over the cellular machinery for et al. 2006), but this association is transient their own replication. After entering the ER, the and not observed under steady state conditions best studied of the viruses—the mouse polyoma (Chigorno et al. 2000). virus (mPy) and simian virus 40 (SV40)—con- Because of the high content of long, satu- tinue their voyage to the nucleus to replicate. rated alkyl chains and the propensity to as- Tables 1 and 2 list some of the pathogenic sociate with other sphingolipids and choleste- ligands in question and some of their pro- rol, glycosphingolipids are thought to promote perties. In the case of Cholera (CTX) and Shiga Table 1. Toxins that use glycosphingolipids as cell surface receptors Bacterial toxins Cholera toxin Vibrio cholera A1B5 GM1; Heyningen 1974 Shiga toxin Shigella dysenteriae A1A2B5 Gb3 (CD77); Lindberg et al. 1987 Shiga-like toxins (SLT1 and SLT 2) Escherichia coli A1A2B5 Gb3 (CD77) Heat labile toxin 1 E. coli A1B5 GM1; Lencer and Saslowsky 2005 Heat labile toxin IIb E. coli A1B5 GD1a Tetanus neurotoxin TeNT Clostridium tetani GT1b, GD1b, Brunger and Rummel 2009 GQ1b, etc. Botulinium toxin BoNT Clostridium botulinum GD1a, GT1b, etc. Plant toxins Ricin AB Protein and lipid-linked galactosides; Sandvig and van Deurs 2000 Abrin AB Same 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004721 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Lipid-Mediated Endocytosis Table 2. Viruses that use glycosphingolipids as cell excluded. Polyomaviruses are nonenveloped surface receptors DNA viruses that replicate in the nucleus. Sev- Nonenveloped eral members of the family are recognized as viruses Organization Specificity human pathogens. Simian virus 40 VP1 pentamers GM1 The viral capsids are icosahedral with 72 Murine VP1 pentamers GD1a, GT1b VP1 protein pentamers serving as basic struc- polyomavirus tural units (Liddington et al. 1991; Stehle et al. BK virus Likely VP1 GD1b, GT1b 1994). The VP1 pentamers carry five glyco- pentamers sphingolipid binding sites as shown in Figure 1. Merkel cell Likely VP1 GT1b There is no sequence homology between VP1 polyomavirus pentamers and the bacterial toxins, but the overall Murine norovirus VP1? GD1a pentameric structures are remarkably similar compared to the equally pentameric, membrane-binding B-subunits of STX and CTX, so (STX) toxins, the glycosphingolipids GM1 called AB5 toxins (Fig. 1). Especially striking is (Heyningen 1974) and globotriasylceramide, the similar organization of binding sites always Gb3 (Lindberg et al. 1987), respectively, are spaced about 3 nm from each other. Noroviruses likely to be the main receptors needed for endo- are RNAviruses and replicate in the cytosol, but cytosis. In the case of the clostridium neuro- little is known about their entry mechanisms. toxins, TeNTand BoNT, polysialic gangliosides serve as attachment receptors. They concentrate INITIAL BINDING the toxins on the cell surface, and promote sub- sequent binding to specific protein receptors Binding of viruses and toxins to glycosphingo- such as synaptotagmin expressed in presynaptic lipids is highly specific. In gangliosides, the membranes (Montecucco et al. 1996; Brunger sialic acids play a central role in defining the and Rummel 2009). specificity. In the case of SV40, it is interesting Most of the toxins in Table 1 contain two to note in this context that a single atom in subunits (A and B). These are usually derived the carbohydrate moiety can make a difference. from a common precursor protein through Thus N-acetyl sialic acid in human GM1 pro- cleavage by target cell proteases. The A-subunits vides less efficient binding to cells and less effi- are the actual toxins or effectomers delivered cient infection than the N-glycolyl group to the cytosol. The B-subunits are so called hap- present in simian GM1 (Campanero-Rhodes tomers responsible for binding to the carbohy- et al. 2007). drate moiety of GSLs and internalization. The The crystal structures available for the tox- B-subunits are often five in number, and organ- ins and viruses in association with their recep- ized as a flat ring with a single A-subunit on one tors show that 2–3 of the saccharides in the

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