Lipids as modulators of membrane fusion mediated by viral fusion proteins

Abstract

Enveloped viruses infect host cells by fusion of viral and target membranes. This fusion event is triggered by specific glycoproteins in the viral envelope. Fusion glycoproteins belong to either class I, class II or the newly described third class, depending upon their arrangement at the surface of the virion, their tri-dimensional structure and the location within the protein of a short stretch of hydrophobic amino acids called the fusion peptide, which is able to induce the initial lipid destabilization at the onset of fusion. Viral fusion occurs either with the plasma membrane for pH-independent viruses, or with the endosomal membranes for pH-dependent viruses. Although, viral fusion proteins are parted in three classes and the subcellular localization of fusion might vary, these proteins have to act, in common, on lipid assemblies. Lipids contribute to fusion through their physical, mechanical and/or chemical properties. Lipids can thus play a role as chemically defined entities, or through their preferential partitioning into membrane microdomains called "rafts", or by modulating the curvature of the membranes involved in the fusion process. The purpose of this review is to make a state of the art on recent findings on the contribution of cholesterol, sphingolipids and glycolipids in cell entry and membrane fusion of a number of viral families, whose members bear either class I or class II fusion proteins, or fusion proteins of the recently discovered third class.

Fig. 1

Schematic pathway of membrane deformation during fusion (fusion proteins are not represented). Intact viral and cellular membranes first come into close apposition, which leads to the first step of the fusion process, the fusion of the outer leaflets of membranes (hemifusion). This step can be blocked by the presence of lysolipids in that leaflet, or promoted by unsaturated PE, cholesterol or monoolein. The mixing of the inner leaflets of membranes evolves into an early fusion pore, which enlarges to give rise to the late fusion pore. At that stage viral genetic material is delivered to the cell cytoplasm

Fig. 2

3D-structures of a prototype of each class of fusion proteins; for class I, trimer of the influenza hemagglutinin at low pH [1HTM PDB accession number, (Bullough et al. 1994)], displaying a three-stranded coiled coil of alpha-helices (note that the fusion peptides are absent from this structure); for class II, monomer of the E protein of TBEV at neutral pH, mainly composed of beta-strands (the fusion peptide is at the top) [1SVB PDB accession number, (Rey et al. 1995)]; for the newly described class of proteins, trimer of VSV-G at low pH [2CMZ PDB accession number, (Roche et al. 2006)], displaying three-stranded coiled coils (bottom), a beta-strand-rich region (top), and a pleckstrin homology domain absent in class I and II fusion proteins (middle). The fusion peptides are at the top

Fig. 3

Hypotheses for the involvement of lipid rafts in HIV entry into its target cells. See text for details

Fig. 4

Backbone 3D-structure of regions including the fusion peptide (FP) of SFV E1. FP is at the extreme right, Cys involved in disulphide bridges essential to the architecture of the FP region are shown as yellow balls (extreme right), Pro226 is shown as a red ball, and His230, Leu44 and Val178 are shown as blue balls. Central domain I is in magenta, the dimerization domain II in yellow (containing the FP) and the C-terminal domain III is in blue (see text for details; balls are symbols for C-alpha). The coordinates of these structures were retrieved from the PDB (protein data base) under accession number 1I9W (Lescar et al. 2001)