The cell biology of receptor-mediated virus entry

Grove, Joe; Marsh, Mark

Additional molecular cues for fusion/penetration may be provided by the lipid composition of endosomal membranes. The fusion of tick-borne encephalitis virus requires cholesterol in the target membrane (Stiasny et al., 2003) , and fusion of Semliki Forest virus is dependent on both cholesterol and sphingolipids (Kielian and Helenius, 1984; Nieva et al., 1994) , both of which are available in the plasma membrane as well as endosomal membranes. Dengue virus transits through the early endosomes to fuse with late endocytic organelles (van der Schaar et al., 2008) . In addition to low pH, Dengue virus fusion requires the target membrane to contain anionic lipids such as lysobisphosphatidic acid, which is predominantly found within the lysosome (Brotherus and Renkonen, 1977; Zaitseva et al., 2010) . Other viruses, including SARS coronavirus and orthoreoviruses, also exhibit atypical pH-dependent entry; in these cases, proteolytic cleavage of the viral envelope or surface proteins by acid-dependent cellular proteases (cathepsins L and B) triggers the structural changes required for fusion (Figs. 3 C and 4; Ebert et al., 2002; Chandran et al., 2005; Simmons et al., 2005) . Ebola virus GP1 glycoprotein also undergoes cleavage by cathepsins to reveal a putative binding domain for the late endosomal/lysosomal cholesterol transporter Niemann-Pick C1 (NPC1; Chandran et al., 2005; Schornberg et al., 2006; Côté et al., 2011) . Depletion of NPC1 from target cells prevents Ebola virus glycoproteindependent fusion, suggesting that NPC1 acts as a postendocytic intracellular receptor necessary for virus penetration (Carette et al., 2011) . These and other recent findings have provided increasing clarity on Ebola virus infection, suggesting a putative entry pathway for this infamous virus (Fig. 4) .