Proteolytic Processing of Filovirus Glycoproteins

Volchkov, Viktor; Klenk, Hans Dieter

Filoviruses (Marburg virus and Ebola virus) have a single envelope glycoprotein (GP) that initiates infection. GP is a class I fusion protein that forms trimeric spikes composed of heterodimers of the subunits GP1 and GP2. GP1 and GP2 are derived from the precursor pre-GP by furin cleavage during exocytosis. GP1 contains a receptor-binding core topped by a glycan cap and a heavily glycosylated mucin-like domain, while GP2 contains a fusion loop and a membrane anchor. After entering cells by macropinocytosis, the glycan cap and the mucin-like domain are removed from GP1 by endosomal cathepsins B and L exposing the binding site for the Niemann-Pick C1 receptor. It appears that there is no strict requirement for specific proteases involved in GP processing. Thus, furin is not indispensible for GP1-2 cleavage, and GP1 may be trimmed not only by cathepsins B and L but also by other endosomal proteases. Two soluble glycoproteins of Ebola virus are also processed by host proteases. A significant amount of GP1,2 is cleaved by the metalloprotease TACE and shed from the surface of infected cells (GP1,2 delta). The secreted protein sGP is derived from the precursor pre-sGP by furin cleavage.