Proteolytic Processing of Filovirus Glycoproteins
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.
KeywordsFiloviruses Marburg virus Ebola virus Class I fusion protein Mucin-like domain Glycan cap Glycoprotein shedding Proprotein convertases Furin Cathepsin Metalloprotease TACE Macropinocytosis Niemann-Pick C1 receptor
- Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, Dal Cin P, Dye JM, Whelan SP, Chandran K, Brummelkamp TR. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477(7364):340–3.CrossRefPubMedPubMedCentralGoogle Scholar
- Wool-Lewis RJ, Bates P. Endoproteolytic processing of the Ebola virus envelope glycoprotein: cleavage is not required for function. J Virol. 1999;73(2):1419–26.Google Scholar