The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases

Abstract

A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly during morphogenesis or extracellularly after egress and during entry in order to produce mature virions activated for infection. Although viruses also take advantage of other proteases, it is when some viruses become reactive with PCs that they may develop high pathogenicity. Besides reacting with furin, some viruses may also react with the PCs of the other specificity group constituted by PC4/PC5/PACE4/PC7. The targeting of PCs for inhibition may result in a useful strategy to treat infections with some highly pathogenic viruses. A wide variety of PC inhibitors have been developed and tested for their antiviral activity in cell-based assays.

Keywords: furin; proprotein convertases; protease inhibitors; proteases.

Figure 1

X-ray crystal structure of human furin. The PC catalytic domain (red) shared by all PCs has the structural fold typical of the subtilin family of serine proteases. The position of the catalytic triad residues is marked in cyan. The P domain (blue) regulates catalytic activity. The PCs differ in their additional domains. PDB ID code 5JXH.

Figure 2

X-ray crystal structure of the HIV-1 envelope pg160 glycoprotein monomer. The fusion machine is composed of three gp160 monomers which are divided into N-terminal gp120 (green) and C-terminal pg41 (gray). Residue in red denotes the end of gp120 and residue in blue the beginning of gp41 after PC cleavage. PDB ID code 6MTJ.

Figure 3

X-ray crystal structure of the HA trimer from the influenza virus A type H5. Each HA monomer is divided into HA₁ (red, blue, and gray) and HA₂ (oarange, cyan, and white, respectively) subunits after the PC cleavage denoted by residues at the end HA₁ (yellow) and the beginning of HA₂ (purple). PDB ID code 2IBX.