The Amino Acid at Position 8 of the Proteolytic Cleavage Site of the Mumps Virus Fusion Protein Affects Viral Proteolysis and Fusogenicity.
The mumps virus (MuV) fusion protein (F) plays a crucial role for the entry process and spread of infection by mediating fusion between viral and cellular membranes as well as between infected and neighboring cells, respectively. The fusogenicity of MuV differs depending on the strain and might correlate with the virulence; however, it is unclear which mechanisms contribute to the differentiated fusogenicity. The cleavage motif of MuV F is highly conserved among all strains, except the amino acid residue at position 8 (P8) that shows a certain variability with a total of four amino acid variants (leucine [L], proline [P], serine [S], and threonine [T]). We demonstrate that P8 affects the proteolytic processing and the fusogenicity of MuV F. The presence of L or S at P8 resulted in a slower proteolysis of MuV F by furin and a reduced ability to mediate cell-cell fusion. However, virus-cell fusion was more efficient for F proteins harboring L or S at P8, suggesting that P8 contributes to the mechanism of viral spread: P and T enable a rapid spread of infection by cell-to-cell fusion, whereas viruses harboring L or S at P8 spread preferentially by the release of infectious viral particles. Our study provides novel insights into the fusogenicity of MuV and its influence on the mechanisms of virus spread within infected tissues. Assuming a correlation between MuV fusogenicity and virulence, sequence information on the amino acid residue at P8 might be helpful to estimate the virulence of circulating and emerging strains.IMPORTANCE Mumps virus (MuV) is the causative agent of the highly infectious disease mumps. Mumps is mainly associated with mild symptoms, but severe complications such as encephalitis, meningitis, or orchitis can also occur. There is evidence that the virulence of different MuV strains and variants might correlate with the ability of the fusion protein (F) to mediate cell-to-cell fusion. However, the relation between virulence and fusogenicity or the mechanisms responsible for the varied fusogenicity of different MuV strains are incompletely understood. Here, we focused on the amino acid residue at position 8 (P8) of the proteolytic cleavage site of MuV F, because this amino acid residue shows a striking variability depending on the genotype of MuV. The P8 residue has a significant effect on the proteolytic processing and fusogenicity of MuV F and might thereby determine the route of viral spread within infected tissues.
['Hüttl|Sarah|S|', 'Hoffmann|Markus|M|0000-0003-4603-7696', 'Steinmetzer|Torsten|T|', 'Sauder|Christian|C|', 'Krüger|Nadine|N|0000-0002-4413-8699']
D000596:Amino Acids D000818:Animals D002459:Cell Fusion D002522:Chlorocebus aethiops D045683:Furin D005838:Genotype D057809:HEK293 Cells D006801:Humans D007700:Kinetics D009107:Mumps D009109:Mumps virus D059748:Proteolysis D017386:Sequence Homology, Amino Acid D014709:Vero Cells D014760:Viral Fusion Proteins D053586:Virus Internalization
mumps virus fusion viral entry