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Paramyxovirus tropism dependent on host proteases activating the viral fusion glycoprotein
Y Nagai1, N M Inocencio, B Gotoh
1Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Japan.
Abstract:
An essential step in paramyxovirus fusion (F) glycoprotein biosynthesis is the posttranslational endoproteolytic cleavage of the inactive precursor glycoprotein Fo by host cell proteases. When the Fo possesses a pair or a cluster of basic residues at the cleavage site, cleavage is catalyzed by a ubiquitous protease(s) and the infection is consequently pantropic. When the site is monobasic with a single arginine, cleavage is allowed to occur only by the enzyme(s) expressed in limited tissue types and the infection is localized there. We have isolated from chick embryo an example of the latter type of endoprotease specific for the single arginine motif and demonstrate its identity with the clotting factor Xa. The ectopic expression of the FXa appeared to be the sole determinant for the viral tropism in chick embryo. The latter type of protease specific for a paired or multiple basic cleavage motif have neither been identified nor characterized extensively. We show here that this cleavage can be induced by the yeast KEX2 protease, a unique subtilisin-like serine protease, responsible for pro factor processing at the paired basic sites.
Insights
Paramyxovirus fusion glycoprotein cleavage dictates viral tropism. Researchers identified clotting factor Xa as a protease specific for monobasic cleavage sites, controlling localized infections.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Paramyxovirus fusion (F) glycoprotein requires posttranslational cleavage by host proteases for activation.
- Cleavage site motif (monobasic vs. multibasic) influences protease specificity and viral tropism.
- Ubiquitous proteases cleave multibasic sites, leading to pantropic infections.
Purpose of the Study:
- To identify the host protease responsible for cleaving monobasic paramyxovirus F precursor glycoproteins.
- To investigate the role of this protease in determining viral tropism.
- To characterize proteases that cleave multibasic sites.
Main Methods:
- Isolation and identification of chick embryo endoprotease specific for monobasic cleavage motif.
- Ectopic expression of identified protease to assess its effect on viral tropism.
- Induction of multibasic cleavage site processing using yeast KEX2 protease.
Main Results:
- Identified chick embryo endoprotease as clotting factor Xa (FXa).
- Ectopic expression of FXa determined viral tropism in chick embryos.
- Yeast KEX2 protease, a subtilisin-like serine protease, induced cleavage at paired basic sites.
Conclusions:
- Clotting factor Xa is a key determinant of paramyxovirus tropism through specific cleavage of monobasic F precursor sites.
- Understanding protease specificity is crucial for controlling viral spread and pathogenesis.
- Yeast KEX2 protease serves as a model for studying multibasic cleavage events.