Subcellular Localization and Calcium and pH Requirements for Proteolytic Processing of the Hendra Virus Fusion Protein

Author:

Pager Cara Theresia1,Wurth Mark Allen,Dutch Rebecca Ellis

Affiliation:

1. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky

Abstract

ABSTRACT Proteolytic cleavage of the Hendra virus fusion (F) protein results in the formation of disulfide-linked F 1 and F 2 subunits, with cleavage occurring after residue K 109 in the sequence GDVK↓L. This unusual cleavage site and efficient propagation of Hendra virus in a furin-deficient cell line indicate that the Hendra F protein is not cleaved by furin, the protease responsible for proteolytic activation of many viral fusion proteins. To identify the subcellular site of Hendra F processing, Vero cells transfected with pCAGGS-Hendra F or pCAGGS-SV5 F were metabolically labeled and chased in the absence and presence of inhibitors of exocytosis. The addition of carbonyl-cyanide-3-chlorophenylhydrazone, monensin, brefeldin A, or NaF-AlCl 3 or incubation of cells at 20°C all inhibited processing of the Hendra F protein, suggesting that cleavage of Hendra F occurs either in secretory vesicles budding from the trans -Golgi network or at the cell surface. In contrast to proteolytic cleavage of the simian virus 5 (SV5) F protein by the Ca 2+ -dependent protease furin, proteolytic cleavage of the Hendra F protein was not significantly inhibited by decreases in Ca 2+ levels following incubation with EGTA or A23187. However, in the presence of weak amines and H + V-ATPase inhibitors, known to raise intracellular pH, cleavage of Hendra F protein was inhibited while processing of the SV5 F protein was not significantly affected. The subcellular location, sensitivity to pH changes, and decreased Ca 2+ requirement suggest that the protease responsible for cleavage of Hendra F protein differs from proteases previously shown to be involved in the processing of other viral glycoproteins.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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