Clathrin-mediated post-Golgi membrane trafficking in the morphogenesis of hepatitis delta virus
Journal
Journal of Virology
Journal Volume
83
Journal Issue
23
Pages
12314-12324
Date Issued
2009
Author(s)
Abstract
Clathrin is involved in the endocytosis and exocytosis of cellular proteins and the process of virus infection. We have previously demonstrated that large hepatitis delta antigen (HDAg-L) functions as a clathrin adaptor, but the detailed mechanisms of clathrin involvement in the morphogenesis of hepatitis delta virus (HDV) are not clear. In this study, we found that clathrin heavy chain (CHC) is a key determinant in the morphogenesis of HDV. HDAg-L with a single amino acid substitution at the clathrin box retained nuclear export activity but failed to interact with CHC and to assemble into virus-like particles. Downregulation of CHC function by a dominant-negative mutant or by short hairpin RNA reduced the efficiency of HDV assembly, but not the secretion of hepatitis B virus subviral particles. In addition, the coexistence of a cell-permeable peptide derived from the C terminus of HDAg-L significantly interfered with the intracellular transport of HDAg-L. HDAg-L, small HBsAg, and CHC were found to colocalize with the trans-Golgi network and were highly enriched on clathrin-coated vesicles. Furthermore, genotype II HDV, which assembles less efficiently than genotype I HDV does, has a putative clathrin box in its HDAg-L but interacted only weakly with CHC. The assembly efficiency of the various HDV genotypes correlates well with the CHC-binding activity of their HDAg-Ls and coincides with the severity of disease outcome. Thus, the clathrin box and the nuclear export signal at the C terminus of HDAg-L are potential new molecular targets for HDV therapy. Copyright ? 2009, American Society for Microbiology. All Rights Reserved.
SDGs
Other Subjects
cell protein; clathrin; hepatitis delta antigen; short hairpin RNA; amino acid substitution; animal cell; article; carboxy terminal sequence; controlled study; down regulation; endocytosis; exocytosis; genotype; Golgi complex; Hepatitis delta virus; human; human cell; intracellular transport; membrane transport; membrane vesicle; nonhuman; nuclear export signal; priority journal; trans Golgi network; virus assembly; virus morphogenesis; virus mutant; virus particle; Animals; Cell Line; Cercopithecus aethiops; Clathrin Heavy Chains; Hepatitis delta Antigens; Hepatitis Delta Virus; Humans; Mutant Proteins; Mutation, Missense; Point Mutation; Protein Binding; Protein Transport; Virus Assembly; Hepatitis B virus; Hepatitis delta virus
Type
journal article