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Journal of Virology, December 2009, p. 12314-12324, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01044-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Clathrin-Mediated Post-Golgi Membrane Trafficking in the Morphogenesis of Hepatitis Delta Virus{triangledown}

Cheng Huang,1 Shin C. Chang,2 Hui-Chin Yang,1 Chung-Liang Chien,3 and Ming-Fu Chang1*

Institute of Biochemistry and Molecular Biology,1 Institute of Microbiology,2 Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan3

Received 22 May 2009/ Accepted 18 September 2009

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.

* Corresponding author. Mailing address: Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, No. 1, Jen-Ai Road, First Section, Taipei, Taiwan. Phone: 886-2-23123456, ext. 88217. Fax: 886-2-23915295. E-mail: mfchang{at}ntu.edu.tw

{triangledown} Published ahead of print on 30 September 2009.

Journal of Virology, December 2009, p. 12314-12324, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01044-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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