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J Biol Chem. 2016 Dec 9;291(50):26226-26238. Epub 2016 Nov 2.

Cellular Nuclear Export Factors TAP and Aly Are Required for HDAg-L-mediated Assembly of Hepatitis Delta Virus.

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From the Department of Applied Science, National Hsinchu University of Education, Hsinchu 30014.
the School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 11219.
the National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11221.
the Ph.D Program for Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 11031.
the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051.
the Department of Chemistry, Chinese Culture University, Taipei 11114.
the Center of Translational Medicine, Taipei Medical University, Taipei 11031.
the Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, and.
the National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11221,
the Department of Earth and Life Sciences, University of Taipei, Taipei 10048, Taiwan.


Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV). HDV genome encodes two forms of hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral replication, and large HDAg (HDAg-L), which is essential for viral assembly. HDAg-L is identical to HDAg-S except that it bears a 19-amino acid extension at the C terminus. Both HDAgs contain a nuclear localization signal (NLS), but only HDAg-L contains a CRM1-independent nuclear export signal at its C terminus. The nuclear export activity of HDAg-L is important for HDV particle formation. However, the mechanisms of HDAg-L-mediated nuclear export of HDV ribonucleoprotein are not clear. In this study, the host cellular RNA export complex TAP-Aly was found to form a complex with HDAg-L, but not with an export-defective HDAg-L mutant, in which Pro205 was replaced by Ala. HDAg-L was found to colocalize with TAP and Aly in the nucleus. The C-terminal domain of HDAg-L was shown to directly interact with the N terminus of TAP, whereas an HDAg-L mutant lacking the NLS failed to interact with full-length TAP. In addition, small hairpin RNA-mediated down-regulation of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions. Furthermore, a peptide, TAT-HDAg-L(198-210), containing the 10-amino acid TAT peptide and HDAg-L(198-210), inhibited the interaction between HDAg-L and TAP and blocked HDV virion assembly and secretion. These data demonstrate that formation and release of HDV particles are mediated by TAP and Aly.


Aly; TAP; hepatitis delta antigen; hepatitis virus; nuclear export factor; nuclear transport; protein translocation; viral replication; virus assembly

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