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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.

Author information

1
From the Department of Applied Science, National Hsinchu University of Education, Hsinchu 30014.
2
the School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 11219.
3
the National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11221.
4
the Ph.D Program for Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 11031.
5
the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051.
6
the Department of Chemistry, Chinese Culture University, Taipei 11114.
7
the Center of Translational Medicine, Taipei Medical University, Taipei 11031.
8
the Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, and.
9
the National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11221, chengh@nricm.edu.tw.
10
the Department of Earth and Life Sciences, University of Taipei, Taipei 10048, Taiwan.

Abstract

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.

KEYWORDS:

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

PMID:
27807029
PMCID:
PMC5207089
DOI:
10.1074/jbc.M116.754853
[Indexed for MEDLINE]
Free PMC Article

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