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.
Highlights
Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV)
Several nuclear export signal (NES) of viral proteins that pass through the chromosome region maintenance 1 (CRM1)-independent nuclear export pathway utilize the host nuclear export factors TAP and Aly to facilitate the morphogenesis of the virion (24 –28)
These results show that hepatitis delta antigen (HDAg)-L and TAP or Aly were present in the same complex in cells
Summary
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. Small hairpin RNA-mediated down-regulation of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions. 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. Hepatitis delta virus (HDV) is a human pathogen that is associated with fulminant hepatitis and progressive chronic. A peptide consisting of TAT peptide, a 10-amino acid carrier peptide derived from the HIV-1 transactivator of transcription (TAT) sequence, and residues 198 – 210 of HDAg-L, blocked the interaction of HDAg-L with TAP and Aly and inhibited the secretion of HDV virions. Our results demonstrate that TAP and Aly play critical roles during the processes of HDV maturation
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