Molecular determinants within the C-termini of L-HDAg that regulate hepatitis D virus replication and assembly
Background & Aims - Hepatitis D virus (HDV) is the causative agent of chronic hepatitis delta, the most severe form of viral hepatitis. HDV encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additiona...
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| Hauptverfasser: | , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
January 2024
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| In: |
JHEP reports
Year: 2024, Jahrgang: 6, Heft: 1, Pages: 1-11 |
| ISSN: | 2589-5559 |
| DOI: | 10.1016/j.jhepr.2023.100961 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.jhepr.2023.100961 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2589555923002926 
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| Verfasserangaben: | Hongbo Guo, Qiudi Li, Chunyang Li, Yao Hou, Yibo Ding, Dan Liu, Yi Ni, Renxian Tang, Kuiyang Zheng, Stephan Urban, Wenshi Wang |
| Zusammenfassung: | Background & Aims - Hepatitis D virus (HDV) is the causative agent of chronic hepatitis delta, the most severe form of viral hepatitis. HDV encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus, which confer regulatory roles that are distinct from those of S-HDAg. Notably, these residues are divergent between different genotypes. We aimed to elucidate the molecular determinants within the C-termini that are essential for the regulatory role of L-HDAg in HDV replication and assembly. - Methods - Northern blot, reverse-transcription quantitative PCR, and a newly established HDV trans-complementary system were used in this study. - Results - C-termini of L-HDAg, albeit with high sequence variation among different genotypes, are interchangeable with respect to the trans-inhibitory function of L-HDAg and HDV assembly. The C-terminus of L-HDAg features a conserved prenylation CXXQ motif and is enriched with proline and hydrophobic residues. Abolishment of the CXXQ motif attenuated the inhibitory effect of L-HDAg on HDV replication. In contrast, the enrichment of proline and hydrophobic residues per se does not modify the trans-inhibitory function of L-HDAg. Nevertheless, these residues are essential for HDV assembly. Mechanistically, prolines and hydrophobic residues contribute to HDV assembly via a mode of action independent of the prenylated CXXQ motif. - Conclusions - Within the C-terminus of L-HDAg, the CXXQ motif and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg’s regulatory roles in HDV replication and assembly. This intrinsic viral regulatory mechanism we elucidated deepens our understanding of the unique life cycle of HDV. - Impact and implications - Hepatitis D virus (HDV) encodes one protein, hepatitis delta antigen (HDAg), in two isoforms: S- and L-HDAg. They are identical in sequence except that L-HDAg contains an additional 19-20 amino acids at its C-terminus. This C-terminal extension in L-HDAg confers regulatory roles in the HDV life cycle that are distinct from those of S-HDAg. Herein, we found that C-termini of L-HDAg, although with high sequence variation, are interchangeable among different HDV genotypes. Within the C-terminus of L-HDAg, the prenylation motif, and the enrichment of proline and hydrophobic residues are all essential determinants of L-HDAg’s regulatory roles in HDV replication and assembly. |
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| Beschreibung: | Online verfügbar: 15. November 2023, Artikelversion: 19. Dezember 2023 Gesehen am 22.03.2024 |
| Beschreibung: | Online Resource |
| ISSN: | 2589-5559 |
| DOI: | 10.1016/j.jhepr.2023.100961 |