Molecular determinants within the C-termini of L-HDAg that regulate hepatitis D virus replication and assembly

• Verfasst von: Guo, Hongbo [VerfasserIn]
• Verfasst von: Li, Qiudi [VerfasserIn]
• Verfasst von: Li, Chunyang [VerfasserIn]
• Verfasst von: Hou, Yao [VerfasserIn]
• Verfasst von: Ding, Yibo [VerfasserIn]
• Verfasst von: Liu, Dan [VerfasserIn]
• Verfasst von: Ni, Yi [VerfasserIn]
• Verfasst von: Tang, Renxian [VerfasserIn]
• Verfasst von: Zheng, Kuiyang [VerfasserIn]
• Verfasst von: Urban, Stephan [VerfasserIn]
• Verfasst von: Wang, Wenshi [VerfasserIn]
• Titel: Molecular determinants within the C-termini of L-HDAg that regulate hepatitis D virus replication and assembly
• Verf.angabe: Hongbo Guo, Qiudi Li, Chunyang Li, Yao Hou, Yibo Ding, Dan Liu, Yi Ni, Renxian Tang, Kuiyang Zheng, Stephan Urban, Wenshi Wang
• E-Jahr: 2024
• Jahr: January 2024
• Umfang: 11 S.
• Illustrationen: Illustrationen
• Fussnoten: Online verfügbar: 15. November 2023, Artikelversion: 19. Dezember 2023 ; Gesehen am 22.03.2024
• Titel Quelle: Enthalten in: JHEP reports
• Ort Quelle: Amsterdam : Elsevier, 2019
• Jahr Quelle: 2024
• Band/Heft Quelle: 6(2024), 1 vom: Jan., Artikel-ID 100961, Seite 1-11
• ISSN Quelle: 2589-5559
• DOI: doi:10.1016/j.jhepr.2023.100961
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Hepatitis B virus
• Sach-SW: Hepatitis D virus
• Sach-SW: L-HDAg
• Sach-SW: Virion assembly and production
• Sach-SW: Virus replication
• K10plus-PPN: 1884073212

Abstract

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.