Clathrin-Mediated Post-Golgi Membrane Trafficking in the Morphogenesis of Hepatitis Delta Virus

Abstract

Clathrin is involved in the endocytosis and exocytosis of cellular proteins and the process of virus infection.We have previously demonstrated that large hepatitis delta antigen (HDAg-L) functions as a clathrin adaptor, but the detailed mechanisms of clathrin involvement in the morphogenesis of hepatitis delta virus (HDV) are not clear. In this study, we found that clathrin heavy chain (CHC) is a key determinant in the morphogenesis of HDV. HDAg-L with a single amino acid substitution at the clathrin box retained nuclear export activity but failed to interact with CHC and to assemble into virus-like particles. Downregulation of CHC function by a dominant-negative mutant or by short hairpin RNA reduced the efficiency of HDV assembly, but not the secretion of hepatitis B virus subviral particles. In addition, the coexistence of a cell-permeable peptide derived from the C terminus of HDAg-L significantly interfered with the intracellular transport of HDAg-L. HDAg-L, small HBsAg, and CHC were found to colocalize with the trans-Golgi network and were highly enriched on clathrin-coated vesicles. Furthermore, genotype II HDV, which assembles less efficiently than genotype I HDV does, has a putative clathrin box in its HDAg-L but interacted only weakly with CHC. The assembly efficiency of the various HDV genotypes correlates well with the CHC-binding activity of their HDAg-Ls and coincides with the severity of disease outcome. Thus, the clathrin box and the nuclear export signal at the C terminus of HDAg-L are potential new molecular targets for HDV therapy.

Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options

“…As for post-entry trafficking of HDV RNP, clathrin could also be involved in viral particle export (86). Regarding viral components, the farnesylation of the C-terminal sequence of L-HDAg is necessary for HDV envelopment, as it mediates the interaction with the S region of HBsAg (87).…”

Study of the Impact of Hepatitis D Virus Infection on Chronic Hepatitis B Virus Patients in Egypt

“…In the acute stage, HDAg or HDV RNA may be directly cytotoxic to hepatocytes. In the chronic stage, inflammatory cells surround infected hepatocytes, and various autoantibodies have been detected in the serum of patients with CHD, suggesting the possible involvement of immune reaction in HDV pathogenesis (Huang et al, 2009). …”

Clathrin Mediates Infectious Hepatitis C Virus Particle Egress

“…Whereas AP-1 mediates the delivery of proteins to the plasma membrane, AP-2 is involved in endocytic processes (10). On the other hand, clathrin is essential for both the entry and secretion of some viruses into/from host cells (11)(12)(13). Although it is known that HCV entry is a clathrinmediated process (14,15), the possible role of clathrin in other steps of the HCV cycle has not been studied.…”