Abstract
Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication.
Highlights
Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome
In HDV-infected cells, HDV RNA replication leads to the production of three forms of viral RNA: the genomic HDV RNA, the antigenomic RNA replication intermediate, and the messenger RNA for the HDV antigen (HDAg) protein produced under two isoforms: the small and large HDAg (S-HDAg and L-HDAg, respectively)
The ability of ST-small hepatitis delta antigen (S-HDAg) to assist HDV replication was demonstrated in a trans-complementation assay using the replication-defective plasmid pSVL-D2M that allows for transcription of a full-length HDV RNA defective for S-HDAg synthesis and sustains replication when a functional S-HDAg is provided in trans[4]
Summary
Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. 6 Department of Hepatology, Hôpital de la Croix Rousse, Hospices Civils de Lyon and Université Lyon I, 103 Grande Rue de la Croix-Rousse, 69004 Lyon, France. In the current model of the HDV RNP structure, four to five octamers of HDAg proteins are wrapped by a HDV RNA molecule to form a nucleosome-like structure[13,14,15] According to this model, the RNP would adopt a chromatin-like organization where the viral RNA replaces the cellular DNA as template for HDV RNA synthesis by Pol II. Our results suggest that S-HDAg mimics histone H3 acetylation to recruit BRF complexes and RNA Pol II on the HDV RNP to sustain HDV replication
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