Project description: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 BRF (BAZ2B-Associated Remodeling Factor) ISWI chromatin remodeling complexes. ShRNAs-mediated silencing of BAZ2B or its inactivation with the BAZ2B-BRD inhibitor GSK-2801 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.
Project description:Hepatitis B virus (HBV) is an enveloped, coated, non-cytopathic and hepatotropic partially double-stranded DNA virus in the family Hepadnaviridae genus Orthohepadnavirus. Despite significant progress in the availability of safe vaccines and antiviral therapies against HBV, it still affects approximately 257 million people worldwide and is responsible for about 887,000 deaths per year around the world [4]. HBV infection, which are associated with acute and chronic liver failure responses to viruses attacked the liver, can result in inactive carrier state, chronic hepatitis, or fulminant hepatitis and put them at high risk to develop advanced liver fibrosis and cirrhosis, and even hepatocellular cancer. Many viral factors, which could affect the disparity of clinical outcomes or disease prognosis during chronic HBV infection, have been reported in previous studies; among them, the viral genotype, as well as HBV mutations ascribing the virus to a certain phenotype, was reported to be the most important factor influencing viral pathogenesis, including the change of host immune recognition, the enhanced virulence with increased HBV replication and the facilitation of cell attachment or penetration.
