Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA without altering the translational efficiency of the viral pregenomic or spliced 2.2 kb RNAs. Together, these observations point to a broader role of HDAC5 in regulating RNA splicing and transcript stability while specifically identifying a potentially novel approach toward antiviral HBV therapeutic development.
Author summary
This study demonstrates that HDAC5 deacetylation of host cellular factor(s) results in increased HBV biosynthesis by enhancing viral transcript stability and splicing via direct or indirect binding of host factors to viral intron sequences. This represents the first demonstration of this type of post-transcriptional regulation in the liver and is similar to observations seen for cellular transcripts in neural and cardiac cell types. These observations suggest a more general phenomena which could represent an additional posttranscriptional code governing the regulation of RNA:protein interactions and hence RNA metabolism. Therefore, covalent modifications of RNA binding proteins may modulate post-transcriptional gene expression in an analogous manner to the known histone code that controls gene transcription. Although this analysis primarily relates to the mechanism(s) by which HDAC5 governs HBV RNA metabolism, it does have significant therapeutic implications. The inhibition of HDAC5 in combination with current nucleos(t)ide analog drugs targeting the viral reverse transcriptase/DNA polymerase might aid in the treatment and possible resolution of chronic infections by targeting both host and viral factors. 作者: StephenW 时间: 2020-9-1 18:44