CDK8 and CDK19 Mediator kinases are required for hepatitis delta virus replication

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• Hepatitis delta virus (HDV) relies on host RNA polymerase II (Pol-II) for replication due to lacking its own replicase.
• Transcription by Pol-II is regulated by cyclin-dependent kinases (CDKs).

Purpose of the Study:

• To investigate the role of CDKs in HDV replication.
• To identify specific CDKs involved in HDV RNA transcription.

Main Methods:

• Utilized selective CDK inhibitors and genetic knockouts to assess CDK8/19 activity.
• Employed cell culture models to study HDV replication dynamics.
• Analyzed phosphorylation of Pol-II and HDV small antigen (HDAg).

Main Results:

• CDK8 and its paralog CDK19 were identified as key co-factors for HDV replication.
• Inhibition or knockout of CDK8/19 significantly impaired HDV replication and RNA synthesis.
• Ectopic expression of small HDAg, but not its R13 mutant, restored replication in CDK8/19-deficient cells.
• CDK8/19 inactivation reduced Pol-II C-terminal domain phosphorylation, indicating impaired transcription.

Conclusions:

• CDK8/19 play a crucial role in mediating Pol-II transcriptional activity for HDV replication.
• HDV small HDAg partially counteracts the inhibitory effects of CDK8/19 inactivation on transcription.