Hepatology (Baltimore, Md.) · 2026
CDK8 and CDK19 Mediator kinases are required for hepatitis delta virus replication.
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Prawira Angga, Hilleke Mattis, Chen Mengqian, Roninson Igor B, Bartenschlager Ralf, Urban Stephan, Ni Yi
Аннотация
BACKGROUND AND AIMS: Hepatitis delta virus (HDV) is a satellite virus of the hepatitis B virus (HBV), with a single-stranded and rod-like circular RNA encoding only one protein, the hepatitis delta antigen (HDAg). Lacking its own replicase, the highly self-complementary HDV RNA hijacks host RNA polymerase II (Pol-II), eliciting a unique and incompletely understood RNA-templated transcriptional activity. Because transcription by Pol-II is regulated at multiple steps by various cyclin-dependent kinases (CDKs), we investigated whether CDKs contribute to HDV replication.
APPROACH AND RESULTS: Using selective compounds targeting transcriptional cyclin-dependent kinases (CDKs), we identified the Mediator kinase CDK8 and its paralog CDK19 as key cofactors for HDV replication. Loss of CDK8/19 activity by small-molecule inhibitor MSC2530818 or genetic knockouts completely prevents the establishment of HDV replication in multiple cell culture models and partially suppresses HDV RNA synthesis during the steady-state replication phase. Ectopic expression of the small HDAg, but not its methylation site R13 mutant, restored HDV replication in CDK8/19-deficient cells. Inactivation of CDK8/19 did not alter phosphorylation of small HDAg at Ser177, but was associated with reduced phosphorylation of the C-terminal domain of Pol-II, consistent with impaired transcriptional activity.
CONCLUSIONS: Our findings reveal the essential role of CDK8/19 in mediating the transcriptional activity of Pol-II during HDV replication, which is partially counteracted by HDV-encoded small HDAg.
APPROACH AND RESULTS: Using selective compounds targeting transcriptional cyclin-dependent kinases (CDKs), we identified the Mediator kinase CDK8 and its paralog CDK19 as key cofactors for HDV replication. Loss of CDK8/19 activity by small-molecule inhibitor MSC2530818 or genetic knockouts completely prevents the establishment of HDV replication in multiple cell culture models and partially suppresses HDV RNA synthesis during the steady-state replication phase. Ectopic expression of the small HDAg, but not its methylation site R13 mutant, restored HDV replication in CDK8/19-deficient cells. Inactivation of CDK8/19 did not alter phosphorylation of small HDAg at Ser177, but was associated with reduced phosphorylation of the C-terminal domain of Pol-II, consistent with impaired transcriptional activity.
CONCLUSIONS: Our findings reveal the essential role of CDK8/19 in mediating the transcriptional activity of Pol-II during HDV replication, which is partially counteracted by HDV-encoded small HDAg.