CDK8 and CDK19 Mediator kinases are required for hepatitis delta virus replication
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 poly...
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| Autori principali: | , , , , , , |
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| Natura: | Article (Journal) |
| Lingua: | inglese |
| Pubblicazione: |
August 2026
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| In: |
Hepatology
Year: 2026, Volume: 84, Fascicolo: 2, Pages: 559-572 |
| ISSN: | 1527-3350 |
| DOI: | 10.1097/HEP.0000000000001690 |
| Accesso online: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1097/HEP.0000000000001690 Verlag, lizenzpflichtig, Volltext: https://journals.lww.com/hep/fulltext/9900/cdk8_and_cdk19_mediator_kinases_are_required_for.1553.aspx 
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| Note sull'autore: | Angga Prawira, Mattis Hilleke, Mengqian Chen, Igor B. Roninson, Ralf Bartenschlager, Stephan Urban, Yi Ni |
| Riassunto: | 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. Export |
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| Descrizione del documento: | Gesehen am 01.06.2026 |
| Descrizione fisica: | Online Resource |
| ISSN: | 1527-3350 |
| DOI: | 10.1097/HEP.0000000000001690 |