Cyclin-Dependent Kinase 8 Represents a Positive Regulator of Cytomegalovirus Replication and a Novel Host Target for Antiviral Strategies
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Le résumé fourni par la source
Background. Cyclin-dependent kinase 8 (CDK8) is a multifaceted regulator and represents a catalytic component of the transcriptional Mediator complex. CDK8 activity, on the one hand, increases transcriptional elongation by the recruitment of Mediator/super elongation complexes, but, on the other hand, negatively regulates CDK7-controlled transcriptional initiation through inactivating cyclin H phosphorylation. Recently, these combined properties of CDK8 have also suggested its rate-limiting importance for herpesviral replication. Objectives. In this paper, we focused on human cytomegalovirus (HCMV) and addressed the question of whether the pharmacological inhibition or knock-down of CDK8 may affect viral replication efficiency in cell culture models. Methods. A number of human and animal herpesviruses, as well as non-herpesviruses, were used to analyze the importance of CDK8 for viral replication in cell culture models, and to assess the antiviral efficacy of CDK8 inhibitors. Results. Using clinically relevant CDK8 inhibitors (CCT-251921, MSC-2530818, and BI-1347), HCMV replication was found strongly reduced even at nanomolar drug concentrations. The EC50 values were consistent for three different HCMV strains (i.e., AD169, TB40, and Merlin) analyzed in two human cell types (i.e., primary fibroblasts and astrocytoma cells), and the drugs comprised a low level of cytotoxicity. The findings highlighted the following: (i) the pronounced in vitro SI values of anti-HCMV activity obtained with CDK8 inhibitors; (ii) a confirmation of the anti-HCMV efficacy by CDK8–siRNA knock-down; (iii) a CDK8-dependent reduction in viral immediate early, early, and late protein levels; (iv) a main importance of CDK8 for viral late-stage replication; (v) several mechanistic aspects, which point to a strong impact on viral progeny production and release, but a lack of CDK8 relevance for viral entry or nuclear egress; (vi) a significant anti-HCMV drug synergy for combinations of inhibitors against host CDK8 and the viral kinase vCDK/pUL97 (maribavir); (vii) finally, a broad-spectrum antiviral activity, as seen for the comparison of selected α-, β-, γ-, and non-herpesviruses. Conclusions. In summary, these novel data provide evidence for the importance of CDK8 as a positive regulator of herpesviral replication efficiency, and moreover, suggest its exploitability as an antiviral target for novel strategies of host-directed drug development.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Cyclin-Dependent Kinase 8 Represents a Positive Regulator of Cytomegalovirus Replication and a Novel Host Target for Antiviral Strategies
- Date Crossref
- 23/09/2024
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Friedrich-Alexander-Universität Erlangen-Nürnberg pays non établi dans la noticeUniversité ou école supérieure
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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Charité - Universitätsmedizin Berlin pays non établi dans la noticeÉtablissement de santé
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Biomedical Research Center of the Slovak Academy of Sciences pays non établi dans la noticeStructure de recherche
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Institute of Virology of the Slovak Academy of Sciences pays non établi dans la noticeStructure de recherche
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Comenius University Bratislava pays non établi dans la noticeUniversité ou école supérieure
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Essen University Hospital pays non établi dans la noticeOrganisme public
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Friedrich-Alexander University of Erlangen-Nürnberg (FAU) Institute for Clinical and Molecular Virology pays non établi dans la noticeUniversité ou école supérieure
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Friedrich-Alexander-Universität Erlangen-Nürnberg, Brigham and Women's Hospital et Harvard University, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.