The dual-specificity kinase DYRK1A interacts with the Hepatitis B virus genome and regulates the production of viral RNA

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• dc.contributor.author Pastor, Florentin
• dc.contributor.author Charles, Emilie
• dc.contributor.author Di Vona, Chiara, 1981-
• dc.contributor.author Chapelle, Maëlys
• dc.contributor.author Rivoire, Michel
• dc.contributor.author Passot, Guillaume
• dc.contributor.author Chabot, Benoit
• dc.contributor.author Luna, Susana de la
• dc.contributor.author Lucifora, Julie
• dc.contributor.author Durantel, David
• dc.contributor.author Salvetti, Anna
• dc.date.accessioned 2024-12-09T07:18:26Z
• dc.date.available 2024-12-09T07:18:26Z
• dc.date.issued 2024
• dc.description.abstract The genome of Hepatitis B virus (HBV) persists in infected hepatocytes as a nuclear episome (cccDNA) that is responsible for the transcription of viral genes and viral rebound, following antiviral treatment arrest in chronically infected patients. There is currently no clinically approved therapeutic strategy able to efficiently target cccDNA (Lucifora J 2016). The development of alternative strategies aiming at permanently abrogating HBV RNA production requires a thorough understanding of cccDNA transcriptional and post-transcriptional regulation. In a previous study, we discovered that 1C8, a compound that inhibits the phosphorylation of some cellular RNA-binding proteins, could decrease the level of HBV RNAs. Here, we aimed at identifying kinases responsible for this effect. Among the kinases targeted by 1C8, we focused on DYRK1A, a dual-specificity kinase that controls the transcription of cellular genes by phosphorylating transcription factors, histones, chromatin regulators as well as RNA polymerase II. The results of a combination of genetic and chemical approaches using HBV-infected hepatocytes, indicated that DYRK1A positively regulates the production of HBV RNAs. In addition, we found that DYRK1A associates with cccDNA, and stimulates the production of HBV nascent RNAs. Finally, reporter gene assays showed that DYRK1A up-regulates the activity of the HBV enhancer 1/X promoter in a sequence-dependent manner. Altogether, these results indicate that DYRK1A is a proviral factor that may participate in the HBV life cycle by stimulating the production of HBx, a viral factor absolutely required to trigger the complete cccDNA transcriptional program.
• dc.description.sponsorship This work was funded by Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), and Université Claude Bernard Lyon 1 (UCBL). It was also supported by grants from Ministerio de Ciencia, Innovación y Universidades (PID2022-139904NB to SdlL], Departament de Salut, Generalitat de Catalunya (2021SGR01229 and CERCA Programme to SdlL), Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS, ECTZ11892 to AS, and ECTZ119385 fellowship to FP). BC is supported by grant from Canadian Institute for Health Research (CIHR). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• dc.format.mimetype application/pdf
• dc.identifier.citation Pastor F, Charles E, Di Vona C, Chapelle M, Rivoire M, Passot G, et al. The dual-specificity kinase DYRK1A interacts with the Hepatitis B virus genome and regulates the production of viral RNA. PLoS One. 2024 Oct 15;19(10):e0311655. DOI: 10.1371/journal.pone.0311655
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0311655
• dc.identifier.issn 1932-6203
• dc.identifier.uri http://hdl.handle.net/10230/68935
• dc.language.iso eng
• dc.publisher Public Library of Science (PLoS)
• dc.relation.ispartof PLoS One. 2024 Oct 15;19(10):e0311655
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-139904NB
• dc.rights © 2024 Pastor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Small interfering RNA
• dc.subject.keyword Transfection
• dc.subject.keyword Hepatocytes
• dc.subject.keyword Phosphorylation
• dc.subject.keyword Transcriptional control
• dc.subject.keyword Hepatitis B virus
• dc.subject.keyword Toxicity
• dc.subject.keyword Life cycles
• dc.title The dual-specificity kinase DYRK1A interacts with the Hepatitis B virus genome and regulates the production of viral RNA
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion