Journal Article

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

Lucifora, Julie, Durantel, David, Salvetti, Anna, Chabot, Benoit, de la Luna, Susana, Di Vona, Chiara, Pastor, Florentin, Charles, Emilie, Chapelle, Maëlys, Rivoire, Michel, Passot, Guillaume

2024

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antiviral drugs / Biology and life sciences / Chromatin / Chronic infection / DNA binding proteins / DNA, Circular - genetics / DNA, Circular - metabolism / DNA-directed RNA polymerase / Dyrk Kinases / Gene regulation / Genes / Genetic aspects / Genetic regulation / Genetic transcription / Genome, Viral / Genomes / Genomics / Health aspects / Hep G2 Cells / Hepatitis / Hepatitis B / Hepatitis B virus / Hepatitis B virus - genetics / Hepatitis B virus - physiology / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - virology / Histones / Humans / Kinases / Life Sciences / Medicine and Health Sciences / Phosphorylation / Physiological aspects / Post-transcription / Protein binding / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases - metabolism / Proteins / Reporter gene / Research and Analysis Methods / Ribonucleic acid / RNA / RNA polymerase / RNA polymerase II / RNA viruses / RNA, Viral - genetics / RNA, Viral - metabolism / RNA-binding protein / Trans-Activators / Transcription factors / Viral Regulatory and Accessory Proteins - genetics / Viral Regulatory and Accessory Proteins - metabolism / Virus Replication - genetics