Journal Article

Hepatitis B virus Core protein nuclear interactome identifies SRSF10 as a host RNA-binding protein restricting HBV RNA production

Lucifora, Julie, Fusil, Floriane, Durantel, David, Michelet, Maud, Salvetti, Anna, Auclair, Héloïse, Combet, Christophe, Zoulim, Fabien, Pons, Caroline, Vegna, Serena, Belmudes, Lucid, Rivoire, Michel, Di Bernardo, Ariel, Lopatin, Uri, Couté, Yohann, Chadeuf, Gilliane, Kim, Yujin, Cosset, François-Loïc, Jalaguier, Pascal, Lahlali, Thomas, Chabot, Benoit, Chabrolles, Hélène, Grierson, David, Arnold, Lee D.

2020

Overview

Despite the existence of a preventive vaccine, chronic infection with Hepatitis B virus (HBV) affects more than 250 million people and represents a major global cause of hepatocellular carcinoma (HCC) worldwide. Current clinical treatments, in most of cases, do not eliminate viral genome that persists as a DNA episome in the nucleus of hepatocytes and constitutes a stable template for the continuous expression of viral genes. Several studies suggest that, among viral factors, the HBV core protein (HBc), well-known for its structural role in the cytoplasm, could have critical regulatory functions in the nucleus of infected hepatocytes. To elucidate these functions, we performed a proteomic analysis of HBc-interacting host-factors in the nucleus of differentiated HepaRG, a surrogate model of human hepatocytes. The HBc interactome was found to consist primarily of RNA-binding proteins (RBPs), which are involved in various aspects of mRNA metabolism. Among them, we focused our studies on SRSF10, a RBP that was previously shown to regulate alternative splicing (AS) in a phosphorylation-dependent manner and to control stress and DNA damage responses, as well as viral replication. Functional studies combining SRSF10 knockdown and a pharmacological inhibitor of SRSF10 phosphorylation (1C8) showed that SRSF10 behaves as a restriction factor that regulates HBV RNAs levels and that its dephosphorylated form is likely responsible for the anti-viral effect. Surprisingly, neither SRSF10 knock-down nor 1C8 treatment modified the splicing of HBV RNAs but rather modulated the level of nascent HBV RNA. Altogether, our work suggests that in the nucleus of infected cells HBc interacts with multiple RBPs that regulate viral RNA metabolism. Our identification of SRSF10 as a new anti-HBV restriction factor offers new perspectives for the development of new host-targeted antiviral strategies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antigens / Binding proteins / Biochemistry, Molecular Biology / Biology and life sciences / Carcinoma, Hepatocellular - virology / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Core protein / Deoxyribonucleic acid / DNA / Genetic aspects / Genomes / Genomics / Hepatitis / Hepatitis B / Hepatitis B - virology / Hepatitis B e antigen / Hepatitis B surface antigen / Hepatitis B virus - genetics / Hepatitis B virus - physiology / Hepatocytes / Hepatocytes - virology / Human health and pathology / Humans / Hépatology and Gastroenterology / Infections / Infectious diseases / Life Sciences / Liver diseases / Liver Neoplasms - virology / Medicine and Health Sciences / Microbiology and Parasitology / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Phosphorylation / Physiological aspects / Protein sources / Proteins / Proteomics / Repressor Proteins - genetics / Repressor Proteins - metabolism / Research and Analysis Methods / Ribonucleic acid / RNA / RNA, Viral - metabolism / RNA-binding protein / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Serine-Arginine Splicing Factors - genetics / Serine-Arginine Splicing Factors - metabolism / Viral Core Proteins - genetics / Viral Core Proteins - metabolism / Viral proteins / Virology / Virus Replication / Viruses