A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor

• Published in: Nature communications 2020-06, Vol.11 (1), p.2707-17, Article 2707
• Main Authors: Eller, Carla, Heydmann, Laura, Colpitts, Che C., El Saghire, Houssein, Piccioni, Federica, Jühling, Frank, Majzoub, Karim, Pons, Caroline, Bach, Charlotte, Lucifora, Julie, Lupberger, Joachim, Nassal, Michael, Cowley, Glenn S., Fujiwara, Naoto, Hsieh, Sen-Yung, Hoshida, Yujin, Felli, Emanuele, Pessaux, Patrick, Sureau, Camille, Schuster, Catherine, Root, David E., Verrier, Eloi R., Baumert, Thomas F.
• Format: Article
• Language: English
• Subjects: 13/31; 13/89; 38; 38/61; 38/77; 49; 631/326/596/1550; 631/61/191; 692/4020/4021/234/2513; Biochemistry, Molecular Biology; Cell cycle; Cell Line, Tumor; Chronic infection; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cyclin-Dependent Kinase Inhibitor p18 - metabolism; Enhancers; Gain of Function Mutation; Gene Expression Profiling - methods; Genetic Testing - methods; Genome-Wide Association Study - methods; Genomes; HEK293 Cells; Hep G2 Cells; Hepatitis B - genetics; Hepatitis B - metabolism; Hepatitis B - virology; Hepatitis B virus - physiology; Hepatocytes; Hepatoma; Host Microbial Interactions; Human health and pathology; Humanities and Social Sciences; Humans; Infectious diseases; Kaplan-Meier Estimate; Life cycle assessment; Life cycles; Life Sciences; Liver; Liver - metabolism; Liver - pathology; Liver - virology; Liver cancer; Liver diseases; Microbiology and Parasitology; Molecular biology; multidisciplinary; Permissive cells; Replication; RNA Interference; Science; Science (multidisciplinary); Transcription; Virology; Virus Replication - physiology; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16517-w

Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle. Here the authors perform a gain-of-function screen and identify CDKN2C as a host factor for HBV replication, inducing cell cycle arrest and expression of HBV transcription enhancers. CDKN2C expression correlates with disease progression suggesting a potential role in HBV-induced liver disease.