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

Carla Eller, Laura Heydmann, Che C. Colpitts, Houssein El Saghire, Federica Piccioni, Frank Jühling, Karim Majzoub, Caroline Pons, Charlotte Bach, Julie Lucifora, Joachim Lupberger, Michael Nassal, Glenn S. Cowley, Naoto Fujiwara, Sen-Yung Hsieh, Yujin Hoshida, Emanuele Felli, Patrick Pessaux, Camille Sureau, Catherine Schuster, David E. Root, Eloi R. Verrier () and Thomas F. Baumert ()
Additional contact information
Carla Eller: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Laura Heydmann: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Che C. Colpitts: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Houssein El Saghire: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Federica Piccioni: Broad Institute of Massachusetts Institute of Technology and Harvard
Frank Jühling: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Karim Majzoub: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Caroline Pons: Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard
Charlotte Bach: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Julie Lucifora: Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard
Joachim Lupberger: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Michael Nassal: University Hospital Freiburg
Glenn S. Cowley: Broad Institute of Massachusetts Institute of Technology and Harvard
Naoto Fujiwara: University of Texas Southwestern Medical Center
Sen-Yung Hsieh: Chang Gung Memorial Hospital
Yujin Hoshida: University of Texas Southwestern Medical Center
Emanuele Felli: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Patrick Pessaux: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Camille Sureau: INTS
Catherine Schuster: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
David E. Root: Broad Institute of Massachusetts Institute of Technology and Harvard
Eloi R. Verrier: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000
Thomas F. Baumert: Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16517-w

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