Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000, Strasbourg, France.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
Nat Commun. 2020 Jun 1;11(1):2707. 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.
慢性乙型肝炎病毒（HBV）感染是全球范围内肝脏疾病和癌症的主要病因。目前缺乏治愈方法，对病毒-宿主相互作用的认识仍然有限。本研究采用一种低效率的肝癌细胞系进行全基因组功能获得性筛选，以揭示增强 HBV 感染的宿主因子。在原代人肝细胞中的验证研究表明，CDKN2C 是 HBV 复制的一个重要宿主因子。CDKN2C 在高度许可的细胞和 HBV 感染的患者中过表达。机制研究表明，CDKN2C 通过抑制与 HBV 转录增强子上调相关的 CDK4/6，诱导细胞周期 G1 期阻滞。HBV 感染患者中 CDKN2C 表达与疾病进展之间的相关性提示其在 HBV 诱导的肝脏疾病中发挥作用。综上所述，我们鉴定了一个以前未被发现的具有临床意义的 HBV 宿主因子，为药物发现和 HBV 生命周期研究开发了改进的感染模型系统。
