Functional microRNA screen uncovers O-linked N-acetylglucosamine transferase as a host factor modulating hepatitis C virus morphogenesis and infectivity. Issue 2 (10th May 2019)

• Record Type: Journal Article
• Authors: Herzog, Katharina; Bandiera, Simonetta; Pernot, Sophie; Fauvelle, Catherine; Jühling, Frank; Weiss, Amélie; Bull, Anne; Durand, Sarah C; Chane-Woon-Ming, Béatrice; Pfeffer, Sébastien; Mercey, Marion; Lerat, Hervé; Meunier, Jean-Christophe; Raffelsberger, Wolfgang; Brino, Laurent; Baumert, Thomas F; Zeisel, Mirjam B
• Is Part Of: Gut. Volume 69:Issue 2(2020)
• Page Start: 380
• Page End: 392
• Publication Date: 2019-05-10
• Subjects: hepatitis C -- HCV -- hepatocyte -- molecular mechanisms; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-317423
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Infection of human hepatocytes by the hepatitis C virus (HCV) is a multistep process involving both viral and host factors. microRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Given that miRNAs were indicated to regulate between 30% and 75% of all human genes, we aimed to investigate the functional and regulatory role of miRNAs for the HCV life cycle. Design: To systematically reveal human miRNAs affecting the HCV life cycle, we performed a two-step functional high-throughput miRNA mimic screen in Huh7.5.1 cells infected with recombinant cell culture-derived HCV. miRNA targeting was then assessed using a combination of computational and functional approaches. Results: We uncovered miR-501-3p and miR-619-3p as novel modulators of HCV assembly/release. We discovered that these miRNAs regulate O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) protein expression and identified OGT and O-GlcNAcylation as regulators of HCV morphogenesis and infectivity. Furthermore, increased OGT expression in patient-derived liver tissue was associated with HCV-induced liver disease and cancer. Conclusion: miR-501-3p and miR-619-3p and their target OGT are previously undiscovered regulatory host factors for HCV assembly and infectivity. In addition to its effect on HCV morphogenesis, OGT may play a role in HCV-induced liver disease and hepatocarcinogenesis.