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.
- hepatitis C
- molecular mechanisms
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KH and SB contributed equally.
Contributors MBZ coordinated and supervised research. KH, SB, SP, CF, AW, LB, J-CM and MBZ designed experiments. KH, SB, SP, CF, AW, AB, SCD, MM, HL and J-CM performed experiments. KH, SB, SP, CF, FJ, AW, AB, BC-W-M, SP, J-CM, WR, LB, TFB and MBZ analysed data. KH, SB and MBZ wrote the paper.
Funding This work was supported by the European Union (INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012 to TFB and MBZ, ERC-AdG-2014-671231-HEPCIR, EU H2020-667273-HEPCAR to TFB), ANRS (2012/239 to TFB, MBZ and LB), ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC IHUARC IHU201301187 to TFB), the Impulsion Program of the IDEXLYON (to MBZ), Ligue contre le cancer (to MBZ), Inserm, and University of Strasbourg. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HepSYS, ANR-10-LABX-36 NetRNA and Inserm Plan Cancer 2019-2023 and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future programme. SP and KH were supported by PhD fellowships from the French Ministry of Research and the IdEx programme of the University of Strasbourg, respectively.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.