Mutual antagonism between clock protein Period2 and hepatitis C virus replication in hepatocytes.

Francesca Rappa, Francesco Cappello, Valerio Pazienza, Giorgia Benegiamo, Nunzia Scibetta, Jude Oben, Manlio Vinciguerra, Gianluigi Mazzoccoli, Angelo Andriulli, Francesco Cappello, Roger Williams, Azzura Greco

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22 Citazioni (Scopus)

Abstract

Background: Hepatitis C virus (HCV) infects approximately 3% of the world population and is the leading cause of liverdisease, impacting hepatocyte metabolism, depending on virus genotype. Hepatic metabolic functions show rhythmicfluctuations with 24-h periodicity (circadian), driven by molecular clockworks ticking through translational-transcriptionalfeedback loops, operated by a set of genes, called clock genes, encoding circadian proteins. Disruption of biologic clocks isimplicated in a variety of disorders including fatty liver disease, obesity and diabetes. The relation between HCV replicationand the circadian clock is unknown.Methods: We investigated the relationship between HCV core infection and viral replication and the expression of clockgenes (Rev-Erba, Rora, ARNTL, ARNTL2, CLOCK, PER1, PER2, PER3, CRY1 and CRY2) in two cellular models, the Huh-7 cellstransiently expressing the HCV core protein genotypes 1b or 3a, and the OR6 cells stably harboring the full-length hepatitisC genotype 1b replicon, and in human liver biopsies, using qRT-PCR, immunoblotting, luciferase assays andimmunohistochemistry.Results: In Huh-7 cells expressing the HCV core protein genotype 1b, but not 3a, and in OR6 cells, transcript and proteinlevels of PER2 and CRY2 were downregulated. Overexpression of PER2 led to a consistent decrease in HCV RNA replicatinglevels and restoration of altered expression pattern of a subset of interferon stimulated genes (ISGs) in OR6 cells.Furthermore, in liver biopsies from HCV genotype 1b infected patients, PER2 was markedly localized to the nucleus,consistent with an auto-inhibitory transcriptional feedback loop.Conclusions: HCV can modulate hepatic clock gene machinery, and the circadian protein PER2 counteracts viral replication.Further understanding of circadian regulation of HCV replication and rhythmic patterns of host-hosted relationship mayimprove the effectiveness of HCV antiviral therapy. This would extend to hepatic viral infections the current spectrum ofchronotherapies, implemented to treat metabolic, immune related and neoplastic disease.
Lingua originaleEnglish
Numero di pagine10
RivistaPLoS One
Volume8
Stato di pubblicazionePublished - 2013

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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Rappa, F., Cappello, F., Pazienza, V., Benegiamo, G., Scibetta, N., Oben, J., Vinciguerra, M., Mazzoccoli, G., Andriulli, A., Cappello, F., Williams, R., & Greco, A. (2013). Mutual antagonism between clock protein Period2 and hepatitis C virus replication in hepatocytes. PLoS One, 8.