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Article

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle

by
Natalia F. Zakirova
1,†,
Olga A. Khomich
1,2,†,
Olga A. Smirnova
1,†,
Jennifer Molle
2,
Sarah Duponchel
2,
Dmitry V. Yanvarev
1,
Vladimir T. Valuev-Elliston
1,
Lea Monnier
2,
Boyan Grigorov
2,
Olga N. Ivanova
1,
Inna L. Karpenko
1,
Mikhail V. Golikov
1,
Cedric Bovet
3,
Barbara Rindlisbacher
3,
Alex R. Khomutov
1,
Sergey N. Kochetkov
1,
Birke Bartosch
2 and
Alexander V. Ivanov
1,*
1
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
2
INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, 69434 Lyon, France
3
University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2024, 13(12), 1036; https://doi.org/10.3390/cells13121036
Submission received: 29 April 2024 / Revised: 5 June 2024 / Accepted: 11 June 2024 / Published: 14 June 2024
(This article belongs to the Special Issue Viruses and Cancer: From Cellular Mechanism to Therapeutic Aspects)
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Abstract

Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV’s imprint on cell metabolism.
Keywords: hepatitis C virus; polyamines; urea cycle; proline metabolism; antiviral agents hepatitis C virus; polyamines; urea cycle; proline metabolism; antiviral agents

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MDPI and ACS Style

Zakirova, N.F.; Khomich, O.A.; Smirnova, O.A.; Molle, J.; Duponchel, S.; Yanvarev, D.V.; Valuev-Elliston, V.T.; Monnier, L.; Grigorov, B.; Ivanova, O.N.; et al. Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle. Cells 2024, 13, 1036. https://doi.org/10.3390/cells13121036

AMA Style

Zakirova NF, Khomich OA, Smirnova OA, Molle J, Duponchel S, Yanvarev DV, Valuev-Elliston VT, Monnier L, Grigorov B, Ivanova ON, et al. Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle. Cells. 2024; 13(12):1036. https://doi.org/10.3390/cells13121036

Chicago/Turabian Style

Zakirova, Natalia F., Olga A. Khomich, Olga A. Smirnova, Jennifer Molle, Sarah Duponchel, Dmitry V. Yanvarev, Vladimir T. Valuev-Elliston, Lea Monnier, Boyan Grigorov, Olga N. Ivanova, and et al. 2024. "Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle" Cells 13, no. 12: 1036. https://doi.org/10.3390/cells13121036

APA Style

Zakirova, N. F., Khomich, O. A., Smirnova, O. A., Molle, J., Duponchel, S., Yanvarev, D. V., Valuev-Elliston, V. T., Monnier, L., Grigorov, B., Ivanova, O. N., Karpenko, I. L., Golikov, M. V., Bovet, C., Rindlisbacher, B., Khomutov, A. R., Kochetkov, S. N., Bartosch, B., & Ivanov, A. V. (2024). Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle. Cells, 13(12), 1036. https://doi.org/10.3390/cells13121036

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