Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway

A bidirectional negative relationship between Hepatitis C virus (HCV) replication and gene expression of the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) was previously shown in the liver and attributed at least to an association of DDC with phosphatidylinositol 3-kinase (PI3K). Here...

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Autores principales:	George Mpekoulis, Vassilina Tsopela, Georgios Panos, Vasileiοs Siozos, Katerina I. Kalliampakou, Efseveia Frakolaki, Constantinos D. Sideris, Alice G. Vassiliou, Diamantis C. Sideris, Dido Vassilacopoulou, Niki Vassilaki
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Hepatitis C virus viral replication catecholamine biosynthetic/metabolic pathway L-Dopa decarboxylase tyrosine hydroxylase dopamine beta-hydroxylase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7605773ce213478e9b3a867ad0333cc0
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spelling	oai:doaj.org-article:7605773ce213478e9b3a867ad0333cc02021-11-25T19:12:38ZAssociation of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway10.3390/v131121391999-4915https://doaj.org/article/7605773ce213478e9b3a867ad0333cc02021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2139https://doaj.org/toc/1999-4915A bidirectional negative relationship between Hepatitis C virus (HCV) replication and gene expression of the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) was previously shown in the liver and attributed at least to an association of DDC with phosphatidylinositol 3-kinase (PI3K). Here, we report that the biosynthesis and uptake of catecholamines restrict HCV replication in hepatocytes, while HCV has developed ways to reduce catecholamine production. By employing gene silencing, chemical inhibition or induction of the catecholamine biosynthetic and metabolic enzymes and transporters, and by applying the substrates or the products of the respective enzymes, we unravel the role of the different steps of the pathway in viral infection. We also provide evidence that the effect of catecholamines on HCV is strongly related with oxidative stress that is generated by their autoxidation in the cytosol, while antioxidants or treatments that lower cytosolic catecholamine levels positively affect the virus. To counteract the effect of catecholamines, HCV, apart from the already reported effects on DDC, causes the down-regulation of tyrosine hydroxylase that encodes the rate-limiting enzyme of catecholamine biosynthesis and suppresses dopamine beta-hydroxylase mRNA and protein amounts, while increasing the catecholamine degradation enzyme monoamine oxidase. Moreover, the NS4B viral protein is implicated in the effect of HCV on the ratio of the ~50 kDa DDC monomer and a ~120 kDa DDC complex, while the NS5A protein has a negative effect on total DDC protein levels.George MpekoulisVassilina TsopelaGeorgios PanosVasileiοs SiozosKaterina I. KalliampakouEfseveia FrakolakiConstantinos D. SiderisAlice G. VassiliouDiamantis C. SiderisDido VassilacopoulouNiki VassilakiMDPI AGarticleHepatitis C virusviral replicationcatecholamine biosynthetic/metabolic pathwayL-Dopa decarboxylasetyrosine hydroxylasedopamine beta-hydroxylaseMicrobiologyQR1-502ENViruses, Vol 13, Iss 2139, p 2139 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hepatitis C virus viral replication catecholamine biosynthetic/metabolic pathway L-Dopa decarboxylase tyrosine hydroxylase dopamine beta-hydroxylase Microbiology QR1-502
spellingShingle	Hepatitis C virus viral replication catecholamine biosynthetic/metabolic pathway L-Dopa decarboxylase tyrosine hydroxylase dopamine beta-hydroxylase Microbiology QR1-502 George Mpekoulis Vassilina Tsopela Georgios Panos Vasileiοs Siozos Katerina I. Kalliampakou Efseveia Frakolaki Constantinos D. Sideris Alice G. Vassiliou Diamantis C. Sideris Dido Vassilacopoulou Niki Vassilaki Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway
description	A bidirectional negative relationship between Hepatitis C virus (HCV) replication and gene expression of the catecholamine biosynthetic enzyme L-Dopa decarboxylase (DDC) was previously shown in the liver and attributed at least to an association of DDC with phosphatidylinositol 3-kinase (PI3K). Here, we report that the biosynthesis and uptake of catecholamines restrict HCV replication in hepatocytes, while HCV has developed ways to reduce catecholamine production. By employing gene silencing, chemical inhibition or induction of the catecholamine biosynthetic and metabolic enzymes and transporters, and by applying the substrates or the products of the respective enzymes, we unravel the role of the different steps of the pathway in viral infection. We also provide evidence that the effect of catecholamines on HCV is strongly related with oxidative stress that is generated by their autoxidation in the cytosol, while antioxidants or treatments that lower cytosolic catecholamine levels positively affect the virus. To counteract the effect of catecholamines, HCV, apart from the already reported effects on DDC, causes the down-regulation of tyrosine hydroxylase that encodes the rate-limiting enzyme of catecholamine biosynthesis and suppresses dopamine beta-hydroxylase mRNA and protein amounts, while increasing the catecholamine degradation enzyme monoamine oxidase. Moreover, the NS4B viral protein is implicated in the effect of HCV on the ratio of the ~50 kDa DDC monomer and a ~120 kDa DDC complex, while the NS5A protein has a negative effect on total DDC protein levels.
format	article
author	George Mpekoulis Vassilina Tsopela Georgios Panos Vasileiοs Siozos Katerina I. Kalliampakou Efseveia Frakolaki Constantinos D. Sideris Alice G. Vassiliou Diamantis C. Sideris Dido Vassilacopoulou Niki Vassilaki
author_facet	George Mpekoulis Vassilina Tsopela Georgios Panos Vasileiοs Siozos Katerina I. Kalliampakou Efseveia Frakolaki Constantinos D. Sideris Alice G. Vassiliou Diamantis C. Sideris Dido Vassilacopoulou Niki Vassilaki
author_sort	George Mpekoulis
title	Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway
title_short	Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway
title_full	Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway
title_fullStr	Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway
title_full_unstemmed	Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway
title_sort	association of hepatitis c virus replication with the catecholamine biosynthetic pathway
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7605773ce213478e9b3a867ad0333cc0
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Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway

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