Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.

4-anilino quinazolines have been identified as inhibitors of HCV replication. The target of this class of compounds was proposed to be the viral protein NS5A, although unequivocal proof has never been presented. A 4-anilino quinazoline moiety is often found in kinase inhibitors, leading us to formul...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Annalisa Bianco, Veronica Reghellin, Lorena Donnici, Simone Fenu, Reinaldo Alvarez, Chiara Baruffa, Francesco Peri, Massimiliano Pagani, Sergio Abrignani, Petra Neddermann, Raffaele De Francesco
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0c7408dee75a4019a571d0424fdeb602
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0c7408dee75a4019a571d0424fdeb602
record_format	dspace
spelling	oai:doaj.org-article:0c7408dee75a4019a571d0424fdeb6022021-11-18T06:04:40ZMetabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.1553-73661553-737410.1371/journal.ppat.1002576https://doaj.org/article/0c7408dee75a4019a571d0424fdeb6022012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22412376/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-73744-anilino quinazolines have been identified as inhibitors of HCV replication. The target of this class of compounds was proposed to be the viral protein NS5A, although unequivocal proof has never been presented. A 4-anilino quinazoline moiety is often found in kinase inhibitors, leading us to formulate the hypothesis that the anti-HCV activity displayed by these compounds might be due to inhibition of a cellular kinase. Type III phosphatidylinositol 4-kinase α (PI4KIIIα) has recently been identified as a host factor for HCV replication. We therefore evaluated AL-9, a compound prototypical of the 4-anilino quinazoline class, on selected phosphatidylinositol kinases. AL-9 inhibited purified PI4KIIIα and, to a lesser extent, PI4KIIIβ. In Huh7.5 cells, PI4KIIIα is responsible for the phosphatidylinositol-4 phosphate (PI4P) pool present in the plasma membrane. Accordingly, we observed a gradual decrease of PI4P in the plasma membrane upon incubation with AL-9, indicating that this agent inhibits PI4KIIIα also in living cells. Conversely, AL-9 did not affect the level of PI4P in the Golgi membrane, suggesting that the PI4KIIIβ isoform was not significantly inhibited under our experimental conditions. Incubation of cells expressing HCV proteins with AL-9 induced abnormally large clusters of NS5A, a phenomenon previously observed upon silencing PI4KIIIα by RNA interference. In light of our findings, we propose that the antiviral effect of 4-anilino quinazoline compounds is mediated by the inhibition of PI4KIIIα and the consequent depletion of PI4P required for the HCV membranous web. In addition, we noted that HCV has a profound effect on cellular PI4P distribution, causing significant enrichment of PI4P in the HCV-membranous web and a concomitant depletion of PI4P in the plasma membrane. This observation implies that HCV--by recruiting PI4KIIIα in the RNA replication complex--hijacks PI4P metabolism, ultimately resulting in a markedly altered subcellular distribution of the PI4KIIIα product.Annalisa BiancoVeronica ReghellinLorena DonniciSimone FenuReinaldo AlvarezChiara BaruffaFrancesco PeriMassimiliano PaganiSergio AbrignaniPetra NeddermannRaffaele De FrancescoPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 3, p e1002576 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Annalisa Bianco Veronica Reghellin Lorena Donnici Simone Fenu Reinaldo Alvarez Chiara Baruffa Francesco Peri Massimiliano Pagani Sergio Abrignani Petra Neddermann Raffaele De Francesco Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.
description	4-anilino quinazolines have been identified as inhibitors of HCV replication. The target of this class of compounds was proposed to be the viral protein NS5A, although unequivocal proof has never been presented. A 4-anilino quinazoline moiety is often found in kinase inhibitors, leading us to formulate the hypothesis that the anti-HCV activity displayed by these compounds might be due to inhibition of a cellular kinase. Type III phosphatidylinositol 4-kinase α (PI4KIIIα) has recently been identified as a host factor for HCV replication. We therefore evaluated AL-9, a compound prototypical of the 4-anilino quinazoline class, on selected phosphatidylinositol kinases. AL-9 inhibited purified PI4KIIIα and, to a lesser extent, PI4KIIIβ. In Huh7.5 cells, PI4KIIIα is responsible for the phosphatidylinositol-4 phosphate (PI4P) pool present in the plasma membrane. Accordingly, we observed a gradual decrease of PI4P in the plasma membrane upon incubation with AL-9, indicating that this agent inhibits PI4KIIIα also in living cells. Conversely, AL-9 did not affect the level of PI4P in the Golgi membrane, suggesting that the PI4KIIIβ isoform was not significantly inhibited under our experimental conditions. Incubation of cells expressing HCV proteins with AL-9 induced abnormally large clusters of NS5A, a phenomenon previously observed upon silencing PI4KIIIα by RNA interference. In light of our findings, we propose that the antiviral effect of 4-anilino quinazoline compounds is mediated by the inhibition of PI4KIIIα and the consequent depletion of PI4P required for the HCV membranous web. In addition, we noted that HCV has a profound effect on cellular PI4P distribution, causing significant enrichment of PI4P in the HCV-membranous web and a concomitant depletion of PI4P in the plasma membrane. This observation implies that HCV--by recruiting PI4KIIIα in the RNA replication complex--hijacks PI4P metabolism, ultimately resulting in a markedly altered subcellular distribution of the PI4KIIIα product.
format	article
author	Annalisa Bianco Veronica Reghellin Lorena Donnici Simone Fenu Reinaldo Alvarez Chiara Baruffa Francesco Peri Massimiliano Pagani Sergio Abrignani Petra Neddermann Raffaele De Francesco
author_facet	Annalisa Bianco Veronica Reghellin Lorena Donnici Simone Fenu Reinaldo Alvarez Chiara Baruffa Francesco Peri Massimiliano Pagani Sergio Abrignani Petra Neddermann Raffaele De Francesco
author_sort	Annalisa Bianco
title	Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.
title_short	Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.
title_full	Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.
title_fullStr	Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.
title_full_unstemmed	Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.
title_sort	metabolism of phosphatidylinositol 4-kinase iiiα-dependent pi4p is subverted by hcv and is targeted by a 4-anilino quinazoline with antiviral activity.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/0c7408dee75a4019a571d0424fdeb602
work_keys_str_mv	AT annalisabianco metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT veronicareghellin metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT lorenadonnici metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT simonefenu metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT reinaldoalvarez metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT chiarabaruffa metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT francescoperi metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT massimilianopagani metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT sergioabrignani metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT petraneddermann metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity AT raffaeledefrancesco metabolismofphosphatidylinositol4kinaseiiiadependentpi4pissubvertedbyhcvandistargetedbya4anilinoquinazolinewithantiviralactivity
_version_	1718424584131182592

Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P Is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity.

Ejemplares similares