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The biogenesis of Dengue virus replication organelles requires the ATPase activity of valosin-containing protein

The dengue virus (DENV) causes the most prevalent arthropod-borne viral disease worldwide. While its incidence is increasing in many countries, there is no approved antiviral therapy currently available. In infected cells, the DENV induces extensive morphological alterations of the endoplasmic retic...

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Hauptverfasser: Mazeaud, Clément (VerfasserIn) , Anton, Anaïs (VerfasserIn) , Pahmeier, Felix (VerfasserIn) , Sow, Aïssatou Aïcha (VerfasserIn) , Cerikan, Berati (VerfasserIn) , Freppel, Wesley (VerfasserIn) , Cortese, Mirko (VerfasserIn) , Bartenschlager, Ralf (VerfasserIn) , Chatel-Chaix, Laurent (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 18 October 2021
In: Viruses
Year: 2021, Jahrgang: 13, Heft: 10, Pages: 1-19
ISSN:1999-4915
DOI:10.3390/v13102092
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/v13102092
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1999-4915/13/10/2092
Volltext
Verfasserangaben:Clément Mazeaud, Anaïs Anton, Felix Pahmeier, Aïssatou Aïcha Sow, Berati Cerikan, Wesley Freppel, Mirko Cortese, Ralf Bartenschlager and Laurent Chatel-Chaix
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Zusammenfassung:The dengue virus (DENV) causes the most prevalent arthropod-borne viral disease worldwide. While its incidence is increasing in many countries, there is no approved antiviral therapy currently available. In infected cells, the DENV induces extensive morphological alterations of the endoplasmic reticulum (ER) to generate viral replication organelles (vRO), which include convoluted membranes (CM) and vesicle packets (VP) hosting viral RNA replication. The viral non-structural protein NS4B localizes to vROs and is absolutely required for viral replication through poorly defined mechanisms, which might involve cellular protein partners. Previous interactomic studies identified the ATPase valosin-containing protein (VCP) as a DENV NS4B-interacting host factor in infected cells. Using both pharmacological and dominant-negative inhibition approaches, we show, in this study, that VCP ATPase activity is required for efficient DENV replication. VCP associates with NS4B when expressed in the absence of other viral proteins while in infected cells, both proteins colocalize within large DENV-induced cytoplasmic structures previously demonstrated to be CMs. Consistently, VCP inhibition dramatically reduces the abundance of DENV CMs in infected cells. Most importantly, using a recently reported replication-independent plasmid-based vRO induction system, we show that de novo VP biogenesis is dependent on VCP ATPase activity. Overall, our data demonstrate that VCP ATPase activity is required for vRO morphogenesis and/or stability. Considering that VCP was shown to be required for the replication of other flaviviruses, our results argue that VCP is a pan-flaviviral host dependency factor. Given that new generation VCP-targeting drugs are currently evaluated in clinical trials for cancer treatment, VCP may constitute an attractive broad-spectrum antiviral target in drug repurposing approaches.
Beschreibung:Gesehen am 07.01.2022
Beschreibung:Online Resource
ISSN:1999-4915
DOI:10.3390/v13102092

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