Valosin-containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus-induced cell death
| Autor: | Wesley Freppel, Nicolas Tremblay, Ian Gaël Rodrigue-Gervais, Anaïs Anton, Marie Roy, Claudia Gilbert, Aïssatou Aïcha Sow, Clément Mazeaud, Laurent Chatel-Chaix |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Indoles Valosin-containing protein Immunology Apoptosis Dengue virus medicine.disease_cause Microbiology Virus 03 medical and health sciences Valosin Containing Protein Virology Cell Line Tumor Chlorocebus aethiops medicine Animals Humans Endomembrane system Benzothiazoles Vero Cells 030304 developmental biology Host factor Adenosine Triphosphatases 0303 health sciences NS3 biology Host Microbial Interactions 030306 microbiology Zika Virus 3. Good health Cell biology Mitochondria HEK293 Cells Pyrimidines Viral replication Gene Expression Regulation biology.protein Acetanilides |
| Zdroj: | Cellular microbiologyREFERENCES. 23(4) |
| ISSN: | 1462-5822 |
| Popis: | With no available therapies, infections with Zika virus (ZIKV) constitute a major public health concern as they can lead to congenital microcephaly. In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of replication factories via enigmatic mechanisms. In this study, we identified the AAA+ type ATPase valosin-containing protein (VCP) as a cellular interaction partner of ZIKV non-structural protein 4B (NS4B). Importantly, its pharmacological inhibition as well as the expression of a VCP dominant-negative mutant impaired ZIKV replication. In infected cells, VCP is relocalised to large ultrastructures containing both NS4B and NS3, which are reminiscent of dengue virus convoluted membranes. Moreover, short treatment with the VCP inhibitors NMS-873 or CB-5083 drastically decreased the abundance and size of ZIKV-induced convoluted membranes. Furthermore, NMS-873 treatment inhibited ZIKV-induced mitochondria elongation previously reported to be physically and functionally linked to convoluted membranes in case of the closely related dengue virus. Finally, VCP inhibition resulted in enhanced apoptosis of ZIKV-infected cells strongly suggesting that convoluted membranes limit virus-induced cytopathic effects. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV-induced death signals in order to create a cytoplasmic environment favourable to viral replication. |
| Databáze: | OpenAIRE |
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