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Zika Virus Infectious Cell Culture System and the In Vitro Prophylactic Effect of Interferons
Published on: August 23, 2016
CHOP Pro-Apoptotic Transcriptional Program in Response to ER Stress Is Hacked by Zika Virus
Jonathan Turpin1, Daed El-Safadi1, Grégorie Lebeau1
1PIMIT, Processus Infectieux en Milieu Insulaire Tropical, Université de La Réunion, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, 2, rue Maxime Rivière, 97490 Sainte-Clotilde, Ile de La Réunion, France.
Abstract:
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus considered as a threat to human health due to large epidemics and serious clinical outcomes such as microcephaly in new-borns. Like all flaviviruses, ZIKV relies on the cellular machinery to complete its viral cycle, with the endoplasmic reticulum (ER) being the critical site of viral replication factories. The sudden high protein load in the ER induces an ER stress to which the cell responds with an appropriate unfolded protein response (UPR) in an attempt to restore its disturbed homeostasis. When the restoration fails, the cell signalling leads to a programmed cell death by apoptosis with the upregulation of the UPR-induced C/EBP homologous protein (CHOP) which acts as the main trigger for this fatal outcome. Our previous studies have shown the ability of ZIKV to manipulate various cellular responses in order to optimize virus production. ZIKV is able to delay apoptosis to its benefit and although ER stress is induced, the UPR is not complete. Here we discovered that ZIKV impairs the expression of CHOP/DDIT3, the main factor responsible of ER-stress driven apoptosis. Surprisingly, the mechanism does not take place at the transcriptional level but at the translational level.
Insights
Zika virus impairs the cell
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- Zika virus (ZIKV) is an emerging mosquito-borne flavivirus causing significant public health concerns, including microcephaly.
- Viral replication, including ZIKV, heavily relies on the host cell's endoplasmic reticulum (ER).
- ER stress triggers the unfolded protein response (UPR), which can lead to apoptosis if homeostasis is not restored.
Purpose of the Study:
- To investigate how ZIKV manipulates cellular responses, specifically ER stress and apoptosis.
- To elucidate the mechanism by which ZIKV affects the expression of C/EBP homologous protein (CHOP/DDIT3).
Main Methods:
- Analysis of ZIKV-induced ER stress and UPR.
- Investigation of CHOP/DDIT3 expression at both transcriptional and translational levels in ZIKV-infected cells.
Main Results:
- ZIKV induces ER stress but incompletely activates the UPR, delaying apoptosis.
- ZIKV significantly impairs the expression of CHOP/DDIT3, a key mediator of ER-stress-induced apoptosis.
- This impairment occurs at the translational level, not the transcriptional level.
Conclusions:
- ZIKV actively suppresses CHOP/DDIT3 expression translationally to evade apoptosis and promote viral replication.
- Understanding this mechanism offers potential targets for therapeutic interventions against ZIKV infection.
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