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Updated: Sep 5, 2025
Zika Virus Infectious Cell Culture System and the In Vitro Prophylactic Effect of Interferons
Published on: August 23, 2016
Zika virus alters centrosome organization to suppress the innate immune response
Andrew Kodani1, Kristeene A Knopp2,3, Elizabeth Di Lullo4,5
1Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN, USA.
Abstract:
Zika virus (ZIKV) is a flavivirus transmitted via mosquitoes and sex to cause congenital neurodevelopmental defects, including microcephaly. Inherited forms of microcephaly (MCPH) are associated with disrupted centrosome organization. Similarly, we found that ZIKV infection disrupted centrosome organization. ZIKV infection disrupted the organization of centrosomal proteins including CEP63, a MCPH-associated protein. The ZIKV nonstructural protein NS3 bound CEP63, and expression of NS3 was sufficient to alter centrosome architecture and CEP63 localization. Loss of CEP63 suppressed ZIKV-induced centrosome disorganization, indicating that ZIKV requires CEP63 to disrupt centrosome organization. ZIKV infection or CEP63 loss decreased the centrosomal localization and stability of TANK-binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection also increased the centrosomal accumulation of the CEP63 interactor DTX4, a ubiquitin ligase that degrades TBK1. Therefore, we propose that ZIKV disrupts CEP63 function to increase centrosomal DTX4 localization and destabilization of TBK1, thereby tempering the innate immune response.
Insights
Zika virus disrupts centrosome organization by targeting the microcephaly protein CEP63. This interaction impairs the innate immune response, offering new insights into Zika virus pathogenesis.
Area of Science:
- Virology
- Cell Biology
- Neuroscience
Background:
- Zika virus (ZIKV) causes congenital neurodevelopmental defects like microcephaly.
- Inherited microcephaly (MCPH) involves centrosome organization defects.
- ZIKV infection was observed to disrupt centrosome organization.
Purpose of the Study:
- To investigate the mechanism by which ZIKV disrupts centrosome organization.
- To identify ZIKV proteins involved in centrosome disorganization.
- To explore the impact of ZIKV-induced centrosome disruption on innate immunity.
Main Methods:
- ZIKV infection models.
- Immunofluorescence microscopy to assess centrosome protein localization.
- Co-immunoprecipitation to study protein interactions.
- Western blotting to analyze protein stability.
Main Results:
- ZIKV infection disrupted centrosome organization and the localization of CEP63, a microcephaly-associated protein.
- The ZIKV NS3 protein directly bound CEP63, altering centrosome architecture.
- Loss of CEP63 suppressed ZIKV-induced centrosome disorganization.
- ZIKV infection and CEP63 loss reduced centrosomal TBK1 levels.
- ZIKV increased DTX4 accumulation at the centrosome, leading to TBK1 degradation.
Conclusions:
- ZIKV requires CEP63 to disrupt centrosome organization.
- ZIKV disrupts CEP63 function, increasing centrosomal DTX4 and destabilizing TBK1.
- This mechanism likely tempers the innate immune response during ZIKV infection.
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