Flaviviruses limit the cell stress response by preventing the formation of stress granules (SGs) and modulate viral gene expression by subverting different
proteins involved in the stress granule pathway. In this study, we investigated the formation of stress granules during Zika virus (
ZIKV) infection and the role stress granule
proteins play during the viral life cycle. Using immunofluorescence and confocal microscopy, we determined that ZIKV disrupted the formation of
arsenite-induced stress granules and changed the subcellular distribution, but not the abundance or integrity, of stress granule
proteins. We also investigated the role of different stress granule
proteins in
ZIKV infection by using target-specific short interfering RNAs to deplete Ataxin2, G3BP1, HuR, TIA-1, TIAR, and YB1. Knockdown of TIA-1 and TIAR affected ZIKV
protein and
RNA levels but not viral titers. Conversely, depletion of Ataxin2 and YB1 decreased virion production despite having only a small effect on ZIKV
protein expression. Notably, however, depletion of G3BP1 and HuR decreased and increased ZIKV gene expression and virion production, respectively. Using an MR766 Gaussia
Luciferase reporter genome together with knockdown and overexpression assays, G3BP1 and HuR were found to modulate ZIKV replication. These data indicate that ZIKV disrupts the formation of stress granules by sequestering stress granule
proteins required for replication, where G3BP1 functions to promote
ZIKV infection while HuR exhibits an
antiviral effect. The results of ZIKV relocalizing and subverting select stress granule
proteins might have broader consequences on cellular
RNA homeostasis and contribute to cellular gene dysregulation and ZIKV pathogenesis.IMPORTANCE Many viruses inhibit SGs. In this study, we observed that ZIKV restricts SG assembly, likely by relocalizing and subverting specific SG
proteins to modulate ZIKV replication. This ZIKV-SG
protein interaction is interesting, as many SG
proteins are also known to function in neuronal granules, which are critical in neural development and function. Moreover, dysregulation of different SG
proteins in neurons has been shown to play a role in the progression of
neurodegenerative diseases. The likely consequences of ZIKV modulating SG assembly and subverting specific SG
proteins are alterations to cellular
mRNA transcription, splicing, stability, and translation. Such changes in cellular ribostasis could profoundly affect neural development and contribute to the devastating developmental and neurological anomalies observed following intrauterine
ZIKV infection. Our study provides new insights into virus-host interactions and the identification of the SG
proteins that may contribute to the unusual pathogenesis associated with this reemerging arbovirus.