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The Zika virus (ZIKV) non-structural protein 5 (NS5) plays multiple viral and cellular roles during infection, with its primary role in virus RNA replication taking place in the cytoplasm. However, immunofluorescence assay studies have detected the presence of ZIKV NS5 in unique spherical shell-like structures in the nuclei of infected cells, suggesting potentially important cellular roles of ZIKV NS5 in the nucleus. Hence ZIKV NS5′s subcellular distribution and localization must be tightly regulated during ZIKV infection. Both ZIKV NS5 expression or ZIKV infection antagonizes type I interferon signaling, and induces a pro-inflammatory transcriptional response in a cell type-specific manner, but the mechanisms involved and the role of nuclear ZIKV NS5 in these cellular functions has not been elucidated. Intriguingly, these cells originate from the brain and placenta, which are also organs that exhibit a pro-inflammatory signature and are known sites of pathogenesis during ZIKV infection in animal models and humans. Here, we discuss the regulation of the subcellular localization of the ZIKV NS5 protein, and its putative role in the induction of an inflammatory response and the occurrence of pathology in specific organs during ZIKV infection. [ABSTRACT FROM AUTHOR]