The Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection.

Min Jie Alvin Tan,Chin Piaw Gwee,Subhash G Vasudevan,Kitti Wing Ki Chan,Satoru Watanabe,Sean Yao Zu Kong,Ivan H W Ng

doi:10.3390/cells8121519

Min Jie Alvin Tan, Chin Piaw Gwee + Show 5 more

Open Access

https://doi.org/10.3390/cells8121519

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Abstract

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.

Highlights

Flaviviruses are small, enveloped RNA viruses that make up one genus in the Flaviviridae family of viruses
In the second part of this review, we will discuss the possible role of Zika virus (ZIKV) NS50 s subcellular localization in the modulation of the host immune response during ZIKV infection, and the pathological outcome in specific tissue during infection
It is believed to contain a guanylyltransferase activity required for RNA cap formation [41,42]. While these flavivirus functions occur in the cytoplasm of infected cells, the non-structural protein 5 (NS5) protein from several flaviviruses are already present in the nucleus of the infected cells from earliest detectable time points post-infection [15,16,17,18,19,20,21,22,23,24] (Figure 1)

Summary

Introduction

Flaviviruses are small, enveloped RNA viruses that make up one genus in the Flaviviridae family of viruses. The non-structural protein 5 (NS5) is the largest and most conserved protein encoded by the members of the flaviviruses [13,14], and plays crucial enzymatic roles during virus RNA replication as part of the virus RC Apart from these functions, flavivirus NS5 has other viral and cellular roles during virus infection, including the modulation of the host immune response. Flaviviruses do so by encoding multiple virus proteins that can antagonize or suppress the host immune response [28], as multiple DENV [29,30,31] and WNV NS proteins [32,33,34] have been described to repress antiviral pathways such as the type I interferon signaling pathway. In the second part of this review, we will discuss the possible role of ZIKV NS50 s subcellular localization in the modulation of the host immune response during ZIKV infection, and the pathological outcome in specific tissue during infection

Subcellular Localization of Flavivirus NS5

The Nuclear Localization Signal Sequence of ZIKV NS5