Importance of Zika Virus NS5 Protein for Viral Replication

Abstract

Zika virus is the latest addition to an ever-growing list of arboviruses that are causing outbreaks with serious consequences. A few mild cases were recorded between 1960 and 1980 until the first major outbreak in 2007 on Yap Island. This was followed by more severe outbreaks in French Polynesia (2013) and Brazil (2015), which significantly increased both Guillain-Barre syndrome and microcephaly cases. No current vaccines or treatments are available, however, recent studies have taken interest in the NS5 protein which encodes both the viral methyltransferase and RNA-dependent RNA polymerase. This makes it important for viral replication alongside other important functions such as inhibiting the innate immune system thus ensuring virus survival and replication. Structural studies can help design inhibitors, while biochemical studies can help understand the various mechanisms utilized by NS5 thus counteracting them might inhibit or abolish the viral infection. Drug repurposing targeting the NS5 protein has also proven to be an effective tool since hundreds of thousands of compounds can be screened therefore saving time and resources, moreover information on these compounds might already be available especially if they are used to treat other ailments.

Keywords: Arbovirus; Flavivirus; IFN1; IFN3; MTase; NS5; RdRp; STAT2; TBK1; Zika.

Figure 1

Zika virus (ZIKV) single stranded positive RNA with its single open reading frame (ORF) flanked by the 5′ and 3′ untranslated regions (UTRs). The regions coding for the structural and non-structural proteins are shown, as well as the individual proteins.

Figure 2

Cascade of events that leads to interferons (IFN) mediated antiviral response. The blue pathway leads to the phosphorylation and nuclear translocation of IRF3 thus activating the transcription of the IFN1 and IFN3 genes. This allows the secretion of both IFNs followed by the binding to their respective receptors leading to the activation of the JAK1/TYK2 pathway (depicted in orange). This is followed by the formation of the tripartite transcription factor (ISGF3) complex thus activating interferon stimulated response elements (ISRE) sites resulting in an effective antiviral response (depicted in green). After STAT2 degradation, STAT1 phosphorylation and homo-dimerization increases leading to the formation of gamma activated factor (GAF) elements and up-regulation of IRF1 [44]. This leads to the up-regulation of pro-inflammatory cytokines. ZIKV NS5 interferes at the steps colored in yellow; NS5 binds to TBK1 preventing its phosphorylation and activation by the TRAF’s and also binds STAT2 marking it for proteasomal degradation [26,27,45].