Dengue Virus Non-Structural Protein 5 as a Versatile, Multi-Functional Effector in Host-Pathogen Interactions.

Priya Bhatnagar,Gopinathan Pillai Sreekanth,Anmol Chandele,Ramakrishnan Sitaraman,Kaja Murali-Krishna

doi:10.3389/fcimb.2021.574067

Abstract

Dengue is emerging as one of the most prevalent mosquito-borne viral diseases of humans. The 11kb RNA genome of the dengue virus encodes three structural proteins (envelope, pre-membrane, capsid) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), all of which are translated as a single polyprotein that is subsequently cleaved by viral and host cellular proteases at specific sites. Non-structural protein 5 (NS5) is the largest of the non-structural proteins, functioning as both an RNA-dependent RNA polymerase (RdRp) that replicates the viral RNA and an RNA methyltransferase enzyme (MTase) that protects the viral genome by RNA capping, facilitating polyprotein translation. Within the human host, NS5 interacts with several proteins such as those in the JAK-STAT pathway, thereby interfering with anti-viral interferon signalling. This mini-review presents annotated, consolidated lists of known and potential NS5 interactors in the human host as determined by experimental and computational approaches respectively. The most significant protein interactors and the biological pathways they participate in are also highlighted and their implications discussed, along with the specific serotype of dengue virus as appropriate. This information can potentially stimulate and inform further research efforts towards providing an integrative understanding of the mechanisms by which NS5 manipulates the human-virus interface in general and the innate and adaptive immune responses in particular.

Highlights

Dengue is a global epidemic resulting in over 100 million clinical cases globally each year with symptoms ranging from fever to hemorrhage and/or shock that can be fatal, especially among children (Guzman et al, 2010; Bhatt et al, 2013)
Yeast two-hybrid (Y2H) studies suggest that nuclear translocation may occur because the nuclear import receptor importin-b competes with dengue virus (DENV)-NS3 for binding with Non-structural protein 5 (NS5) (Johansson et al, 2001)
While the nuclear accumulation of NS5 does not seem to be essential for viral replication (Kumar et al, 2013), it appears to be linked to an increase in the production of the cytokine IL-8 that has been historically correlated with severe dengue (Medin et al, 2005)

Summary

Introduction

Dengue is a global epidemic resulting in over 100 million clinical cases globally each year with symptoms ranging from fever to hemorrhage and/or shock that can be fatal, especially among children (Guzman et al, 2010; Bhatt et al, 2013). NS5 interacts with host proteins such as STAT2 that are critical for type 1 interferon (IFN-I) signaling and innate responses and inhibits host anti-viral responses (reviewed recently by (Ashour et al, 2009; El Sahili and Lescar, 2017).

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Conclusion