Abstract
Flaviviruses, most of which are emerging and re-emerging human pathogens and significant public health concerns worldwide, are positive-sense RNA viruses. Flavivirus replication occurs on the ER and is regulated by many mechanisms and factors. NS5, which consists of a C-terminal RdRp domain and an N-terminal methyltransferase domain, plays a pivotal role in genome replication and capping. The C-terminal RdRp domain acts as the polymerase for RNA synthesis and cooperates with diverse viral proteins to facilitate productive RNA proliferation within the replication complex. Here, we provide an overview of the current knowledge of the functions and characteristics of the RdRp, including the subcellular localization of NS5, as well as the network of interactions formed between the RdRp and genome UTRs, NS3, and the methyltransferase domain. We posit that a detailed understanding of RdRp functions may provide a target for antiviral drug discovery and therapeutics.
Highlights
Flaviviruses, which belong to the Flavivirus genus, and Flaviviridae family, are globally significant arthropod-borne viruses that cause disease in hundreds of millions of people annually across half of the world; flaviviruses include Dengue virus (DENV, serotypes 1–4), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and tick-borne encephalitis virus (TBEV) [1].Flaviviruses are enveloped viruses with a single-stranded RNA genome, composed of one large open reading frame (ORF), flanked at both its 50 and 30 ends by short noncoding sequences termed untranslated regions (UTRs); the flavivirus genome contains a type I cap structure (m7 GpppAmp) at its 50 end, and characteristically lacks a poly(A) tail at its 30 end
The recently attained structure of HCV RdRp in complex with a double-stranded RNA model revealed that removal of a β-hairpin loop that impedes access of the template RNA to the thumb domain in NS5B increased de novo RNA synthesis by >100-fold, promoted RNA binding, and induced significant conformational changes producing an open form, allowing primer-template RNA duplex access to the catalytic core [73]. These findings indicate that cooperation between the 30 SL and RdRp is required for RNA synthesis. 50 -30 -Hybridization brings the 30 end of the RNA near the 50 promoter, and plays a role in making the 30 -terminal nucleotides of the viral genome available for the viral RdRp during the initiation of RNA synthesis
There are still gaps in our understanding of how the RdRp interacts with viral proteins and genomic RNA to efficiently coordinate their respective functions during RNA synthesis and capping
Summary
Flaviviruses, which belong to the Flavivirus genus, and Flaviviridae family, are globally significant arthropod-borne viruses that cause disease in hundreds of millions of people annually across half of the world; flaviviruses include Dengue virus (DENV, serotypes 1–4), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), and tick-borne encephalitis virus (TBEV) [1]. Membrane and encodes a long single polyprotein that is co- and posttranslationally processed by viral and host cellular proteases, yielding the structural proteins C, prM, and E, and seven nonstructural (NS). The NS proteins cooperate with an array of host factors to form a membrane-bound replication complex (RC) where viral RNA (vRNA) synthesis takes place. We emphasize the process of viral genome biogenesis within the replication complex and discuss molecular interactions between the RdRp and other viral proteins and genomic RNA. Knowledge of these processes may provide new targets for antiviral compound development and the design of vaccine candidates
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