Abstract
Non-segmented negative strand (NNS) RNA viruses belonging to the order Mononegavirales are highly diversified eukaryotic viruses including significant human pathogens, such as rabies, measles, Nipah, and Ebola. Elucidation of their unique strategies to replicate in eukaryotic cells is crucial to aid in developing anti-NNS RNA viral agents. Over the past 40 years, vesicular stomatitis virus (VSV), closely related to rabies virus, has served as a paradigm to study the fundamental molecular mechanisms of transcription and replication of NNS RNA viruses. These studies provided insights into how NNS RNA viruses synthesize 5′-capped mRNAs using their RNA-dependent RNA polymerase L proteins equipped with an unconventional mRNA capping enzyme, namely GDP polyribonucleotidyltransferase (PRNTase), domain. PRNTase or PRNTase-like domains are evolutionally conserved among L proteins of all known NNS RNA viruses and their related viruses belonging to Jingchuvirales, a newly established order, in the class Monjiviricetes, suggesting that they may have evolved from a common ancestor that acquired the unique capping system to replicate in a primitive eukaryotic host. This article reviews what has been learned from biochemical and structural studies on the VSV RNA biosynthesis machinery, and then focuses on recent advances in our understanding of regulatory and catalytic roles of the PRNTase domain in RNA synthesis and capping.
Highlights
The order Mononegavirales comprises highly diversified eukaryotic viruses with a monopartite negative strand RNA genome, which includes important human pathogens [e.g., rabies virus (RABV), measles virus (MeV), Nipah virus (NiV), human respiratory syncytial virus (HRSV), Ebola virus (EBOV)] (Lamb, 2013)
As described in this review article, the numerous biochemical and structural studies on the vesicular stomatitis virus (VSV) RNA biosynthesis machinery have led to the remarkable discoveries, provoking paradigm shifts in understanding unique roles of non-segmented negative strand (NNS) RNA viral proteins in transcription and replication
Those include the finding that the rhabdoviral L proteins catalyze the unique mRNA capping reaction by the unconventional mechanism involving their guanosine -triphosphatase (GTPase) and PRNTase activities
Summary
The order Mononegavirales comprises highly diversified eukaryotic viruses with a monopartite negative strand RNA genome (rarely bipartite genomes), which includes important human pathogens [e.g., rabies virus (RABV), measles virus (MeV), Nipah virus (NiV), human respiratory syncytial virus (HRSV), Ebola virus (EBOV)] (Lamb, 2013). Since gene products as well as RNA genomes of these non-segmented negative strand (NNS) RNA viruses share structural and functional similarities, they are believed to have evolved from a common ancestor. NNS RNA viruses belonging to the Rhabdoviridae (e.g., RABV), Paramyxoviridae (e.g., MeV), Pneumoviridae (e.g., HRSV), Filoviridae (e.g., EBOV), Bornaviridae [e.g., Borna disease virus-1 (BoDV-1)], Nyamiviridae [e.g., Nyamanini virus (NYMV)], and other families share the same gene organization with VSV, but have diversified their structural genes and often acquired additional structural and/or non-structural genes during evolution (Lamb, 2013; Amarasinghe et al, 2018). We outline the lessons learned from five decades of biochemical and structural studies on NNS RNA viral replication using VSV as a prototype, and focus on recent findings regarding unique roles of rhabdoviral L proteins in RNA synthesis and cap formation
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