Structures of the Mononegavirales Polymerases

• Type of Material: Article
• Authors: Bo Liang, Emory University
• Language: English
• Date: 2020-11-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Liang.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.00175-20
• Title of Journal or Parent Work: JOURNAL OF VIROLOGY
• Volume: 94
• Issue: 22
• Grant/Funding Information: The research programs in the Liang laboratory at Emory are supported by the U.S. National Institute of General Medical Sciences (NIGMS), National Institutes of Health (NIH), under award number R01GM130950 and by the Research Start-Up Fund at Emory University School of Medicine.
• Keywords: human respiratory syncytial virus (HRSV); human metapneumovirus (HMPV); cryo-EM structures; Mononegavirales polymerases; RNA-dependent RNA polymerase; rabies virus (RABV); vesicular stomatitis virus (VSV)
• Research Categories: Biology, Genetics; Biology, Virology

Abstract

Mononegavirales, known as nonsegmented negative-sense (NNS) RNA viruses, are a class of pathogenic and sometimes deadly viruses that include rabies virus (RABV), human respiratory syncytial virus (HRSV), and Ebola virus (EBOV). Unfortunately, no effective vaccines and antiviral therapeutics against many Mononegavirales are currently available. Viral polymerases have been attractive and major antiviral therapeutic targets. Therefore, Mononegavirales polymerases have been extensively investigated for their structures and functions. Mononegavirales mimic RNA synthesis of their eukaryotic counterparts by utilizing multifunctional RNA polymerases to replicate entire viral genomes and transcribe viral mRNAs from individual viral genes as well as synthesize 5′ methylated cap and 3′ poly(A) tail of the transcribed viral mRNAs. The catalytic subunit large protein (L) and cofactor phosphoprotein (P) constitute the Mononegavirales polymerases. In this review, we discuss the shared and unique features of RNA synthesis, the monomeric multifunctional enzyme L, and the oligomeric multimodular adapter P of Mononegavirales. We outline the structural analyses of the Mononegavirales polymerases since the first structure of the vesicular stomatitis virus (VSV) L protein determined in 2015 and highlight multiple high-resolution cryo-electron microscopy (cryo-EM) structures of the polymerases of Mononegavirales, namely, VSV, RABV, HRSV, human metapneumovirus (HMPV), and human parainfluenza virus (HPIV), that have been reported in recent months (2019 to 2020). We compare the structures of those polymerases grouped by virus family, illustrate the similarities and differences among those polymerases, and reveal the potential RNA synthesis mechanisms and models of highly conserved Mononegavirales. We conclude by the discussion of remaining questions, evolutionary perspectives, and future directions.