Curated Papers > Recent research on high-impact "mRNA vaccines" (IF≥30, in the past 5 years)

Structural insights into RNA polymerases of negative-sense RNA viruses.

Literature Information

DOI	10.1038/s41579-020-00501-8
PMID	33495561
Journal	Nature reviews. Microbiology
Impact Factor	103.3
JCR Quartile	Q1
Publication Year	2021
Times Cited	59
Keywords	negative-sense RNA viruses, RNA polymerases, structural insights, viral transcription, antiviral drug design
Literature Type	Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN	1740-1526
Pages	303-318
Issue	19(5)
Authors	Aartjan J W Te Velthuis, Jonathan M Grimes, Ervin Fodor

TL;DR

This review examines the high-resolution structures of RNA-dependent RNA polymerases from various negative-sense RNA viruses, highlighting their roles in genome replication and transcription. The findings enhance our understanding of viral molecular mechanisms and provide valuable targets for developing antiviral drugs.

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negative-sense RNA viruses · RNA polymerases · structural insights · viral transcription · antiviral drug design

Abstract

RNA viruses include many important human and animal pathogens, such as the influenza viruses, respiratory syncytial virus, Ebola virus, measles virus and rabies virus. The genomes of these viruses consist of single or multiple RNA segments that assemble with oligomeric viral nucleoprotein into ribonucleoprotein complexes. Replication and transcription of the viral genome is performed by ~250-450 kDa viral RNA-dependent RNA polymerases that also contain capping or cap-snatching activity. In this Review, we compare recent high-resolution X-ray and cryoelectron microscopy structures of RNA polymerases of negative-sense RNA viruses with segmented and non-segmented genomes, including orthomyxoviruses, peribunyaviruses, phenuiviruses, arenaviruses, rhabdoviruses, pneumoviruses and paramyxoviruses. In addition, we discuss how structural insights into these enzymes contribute to our understanding of the molecular mechanisms of viral transcription and replication, and how we can use these insights to identify targets for antiviral drug design.

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Primary Questions Addressed

1. How do the structural differences between segmented and non-segmented RNA viruses influence their replication mechanisms?
2. What specific roles do the capping or cap-snatching activities of RNA-dependent RNA polymerases play in the viral life cycle?
3. How can the structural insights gained from high-resolution imaging techniques aid in the development of antiviral therapies?
4. In what ways do the structural features of RNA polymerases vary among different families of negative-sense RNA viruses?
5. What are the implications of understanding the molecular mechanisms of viral transcription for vaccine development against RNA viruses?

Key Findings

Research Background and Purpose

Negative-sense RNA viruses (NSVs) are significant human and animal pathogens responsible for diseases such as respiratory infections and hemorrhagic fevers. Understanding the molecular mechanisms of NSV replication and transcription is crucial for developing antiviral therapies. This review focuses on the structural insights into RNA polymerases of NSVs, comparing recent high-resolution structures and discussing their implications for antiviral drug design.

Main Methods/Materials/Experimental Design

The review synthesizes findings from various structural studies, particularly using X-ray crystallography and cryo-electron microscopy (cryo-EM), to elucidate the architecture and function of NSV RNA polymerases. The structural features of RNA polymerases from both segmented (sNSVs) and non-segmented (nsNSVs) viruses are compared, highlighting differences in their organization and functional domains.

Key Results and Findings

1. RNA Polymerase Structures: The review details the structures of RNA polymerases from various NSVs, highlighting their modular architecture. Key domains include the RNA-dependent RNA polymerase (RdRP) domain, endonuclease (Endo) domain, and cap-binding (CapB) domain.
2. Capping Mechanisms: Non-segmented NSVs utilize a capping mechanism involving cap-snatching, while segmented NSVs have intrinsic capping activities.
3. Conformational Flexibility: The polymerases exhibit significant conformational flexibility, crucial for their function in transcription and replication. This flexibility allows for different initiation and elongation states during RNA synthesis.
4. Transcription and Replication Mechanisms: The review outlines the processes of transcription and replication in detail, emphasizing how viral RNA polymerases interact with RNA templates and utilize host factors for efficient transcription.

Main Conclusions/Significance/Innovation

The review highlights the critical advancements in understanding the structure and function of NSV RNA polymerases. These insights pave the way for the development of novel antiviral strategies targeting specific enzymatic activities of these polymerases. The comparison of structural features between sNSVs and nsNSVs provides a framework for future research aimed at elucidating remaining unknowns in viral replication mechanisms.

Research Limitations and Future Directions

1. Structural Gaps: Despite significant progress, there are still gaps in our understanding of nsNSV polymerases, particularly regarding their RNA-binding mechanisms and conformational changes during transcription and replication.
2. Antiviral Development: The rapid emergence of resistance to existing antiviral agents underscores the need for continuous development of new therapeutics. Future research should focus on identifying novel targets within the polymerases and understanding host-virus interactions that facilitate viral replication.
3. Mechanistic Studies: Further studies using advanced structural techniques and in vivo models are needed to capture dynamic conformational changes in RNA polymerases during the viral life cycle.

Summary Table of Key Findings

Feature	Non-Segmented NSVs (nsNSVs)	Segmented NSVs (sNSVs)
Polymerase Structure	Single polypeptide (L protein)	Heterotrimeric (PB1, PB2, PA)
Capping Mechanism	Cap-snatching	Intrinsic capping
Conformational Flexibility	High, critical for function	High, allows different states
RNA Interaction	Less understood	Well-characterized
Antiviral Targeting	Focus on polymerase activities	Target both polymerase and host interactions

This structured summary encapsulates the critical aspects of the review, providing a clear understanding of the insights gained into NSV RNA polymerases and their implications for future research and antiviral development.

References

1. Nucleoproteins and nucleocapsids of negative-strand RNA viruses. - Rob W H Ruigrok;Thibaut Crépin;Dan Kolakofsky - Current opinion in microbiology (2011)
2. Structural studies of influenza virus RNPs by electron microscopy indicate molecular contortions within NP supra-structures. - John R Gallagher;Udana Torian;Dustin M McCraw;Audray K Harris - Journal of structural biology (2017)
3. Structural insights into influenza A virus ribonucleoproteins reveal a processive helical track as transcription mechanism. - Rocío Coloma;Rocío Arranz;José M de la Rosa-Trevín;Carlos O S Sorzano;Sandie Munier;Diego Carlero;Nadia Naffakh;Juan Ortín;Jaime Martín-Benito - Nature microbiology (2020)
4. Polymerases of paramyxoviruses and pneumoviruses. - Rachel Fearns;Richard K Plemper - Virus research (2017)
5. Structure of the L Protein of Vesicular Stomatitis Virus from Electron Cryomicroscopy. - Bo Liang;Zongli Li;Simon Jenni;Amal A Rahmeh;Benjamin M Morin;Timothy Grant;Nikolaus Grigorieff;Stephen C Harrison;Sean P J Whelan - Cell (2015)
6. Mechanism of RNA synthesis initiation by the vesicular stomatitis virus polymerase. - Benjamin Morin;Amal A Rahmeh;Sean P J Whelan - The EMBO journal (2012)
7. The Cap-Snatching Mechanism of Bunyaviruses. - Silke Olschewski;Stephen Cusack;Maria Rosenthal - Trends in microbiology (2020)
8. Sequencing the cap-snatching repertoire of H1N1 influenza provides insight into the mechanism of viral transcription initiation. - David Koppstein;Joseph Ashour;David P Bartel - Nucleic acids research (2015)
9. Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection. - Jessica Sook Yuin Ho;Matthew Angel;Yixuan Ma;Elizabeth Sloan;Guojun Wang;Carles Martinez-Romero;Marta Alenquer;Vladimir Roudko;Liliane Chung;Simin Zheng;Max Chang;Yesai Fstkchyan;Sara Clohisey;Adam M Dinan;James Gibbs;Robert Gifford;Rong Shen;Quan Gu;Nerea Irigoyen;Laura Campisi;Cheng Huang;Nan Zhao;Joshua D Jones;Ingeborg van Knippenberg;Zeyu Zhu;Natasha Moshkina;Léa Meyer;Justine Noel;Zuleyma Peralta;Veronica Rezelj;Robyn Kaake;Brad Rosenberg;Bo Wang;Jiajie Wei;Slobodan Paessler;Helen M Wise;Jeffrey Johnson;Alessandro Vannini;Maria João Amorim;J Kenneth Baillie;Emily R Miraldi;Christopher Benner;Ian Brierley;Paul Digard;Marta Łuksza;Andrew E Firth;Nevan Krogan;Benjamin D Greenbaum;Megan K MacLeod;Harm van Bakel;Adolfo Garcìa-Sastre;Jonathan W Yewdell;Edward Hutchinson;Ivan Marazzi - Cell (2020)
10. Synergistic effects of gene-end signal mutations and the M2-1 protein on transcription termination by respiratory syncytial virus. - K A Sutherland;P L Collins;M E Peeples - Virology (2001)

Literatures Citing This Work

1. Hemagglutinin Stability and Its Impact on Influenza A Virus Infectivity, Pathogenicity, and Transmissibility in Avians, Mice, Swine, Seals, Ferrets, and Humans. - Charles J Russell - Viruses (2021)
2. Influenza Virus RNA Synthesis and the Innate Immune Response. - Sabrina Weis;Aartjan J W Te Velthuis - Viruses (2021)
3. How SARS-CoV-2 and Other Viruses Build an Invasion Route to Hijack the Host Nucleocytoplasmic Trafficking System. - Elma Sakinatus Sajidah;Keesiang Lim;Richard W Wong - Cells (2021)
4. Structural Analysis of the Menangle Virus P Protein Reveals a Soft Boundary between Ordered and Disordered Regions. - Melissa N Webby;Nicole Herr;Esther M M Bulloch;Michael Schmitz;Jeremy R Keown;David C Goldstone;Richard L Kingston - Viruses (2021)
5. Structure of Machupo virus polymerase in complex with matrix protein Z. - Jun Ma;Shuangyue Zhang;Xinzheng Zhang - Nature communications (2021)
6. Influenza A Virus Defective Viral Genomes Are Inefficiently Packaged into Virions Relative to Wild-Type Genomic RNAs. - Fadi G Alnaji;William K Reiser;Joel Rivera-Cardona;Aartjan J W Te Velthuis;Christopher B Brooke - mBio (2021)
7. Comparison of RNA synthesis initiation properties of non-segmented negative strand RNA virus polymerases. - Afzaal M Shareef;Barbara Ludeke;Paul Jordan;Jerome Deval;Rachel Fearns - PLoS pathogens (2021)
8. The Host Factor ANP32A Is Required for Influenza A Virus vRNA and cRNA Synthesis. - Benjamin E Nilsson-Payant;Benjamin R tenOever;Aartjan J W Te Velthuis - Journal of virology (2022)
9. Mapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies. - Jeremy R Keown;Zihan Zhu;Loïc Carrique;Haitian Fan;Alexander P Walker;Itziar Serna Martin;Els Pardon;Jan Steyaert;Ervin Fodor;Jonathan M Grimes - Nature communications (2022)
10. The C-Terminal Domains of the PB2 Subunit of the Influenza A Virus RNA Polymerase Directly Interact with Cellular GTPase Rab11a. - Hana Veler;Haitian Fan;Jeremy R Keown;Jane Sharps;Marjorie Fournier;Jonathan M Grimes;Ervin Fodor - Journal of virology (2022)

... (49 more literatures)

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