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Viruses
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Transcription and Replication of the Negative-Strand RNA Viruses
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Transcription and Replication of the Negative-Strand RNA Viruses

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 11362

Special Issue Editors

Prof. Dr. Rob W Ruigrok

E-Mail Website
Guest Editor
Institut de Biologie Structurale (IBS), CEA, CNRS, Université Grenoble Alpes, 38058 Grenoble, France
Interests: negative strand RNA viruses; structural biology of viruses; structure of RNA of viruses
Special Issues, Collections and Topics in MDPI journals
Dr. Martin Blackledge

E-Mail Website
Guest Editor
Institut de Biologie Structurale (IBS), CEA, CNRS, Université Grenoble Alpes, 38058 Grenoble, France
Interests: protein dynamics; nuclear magnetic resonance spectroscopy; intrinsically disordered proteins; self-assembly
Special Issues, Collections and Topics in MDPI journals
Dr. Nadia Naffakh

E-Mail Website
Guest Editor
Unité Biologie des ARN et Virus Influenza, Institut Pasteur, 75015 Paris, France
Interests: Influenza A viruses; RNA Biology of Influenza Virus; Host-pathogen interactions

Special Issue Information

Dear Colleagues,

The viral RNA of negative-strand RNA viruses is always bound to the nucleoprotein (N), creating a helical or double-helical structure (nucleocapsid). Last year, we made a call for manuscripts on the biochemistry and structure of the nucleocapsids of Paramyxoviruses. This year, the call will be on the biochemistry and structure of the transcription and replication of all negative-stand RNA viruses; this includes influenza viruses (Orthomyxoviridae), bunyaviruses (Bunyaviridae) and Mononegavirales, viruses such as measles, respiratory syncytial, Ebola, rabies/VSV and Borna-viruses.

This call for manuscripts concentrates on the structure and biochemistry of RNA and the proteins in the nucleocapsid, N, P and polymerase (L), shorter proteins from the gene of P (V and C), and all cellular proteins that bind to these viral proteins and complexes.

Recently, N and P have also been shown to form liquid-like, membrane-less compartments (via liquid–liquid phase separation, LLPS, of viral proteins) which comprise different components of the viral replication complex, forming so-called viral factories. LLPS could also provide protection of the viral RNA and associated RNA transcription machinery from the innate immune system. We are interested in potential manuscripts relating to these findings.

The end of this call for manuscripts will be at the end of October 2022.

Prof. Dr. Rob W Ruigrok
Dr. Martin Blackledge
Dr. Nadia Naffakh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Research

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22 pages, 6870 KiB  
Article
Structural Impact of the Interaction of the Influenza A Virus Nucleoprotein with Genomic RNA Segments
by Erwan Quignon, Damien Ferhadian, Antoine Hache, Valérie Vivet-Boudou, Catherine Isel, Anne Printz-Schweigert, Amélie Donchet, Thibaut Crépin and Roland Marquet
Viruses 2024, 16(3), 421; https://doi.org/10.3390/v16030421 - 09 Mar 2024
Viewed by 920
Abstract
Influenza A viruses (IAVs) possess a segmented genome consisting of eight viral RNAs (vRNAs) associated with multiple copies of viral nucleoprotein (NP) and a viral polymerase complex. Despite the crucial role of RNA structure in IAV replication, the impact of NP binding on [...] Read more.
Influenza A viruses (IAVs) possess a segmented genome consisting of eight viral RNAs (vRNAs) associated with multiple copies of viral nucleoprotein (NP) and a viral polymerase complex. Despite the crucial role of RNA structure in IAV replication, the impact of NP binding on vRNA structure is not well understood. In this study, we employed SHAPE chemical probing to compare the structure of NS and M vRNAs of WSN IAV in various states: before the addition of NP, in complex with NP, and after the removal of NP. Comparison of the RNA structures before the addition of NP and after its removal reveals that NP, while introducing limited changes, remodels local structures in both vRNAs and long-range interactions in the NS vRNA, suggesting a potentially biologically relevant RNA chaperone activity. In contrast, NP significantly alters the structure of vRNAs in vRNA/NP complexes, though incorporating experimental data into RNA secondary structure prediction proved challenging. Finally, our results suggest that NP not only binds single-stranded RNA but also helices with interruptions, such as bulges or small internal loops, with a preference for G-poor and C/U-rich regions. Full article
(This article belongs to the Special Issue Transcription and Replication of the Negative-Strand RNA Viruses)
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16 pages, 1460 KiB  
Article
Nuclease Activity of the Junín Virus Nucleoprotein C-Terminal Domain
by Alicia Armella Sierra, María Eugenia Loureiro, Sebastián Esperante, Silvia Susana Borkosky, Giovanna L. Gallo, Gonzalo de Prat Gay and Nora Lopez
Viruses 2023, 15(9), 1818; https://doi.org/10.3390/v15091818 - 26 Aug 2023
Cited by 1 | Viewed by 973
Abstract
The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the nucleoprotein (NP), a multifunctional, two-domain protein with the primary role as structural component of the viral nucleocapsids, [...] Read more.
The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the nucleoprotein (NP), a multifunctional, two-domain protein with the primary role as structural component of the viral nucleocapsids, used as template for viral polymerase RNA synthesis activities. Here, we report that the C-terminal domain (CTD) of the attenuated Candid#1 strain of the JUNV NP can be purified as a stable soluble form with a secondary structure in line with known NP structures from other mammarenaviruses. We show that the JUNV NP CTD interacts with the viral matrix protein Z in vitro, and that the full-length NP and Z interact with each other in cellulo, suggesting that the NP CTD is responsible for this interaction. This domain comprises an arrangement of four acidic residues and a histidine residue conserved in the active site of exoribonucleases belonging to the DEDDh family. We show that the JUNV NP CTD displays metal-ion-dependent nuclease activity against DNA and single- and double-stranded RNA, and that this activity is impaired by the mutation of a catalytic residue within the DEDDh motif. These results further support this activity, not previously observed in the JUNV NP, which could impact the mechanism of the cellular immune response modulation of this important pathogen. Full article
(This article belongs to the Special Issue Transcription and Replication of the Negative-Strand RNA Viruses)
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21 pages, 4673 KiB  
Article
Assembly of the Tripartite and RNA Condensates of the Respiratory Syncytial Virus Factory Proteins In Vitro: Role of the Transcription Antiterminator M2-1
by Araceli Visentin, Nicolás Demitroff, Mariano Salgueiro, Silvia Susana Borkosky, Vladimir N. Uversky, Gabriela Camporeale and Gonzalo de Prat-Gay
Viruses 2023, 15(6), 1329; https://doi.org/10.3390/v15061329 - 06 Jun 2023
Cited by 2 | Viewed by 1577
Abstract
A wide variety of viruses replicate in liquid-like viral factories. Non-segmented negative stranded RNA viruses share a nucleoprotein (N) and a phosphoprotein (P) that together emerge as the main drivers of liquid–liquid phase separation. The respiratory syncytial virus includes the transcription antiterminator M [...] Read more.
A wide variety of viruses replicate in liquid-like viral factories. Non-segmented negative stranded RNA viruses share a nucleoprotein (N) and a phosphoprotein (P) that together emerge as the main drivers of liquid–liquid phase separation. The respiratory syncytial virus includes the transcription antiterminator M2-1, which binds RNA and maximizes RNA transcriptase processivity. We recapitulate the assembly mechanism of condensates of the three proteins and the role played by RNA. M2-1 displays a strong propensity for condensation by itself and with RNA through the formation of electrostatically driven protein–RNA coacervates based on the amphiphilic behavior of M2-1 and finely tuned by stoichiometry. M2-1 incorporates into tripartite condensates with N and P, modulating their size through an interplay with P, where M2-1 is both client and modulator. RNA is incorporated into the tripartite condensates adopting a heterogeneous distribution, reminiscent of the M2-1-RNA IBAG granules within the viral factories. Ionic strength dependence indicates that M2-1 behaves differently in the protein phase as opposed to the protein–RNA phase, in line with the subcompartmentalization observed in viral factories. This work dissects the biochemical grounds for the formation and fate of the RSV condensates in vitro and provides clues to interrogate the mechanism under the highly complex infection context. Full article
(This article belongs to the Special Issue Transcription and Replication of the Negative-Strand RNA Viruses)
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27 pages, 7112 KiB  
Article
Structure and Dynamics of the Unassembled Nucleoprotein of Rabies Virus in Complex with Its Phosphoprotein Chaperone Module
by Francine C. A. Gérard, Jean-Marie Bourhis, Caroline Mas, Anaïs Branchard, Duc Duy Vu, Sylvia Varhoshkova, Cédric Leyrat and Marc Jamin
Viruses 2022, 14(12), 2813; https://doi.org/10.3390/v14122813 - 16 Dec 2022
Cited by 3 | Viewed by 2015
Abstract
As for all non-segmented negative RNA viruses, rabies virus has its genome packaged in a linear assembly of nucleoprotein (N), named nucleocapsid. The formation of new nucleocapsids during virus replication in cells requires the production of soluble N protein in complex with its [...] Read more.
As for all non-segmented negative RNA viruses, rabies virus has its genome packaged in a linear assembly of nucleoprotein (N), named nucleocapsid. The formation of new nucleocapsids during virus replication in cells requires the production of soluble N protein in complex with its phosphoprotein (P) chaperone. In this study, we reconstituted a soluble heterodimeric complex between an armless N protein of rabies virus (RABV), lacking its N-terminal subdomain (NNT-ARM), and a peptide encompassing the N0 chaperon module of the P protein. We showed that the chaperone module undergoes a disordered−order transition when it assembles with N0 and measured an affinity in the low nanomolar range using a competition assay. We solved the crystal structure of the complex at a resolution of 2.3 Å, unveiling the details of the conserved interfaces. MD simulations showed that both the chaperon module of P and RNA-mediated polymerization reduced the ability of the RNA binding cavity to open and close. Finally, by reconstituting a complex with full-length P protein, we demonstrated that each P dimer could independently chaperon two N0 molecules. Full article
(This article belongs to the Special Issue Transcription and Replication of the Negative-Strand RNA Viruses)
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12 pages, 1480 KiB  
Article
Increased Polymerase Activity of Zoonotic H7N9 Allows Partial Escape from MxA
by Philipp P. Petric, Jacqueline King, Laura Graf, Anne Pohlmann, Martin Beer and Martin Schwemmle
Viruses 2022, 14(11), 2331; https://doi.org/10.3390/v14112331 - 24 Oct 2022
Cited by 3 | Viewed by 1931
Abstract
The interferon-induced myxovirus resistance protein A (MxA) is a potent restriction factor that prevents zoonotic infection from influenza A virus (IAV) subtype H7N9. Individuals expressing antivirally inactive MxA variants are highly susceptible to these infections. However, human-adapted IAVs have acquired specific mutations in [...] Read more.
The interferon-induced myxovirus resistance protein A (MxA) is a potent restriction factor that prevents zoonotic infection from influenza A virus (IAV) subtype H7N9. Individuals expressing antivirally inactive MxA variants are highly susceptible to these infections. However, human-adapted IAVs have acquired specific mutations in the viral nucleoprotein (NP) that allow escape from MxA-mediated restriction but that have not been observed in MxA-sensitive, human H7N9 isolates. To date, it is unknown whether H7N9 can adapt to escape MxA-mediated restriction. To study this, we infected Rag2-knockout (Rag2−/−) mice with a defect in T and B cell maturation carrying a human MxA transgene (MxAtg/−Rag2−/−). In these mice, the virus could replicate for several weeks facilitating host adaptation. In MxAtg/−Rag2−/−, but not in Rag2−/− mice, the well-described mammalian adaptation E627K in the viral polymerase subunit PB2 was acquired, but no variants with MxA escape mutations in NP were detected. Utilizing reverse genetics, we could show that acquisition of PB2 E627K allowed partial evasion from MxA restriction in MxAtg/tg mice. However, pretreatment with type I interferon decreased viral replication in these mice, suggesting that PB2 E627K is not a true MxA escape mutation. Based on these results, we speculate that it might be difficult for H7N9 to acquire MxA escape mutations in the viral NP. This is consistent with previous findings showing that MxA escape mutations cause severe attenuation of IAVs of avian origin. Full article
(This article belongs to the Special Issue Transcription and Replication of the Negative-Strand RNA Viruses)
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Review

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25 pages, 9793 KiB  
Review
Biochemistry of the Respiratory Syncytial Virus L Protein Embedding RNA Polymerase and Capping Activities
by Priscila Sutto-Ortiz, Jean-François Eléouët, François Ferron and Etienne Decroly
Viruses 2023, 15(2), 341; https://doi.org/10.3390/v15020341 - 25 Jan 2023
Cited by 1 | Viewed by 2947
Abstract
The human respiratory syncytial virus (RSV) is a negative-sense, single-stranded RNA virus. It is the major cause of severe acute lower respiratory tract infection in infants, the elderly population, and immunocompromised individuals. There is still no approved vaccine or antiviral treatment against RSV [...] Read more.
The human respiratory syncytial virus (RSV) is a negative-sense, single-stranded RNA virus. It is the major cause of severe acute lower respiratory tract infection in infants, the elderly population, and immunocompromised individuals. There is still no approved vaccine or antiviral treatment against RSV disease, but new monoclonal prophylactic antibodies are yet to be commercialized, and clinical trials are in progress. Hence, urgent efforts are needed to develop efficient therapeutic treatments. RSV RNA synthesis comprises viral transcription and replication that are catalyzed by the large protein (L) in coordination with the phosphoprotein polymerase cofactor (P), the nucleoprotein (N), and the M2-1 transcription factor. The replication/transcription is orchestrated by the L protein, which contains three conserved enzymatic domains: the RNA-dependent RNA polymerase (RdRp), the polyribonucleotidyl transferase (PRNTase or capping), and the methyltransferase (MTase) domain. These activities are essential for the RSV replicative cycle and are thus considered as attractive targets for the development of therapeutic agents. In this review, we summarize recent findings about RSV L domains structure that highlight how the enzymatic activities of RSV L domains are interconnected, discuss the most relevant and recent antivirals developments that target the replication/transcription complex, and conclude with a perspective on identified knowledge gaps that enable new research directions. Full article
(This article belongs to the Special Issue Transcription and Replication of the Negative-Strand RNA Viruses)
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