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Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to...
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Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus

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

Deadline for manuscript submissions: 31 May 2024 | Viewed by 9532

Special Issue Editor

Dr. Christopher Hellen

E-Mail Website
Guest Editor
Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA
Interests: eukaryotic translation mechanisms and their exploitation by viruses

Special Issue Information

Dear Colleagues,

Viruses depend on the translation apparatus of host cells for the synthesis of viral proteins. Infection is consequently influenced by competition between viral mechanisms that act to co-opt the cellular translation apparatus and cellular mechanisms that restrict viral access to it.  Viral strategies include (a) synthesis of proteins that substitute for specific components of the translation apparatus, (b) modification of components of the host translation apparatus such as translation factors, ribosomes, or host mRNAs, thereby restricting cellular translation and the execution of cellular antiviral responses, and (c) exploitation of specialized elements in viral mRNAs to enable them to access the translation apparatus in these conditions. Viral infection imposes stresses on cells that activate signaling pathways and host innate immune defenses that may specifically silence translation of viral mRNAs or lead to a global shut-down of translation. Viruses have, in turn, evolved mechanisms to evade or subvert these host responses, thereby enabling viral translation to be maintained during infection.

This Special Issue will focus on recent advances in identifying viral effects on the cellular translation apparatus, in characterizing specialized viral translation mechanisms that function during infection, and in elucidating details of cellular mechanisms that restrict viral translation.

Dr. Christopher Hellen
Guest Editor

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.

Keywords

  • virus–host interactions
  • IRES elements
  • RNA structure
  • translation initiation
  • translational control
  • innate immune response
  • RNA modification

Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 4145 KiB  
Article
Factor-Dependent Internal Ribosome Entry Site and -1 Programmed Frameshifting Signal in the Bemisia-Associated Dicistrovirus 2
by Yihang Chen, Subash Chapagain, Jodi Chien, Higor Sette Pereira, Trushar R. Patel, Alice K. Inoue-Nagata and Eric Jan
Viruses 2024, 16(5), 695; https://doi.org/10.3390/v16050695 (registering DOI) - 28 Apr 2024
Abstract
The dicistrovirus intergenic (IGR) IRES uses the most streamlined translation initiation mechanism: the IRES recruits ribosomes directly without using protein factors and initiates translation from a non-AUG codon. Several subtypes of dicistroviruses IRES have been identified; typically, the IRESs adopt two -to three [...] Read more.
The dicistrovirus intergenic (IGR) IRES uses the most streamlined translation initiation mechanism: the IRES recruits ribosomes directly without using protein factors and initiates translation from a non-AUG codon. Several subtypes of dicistroviruses IRES have been identified; typically, the IRESs adopt two -to three overlapping pseudoknots with key stem-loop and unpaired regions that interact with specific domains of the ribosomal 40S and 60S subunits to direct translation. We previously predicted an atypical IGR IRES structure and a potential -1 programmed frameshift (-1 FS) signal within the genome of the whitefly Bemisia-associated dicistrovirus 2 (BaDV-2). Here, using bicistronic reporters, we demonstrate that the predicted BaDV-2 -1 FS signal can drive -1 frameshifting in vitro via a slippery sequence and a downstream stem-loop structure that would direct the translation of the viral RNA-dependent RNA polymerase. Moreover, the predicted BaDV-2 IGR can support IRES translation in vitro but does so through a mechanism that is not typical of known factorless dicistrovirus IGR IRES mechanisms. Using deletion and mutational analyses, the BaDV-2 IGR IRES is mapped within a 140-nucleotide element and initiates translation from an AUG codon. Moreover, the IRES does not bind directly to purified ribosomes and is sensitive to eIF2 and eIF4A inhibitors NSC1198983 and hippuristanol, respectively, indicating an IRES-mediated factor-dependent mechanism. Biophysical characterization suggests the BaDV-2 IGR IRES contains several stem-loops; however, mutational analysis suggests a model whereby the IRES is unstructured or adopts distinct conformations for translation initiation. In summary, we have provided evidence of the first -1 FS frameshifting signal and a novel factor-dependent IRES mechanism in this dicistrovirus family, thus highlighting the diversity of viral RNA-structure strategies to direct viral protein synthesis. Full article
(This article belongs to the Special Issue Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus)
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16 pages, 5243 KiB  
Article
Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells
by Stacia M. Dolliver, Caleb Galbraith and Denys A. Khaperskyy
Viruses 2024, 16(2), 212; https://doi.org/10.3390/v16020212 - 31 Jan 2024
Viewed by 951
Abstract
Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is the inhibition of the integrated stress response—the mechanism through which infected cells arrest translation through the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor [...] Read more.
Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is the inhibition of the integrated stress response—the mechanism through which infected cells arrest translation through the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α). We have recently shown that the human common cold betacoronavirus OC43 actively inhibits eIF2α phosphorylation in response to sodium arsenite, a potent inducer of oxidative stress. In this work, we examined the modulation of integrated stress responses by OC43 and demonstrated that the negative feedback regulator of eIF2α phosphorylation GADD34 is strongly induced in infected cells. However, the upregulation of GADD34 expression induced by OC43 was independent from the activation of the integrated stress response and was not required for the inhibition of eIF2α phosphorylation in virus-infected cells. Our work reveals a complex interplay between the common cold coronavirus and the integrated stress response, in which efficient viral protein synthesis is ensured by the inhibition of eIF2α phosphorylation but the GADD34 negative feedback loop is disrupted. Full article
(This article belongs to the Special Issue Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus)
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21 pages, 4237 KiB  
Article
Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance
by Jamie A. Kelly and Jonathan D. Dinman
Viruses 2023, 15(12), 2296; https://doi.org/10.3390/v15122296 - 23 Nov 2023
Cited by 1 | Viewed by 1427
Abstract
A longstanding paradox in molecular biology has centered on the question of how very long proteins are synthesized, despite numerous measurements indicating that ribosomes spontaneously shift reading frame at rates that should preclude their ability completely translate their mRNAs. Shiftless (SFL; C19orf66) was [...] Read more.
A longstanding paradox in molecular biology has centered on the question of how very long proteins are synthesized, despite numerous measurements indicating that ribosomes spontaneously shift reading frame at rates that should preclude their ability completely translate their mRNAs. Shiftless (SFL; C19orf66) was originally identified as an interferon responsive gene encoding an antiviral protein, indicating that it is part of the innate immune response. This activity is due to its ability to bind ribosomes that have been programmed by viral sequence elements to shift reading frame. Curiously, Shiftless is constitutively expressed at low levels in mammalian cells. This study examines the effects of altering Shiftless homeostasis, revealing how it may be used by higher eukaryotes to identify and remove spontaneously frameshifted ribosomes, resolving the apparent limitation on protein length. Data also indicate that Shiftless plays a novel role in the ribosome-associated quality control program. A model is proposed wherein SFL recognizes and arrests frameshifted ribosomes, and depending on SFL protein concentrations, either leads to removal of frameshifted ribosomes while leaving mRNAs intact, or to mRNA degradation. We propose that SFL be added to the growing pantheon of proteins involved in surveilling translational fidelity and controlling gene expression in higher eukaryotes. Full article
(This article belongs to the Special Issue Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus)
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19 pages, 749 KiB  
Review
Host-like RNA Elements Regulate Virus Translation
by Debjit Khan and Paul L. Fox
Viruses 2024, 16(3), 468; https://doi.org/10.3390/v16030468 - 20 Mar 2024
Viewed by 1065
Abstract
Viruses are obligate, intracellular parasites that co-opt host cell machineries for propagation. Critical among these machineries are those that translate RNA into protein and their mechanisms of control. Most regulatory mechanisms effectuate their activity by targeting sequence or structural features at the RNA [...] Read more.
Viruses are obligate, intracellular parasites that co-opt host cell machineries for propagation. Critical among these machineries are those that translate RNA into protein and their mechanisms of control. Most regulatory mechanisms effectuate their activity by targeting sequence or structural features at the RNA termini, i.e., at the 5′ or 3′ ends, including the untranslated regions (UTRs). Translation of most eukaryotic mRNAs is initiated by 5′ cap-dependent scanning. In contrast, many viruses initiate translation at internal RNA regions at internal ribosome entry sites (IRESs). Eukaryotic mRNAs often contain upstream open reading frames (uORFs) that permit condition-dependent control of downstream major ORFs. To offset genome compression and increase coding capacity, some viruses take advantage of out-of-frame overlapping uORFs (oORFs). Lacking the essential machinery of protein synthesis, for example, ribosomes and other translation factors, all viruses utilize the host apparatus to generate virus protein. In addition, some viruses exhibit RNA elements that bind host regulatory factors that are not essential components of the translation machinery. SARS-CoV-2 is a paradigm example of a virus taking advantage of multiple features of eukaryotic host translation control: the virus mimics the established human GAIT regulatory element and co-opts four host aminoacyl tRNA synthetases to form a stimulatory binding complex. Utilizing discontinuous transcription, the elements are present and identical in all SARS-CoV-2 subgenomic RNAs (and the genomic RNA). Thus, the virus exhibits a post-transcriptional regulon that improves upon analogous eukaryotic regulons, in which a family of functionally related mRNA targets contain elements that are structurally similar but lacking sequence identity. This “thrifty” virus strategy can be exploited against the virus since targeting the element can suppress the expression of all subgenomic RNAs as well as the genomic RNA. Other 3′ end viral elements include 3′-cap-independent translation elements (3′-CITEs) and 3′-tRNA-like structures. Elucidation of virus translation control elements, their binding proteins, and their mechanisms can lead to novel therapeutic approaches to reduce virus replication and pathogenicity. Full article
(This article belongs to the Special Issue Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus)
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14 pages, 948 KiB  
Review
Translational Control of Alphavirus–Host Interactions: Implications in Viral Evolution, Tropism and Antiviral Response
by Iván Ventoso, Juan José Berlanga, René Toribio and Irene Díaz-López
Viruses 2024, 16(2), 205; https://doi.org/10.3390/v16020205 - 30 Jan 2024
Viewed by 831
Abstract
Alphaviruses can replicate in arthropods and in many vertebrate species including humankind, but only in vertebrate cells do infections with these viruses result in a strong inhibition of host translation and transcription. Translation shutoff by alphaviruses is a multifactorial process that involves both [...] Read more.
Alphaviruses can replicate in arthropods and in many vertebrate species including humankind, but only in vertebrate cells do infections with these viruses result in a strong inhibition of host translation and transcription. Translation shutoff by alphaviruses is a multifactorial process that involves both host- and virus-induced mechanisms, and some of them are not completely understood. Alphavirus genomes contain cis-acting elements (RNA structures and dinucleotide composition) and encode protein activities that promote the translational and transcriptional resistance to type I IFN-induced antiviral effectors. Among them, IFIT1, ZAP and PKR have played a relevant role in alphavirus evolution, since they have promoted the emergence of multiple viral evasion mechanisms at the translational level. In this review, we will discuss how the adaptations of alphaviruses to vertebrate hosts likely involved the acquisition of new features in viral mRNAs and proteins to overcome the effect of type I IFN. Full article
(This article belongs to the Special Issue Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus)
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27 pages, 3028 KiB  
Review
The Repurposing of Cellular Proteins during Enterovirus A71 Infection
by Sudeshi M. Abedeera, Jesse Davila-Calderon, Christina Haddad, Barrington Henry, Josephine King, Srinivasa Penumutchu and Blanton S. Tolbert
Viruses 2024, 16(1), 75; https://doi.org/10.3390/v16010075 - 31 Dec 2023
Cited by 1 | Viewed by 3191
Abstract
Viruses pose a great threat to people’s lives. Enterovirus A71 (EV-A71) infects children and infants all over the world with no FDA-approved treatment to date. Understanding the basic mechanisms of viral processes aids in selecting more efficient drug targets and designing more effective [...] Read more.
Viruses pose a great threat to people’s lives. Enterovirus A71 (EV-A71) infects children and infants all over the world with no FDA-approved treatment to date. Understanding the basic mechanisms of viral processes aids in selecting more efficient drug targets and designing more effective antivirals to thwart this virus. The 5′-untranslated region (5′-UTR) of the viral RNA genome is composed of a cloverleaf structure and an internal ribosome entry site (IRES). Cellular proteins that bind to the cloverleaf structure regulate viral RNA synthesis, while those that bind to the IRES also known as IRES trans-acting factors (ITAFs) regulate viral translation. In this review, we survey the cellular proteins currently known to bind the 5′-UTR and influence viral gene expression with emphasis on comparing proteins’ functions and localizations pre- and post-(EV-A71) infection. A comprehensive understanding of how the host cell’s machinery is hijacked and reprogrammed by the virus to facilitate its replication is crucial for developing effective antivirals. Full article
(This article belongs to the Special Issue Viral Strategies and Cellular Countermeasures that Regulate mRNA Access to the Translation Apparatus)
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