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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: closed (31 May 2024) | Viewed by 25321

Special Issue Editor

Dr. Christopher Hellen

E-Mail Website
Guest Editor
Department of 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 Issues, Collections and Topics in MDPI journals

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

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Keywords

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

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Related Special Issue

Published Papers (9 papers)

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Research

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31 pages, 115227 KiB  
Article
Translation of Overlapping Open Reading Frames Promoted by Type 2 IRESs in Avian Calicivirus Genomes
by Yani Arhab, Tatyana V. Pestova and Christopher U. T. Hellen
Viruses 2024, 16(9), 1413; https://doi.org/10.3390/v16091413 - 4 Sep 2024
Viewed by 1816
Abstract
Caliciviruses have positive-sense RNA genomes, typically with short 5′-untranslated regions (5′UTRs) that precede the long open reading frame 1 (ORF1). Exceptionally, some avian caliciviruses have long 5′UTRs containing a picornavirus-like internal ribosomal entry site (IRES), which was likely acquired by horizontal gene transfer. [...] Read more.
Caliciviruses have positive-sense RNA genomes, typically with short 5′-untranslated regions (5′UTRs) that precede the long open reading frame 1 (ORF1). Exceptionally, some avian caliciviruses have long 5′UTRs containing a picornavirus-like internal ribosomal entry site (IRES), which was likely acquired by horizontal gene transfer. Here, we identified numerous additional avian calicivirus genomes with IRESs, predominantly type 2, and determined that many of these genomes contain a ~200–300 codon-long ORF (designated ORF1*) that overlaps the 5′-terminal region of ORF1. The activity of representative type 2 IRESs from grey teal calicivirus (GTCV) and Caliciviridae sp. isolate yc-13 (RaCV1) was confirmed by in vitro translation. Toeprinting showed that in cell-free extracts and in vitro reconstituted reactions, ribosomal initiation complexes assembled on the ORF1* initiation codon and at one or two AUG codons in ORF1 at the 3′-border and/or downstream of the IRES. Initiation at all three sites required eIF4A and eIF4G, which bound to a conserved region of the IRES; initiation on the ORF1* and principal ORF1 initiation codons involved eIF1/eIF1A-dependent scanning from the IRES’s 3′-border. Initiation on these IRESs was enhanced by the IRES trans-acting factors (ITAFs) Ebp1/ITAF45, which bound to the apical subdomain Id of the IRES, and PTB (GTCV) or PCBP2 (RaCV1). 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, 2163 KiB  
Article
Tanapox Virus and Yaba Monkey Tumor Virus K3 Orthologs Inhibit Primate Protein Kinase R in a Species-Specific Fashion
by Dewi Megawati, Jeannine N. Stroup, Chorong Park, Taylor Clarkson, Loubna Tazi, Greg Brennan and Stefan Rothenburg
Viruses 2024, 16(7), 1095; https://doi.org/10.3390/v16071095 - 8 Jul 2024
Viewed by 1615
Abstract
Yaba monkey tumor virus (YMTV) and Tanapox virus (TPV) are members of the Yatapoxvirus genus and can infect humans and other primates. Despite the threat posed by yatapoxviruses, the factors determining their host range are poorly understood. In this study, we analyzed the [...] Read more.
Yaba monkey tumor virus (YMTV) and Tanapox virus (TPV) are members of the Yatapoxvirus genus and can infect humans and other primates. Despite the threat posed by yatapoxviruses, the factors determining their host range are poorly understood. In this study, we analyzed the ability of YMTV and TPV orthologs of vaccinia virus K3 (called 012 in YMTV and TPV), which share 75% amino acid identity with one another, to inhibit PKR from 15 different primate species. We first used a luciferase-based reporter, and found that YMTV and TPV K3 orthologs inhibited PKR in a species-specific manner and showed distinct PKR inhibition profiles. TPV 012 inhibited PKR from 11 primates, including humans, substantially better than YMTV 012. In contrast, both K3 orthologs inhibited the other four primate PKRs comparably well. Using YMTV 012 and TPV 012 hybrids, we mapped the region responsible for the differential PKR inhibition to the C- terminus of the K3 orthologs. Next, we generated chimeric vaccinia virus strains to investigate whether TPV K3 and YMTV K3 orthologs could rescue the replication of a vaccinia virus strain that lacks PKR inhibitors K3L and E3L. Virus replication in primate-derived cells generally correlated with the patterns observed in the luciferase-based assay. Together, these observations demonstrate that yatapoxvirus K3 orthologs have distinct PKR inhibition profiles and inhibit PKR in a species-specific manner, which may contribute to the differential susceptibility of primate species to yatapoxvirus infections. 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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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 - 28 Apr 2024
Viewed by 2451
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
Cited by 4 | Viewed by 2051
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 4 | Viewed by 2293
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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Review

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17 pages, 1141 KiB  
Review
Translation Inhibition Mediated by Interferon-Stimulated Genes during Viral Infections
by Alexandria Smart, Orian Gilmer and Neva Caliskan
Viruses 2024, 16(7), 1097; https://doi.org/10.3390/v16071097 - 8 Jul 2024
Viewed by 1718
Abstract
Viruses often pose a significant threat to the host through the exploitation of cellular machineries for their own benefit. In the context of immune responses, myriad host factors are deployed to target viral RNAs and inhibit viral protein translation, ultimately hampering viral replication. [...] Read more.
Viruses often pose a significant threat to the host through the exploitation of cellular machineries for their own benefit. In the context of immune responses, myriad host factors are deployed to target viral RNAs and inhibit viral protein translation, ultimately hampering viral replication. Understanding how “non-self” RNAs interact with the host translation machinery and trigger immune responses would help in the development of treatment strategies for viral infections. In this review, we explore how interferon-stimulated gene products interact with viral RNA and the translation machinery in order to induce either global or targeted translation inhibition. 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
Cited by 2 | Viewed by 3170
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
Cited by 3 | Viewed by 2060
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 4490
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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