Influenza virus mRNAs bear a short capped oligonucleotide sequence at their 5' ends derived from the host cell pre-mRNAs by a "cap-snatching" mechanism, followed immediately by a common viral sequence.
At their 3' ends, they contain a poly A tail. Academic Press Inc.. Advances in Virus Research. Academic Press Inc. Advances in Virus Research, vol. In Advances in Virus Research. Subverting mechanistic target of rapamycin complex 1 mTORC1 signaling to control translation in virus-infected cells. Nutrient, energy, amino acid aa , or oxygen insufficiency physiological stress all repress mTORC1 through discrete effectors. Signaling through mTORC1 allows swift changes in translational output in response to differing environmental and physiological inputs by controlling initiation and elongation.
Initiation is stimulated by phosphorylating and inactivating 4E-BP translational repressor family members e. The impact of mTORC1 activation on translation initiation and elongation is shown, as are viral factors that stimulate green and repress red the indicated cellular effectors. SV40, simian virus 40; calici, calicivirus; noro, norovirus; entero, enterovirus; rhino, rhinovirus.
Unlike acute infections, different viral lifestyles necessitate specialized interactions with host cells. Some, like herpesviruses, establish life-long latency where virus reproduction is suppressed in specific cell types. Periodically, latent infections reactivate and reenter the productive growth cycle, which allows virus reproduction and spread to new hosts.
Reactivation is influenced by host defenses and physiological stress responses induced by disrupting homeostasis.
In contrast, HSV-1 establishes latency in neurons, where inactivation of the translation repressor 4E-BP1 by persistent mTORC1-dependent phosphorylation in response to neurotrophic factor sufficiency promotes latency Camarena et al. Whereas the mRNA targets remain unknown, monitoring host mRNA translation can gauge homeostasis in long-term, latent infections to support latency or trigger virus reproduction. The absolute dependence of viruses on host ribosomes for protein production demands tactics to ensure their recruitment to viral mRNAs.
Shut-off mechanisms suppress host cap-dependent translation and effectively remodel the translation-ready mRNA pool. Ribosome recruitment, however, cannot be left to chance given its vital role in virus reproduction. When eIF4F becomes limiting, cap-dependent translation is restricted. Subsequently, IRESs have been identified in many virus genomes including retroviruses like the human immunodeficiency virus HIV -1, which uses an IRES to express the Gag protein late in infection when cap-dependent initiation is impaired Brasey et al.
Although they share the general capacity to direct initiation when canonical cap-dependent translation mechanisms are suppressed, different IRESs are structurally distinct and show varied functional requirements for eukaryotic initiation factors to load 40S subunits Table 1 Jan et al.
A number of different strategies that are used to commandeer control over the translational machinery by dominating host cell signaling pathways reviewed by Proud have been defined Fig.
Instead of manipulating translation factor abundance, vaccinia virus VACV and ASFV, which replicate in the cytoplasm, increase the effective local concentration of eIFs by sequestering them within discrete replication compartments Katsafanas and Moss ; Walsh et al. This nonlinear ribosome translocation, called ribosome shunting, is used to produce heat shock proteins in uninfected cells subjected to stress and involves base-pairing with 18S rRNA and mRNA cis elements Yueh and Schneider In comparison with initiation, our understanding of whether viruses control translation elongation is much less developed.
Elongation factors are repurposed to function in RNA replication by many bacterial and plant viruses Takeshita and Tomita ; Li et al. Finally, expression of prokaryote-like elongation factors encoded by the giant mimivirus changes in response to nutrient availability Silva et al.
Viruses depend on host ribosomes regardless of whether they use cap-dependent or noncanonical translation initiation mechanisms. Whereas ribosome loading onto mRNAs in eukaryotes is typically reliant on initiation factors, a more direct role for the ribosome itself in regulating translation is emerging. Through discrete functions and modifications of specific protein subunits, ribosomes themselves selectively control viral and host mRNA translation Fig.
Indeed, significant insight into how ribosome composition impacts translation has been gleaned from viral models. Unexpectedly, eS25 is also important for ribosomal shunting, suggesting a potential shared mechanism between these two noncanonical initiation strategies Hertz et al. Consistent with this, adenosine-rich leaders enhance translation in plants where the RACK1 loop region is naturally negatively charged, suggesting that poxviruses have exploited a conserved mechanism to preferentially translate certain capped mRNAs Jha et al.
Ribosomal proteins are required for translation of viral RNAs. Figure based on data in Ben-Shem et al. Both intrasubunit left and solvent surfaces right are shown. These viruses produce capped, polyadenylated transcripts like cellular mRNAs, yet viral mRNAs are efficiently translated by an unknown mechanism even though host protein synthesis is suppressed. Dengue virus NS1 protein associates with ribosomal proteins from both the small and large subunits Cervantes-Salazar et al.
Whether they play a direct role in translation is not known; however, knockdown of eL18 reduced viral titers by one log Cervantes-Salazar et al. They are also required for DENV protein expression early in infection before replication Campos et al. Recent progress using genome-wide, high-throughput technologies has reshaped our understanding of translational control.
Besides uncovering new principles and mechanisms, these methodologies provide a global, unbiased view of the infected cell translational landscape. Virus genomes contain densely packed coding information that is often accessed via specialized translation strategies. Ribosome profiling RP sequencing ribosome-protected fragments allows global translation analysis and direct, experimental annotation of translation events Ingolia et al.
It couples classic nuclease footprinting with deep sequencing and indicates ribosome position with single-nucleotide resolution. Besides identifying precise boundaries of translated regions, the three-nucleotide footprint periodicity reflecting translocation steps indicates which reading frame is being decoded.
Translational start sites can be mapped using conditions that preferentially capture initiating ribosomes Ingolia et al. These approaches allow transcriptome annotation in areas translated in two overlapping reading frames, a frequent occurrence in virus genomes. Ribosome pause sites were identified in coronavirus A59, but their significance remains unknown Irigoyen et al. RP also accurately measures virus gene expression kinetics throughout infection. Application of genome-wide technologies to investigate host shut-off has clarified our understanding of underlying mechanisms and their relative contribution to impairing host translation.
Although many viruses encode endoribonucleases, their specificity varies. Finally, transcription termination of cellular, but not viral, genes was unexpectedly disrupted by HSV-1, broadening our perception of the range of processes that potentially impact host shut-off Rutkowski et al.
The notion of host shut-off as a blunt, indiscriminate instrument to halt host gene expression has been revised by genome-wide studies. While host shut-off curtails host antiviral responses, impairing overall cellular protein production could adversely impact virus reproduction.
Precisely how the infected cell translational landscape impacts viral propagation is just beginning to be shown. Continuous oxidative phosphorylation is important for viral propagation in both cases. Discrimination among targets during host shut-off is likely greater than previously anticipated.
A different tactic was observed in HCMV-infected cells, where host protein synthesis is not globally suppressed, so it was assumed that host protein synthesis proceeded uninterrupted. Using polysome profiling McKinney et al. This translational reprogramming is dependent on mTOR activation, and expression of the virus-encoded UL38 mTORC1 activator in uninfected cells in part recapitulates these translational alterations. These examples show how genome-wide methodologies have revised our understanding of how viruses facilitate selective translation of host mRNAs needed for infection.
Coding genes are biased in the relative frequencies of codons specifying the same amino acid. In some organisms, codon bias reflects optimization for specific tRNAs and elongation rates Gingold and Pilpel Some synonymous codon pairs are used more or less frequently than expected, a phenomenon termed codon pair bias Yarus and Folley that may influence translation efficiency Tats et al. Indeed, altering codon pair frequencies reduced virus replication without affecting protein sequence Coleman et al.
As the resulting virus attenuation depends on numerous mutations, reversion is markedly reduced, providing an exciting opportunity for live-attenuated vaccine development Wimmer et al. However, in addition to codon pair bias and translation efficiency, other viral genome features, such as suppression of CpG and UpA dinucleotide frequencies, and variations in the propensity to mutate, which generate differential access to protein sequence space can contribute to the reduced replication phenotypes Lauring et al.
Therefore, precisely how codon usage impacts virus attenuation and the relative contribution of translation repression requires further investigation. By far the most prevalent internal modified base on mRNAs is a methyl group on the N 6 position of adenosine m 6 A Yue et al. Advances in genome-wide m 6 A mapping on mRNAs and identification of the m 6 A machinery fueled investigations into how this modification influences virus gene expression.
Because these viruses replicate exclusively within the cytoplasm, the m 6 A methyltransferase machinery is apparently active in this compartment. Although the mechanism s through which m 6 A act remain unclear, virus model systems could help clarify how m 6 A controls gene expression. To maximize their genome coding capacity, viruses use multiple strategies, including leaky scanning, polyproteins, reinitiation, translational bypass hopping , readthrough of stop codons, and programmed ribosomal frameshifting PRF Fig.
Strategies to maximize viral genome coding capacity. See the text for a detailed description. A 7-nucleotide slippery site sequence, the spacer region, and structural barriers that stall the ribosome, impact PRF efficiency. Retroviruses generate high levels of Gag and low levels of a Gag-Pol fusion from the same transcript via PRF or by readthrough of a stop codon Hung et al.
Perturbations in this ratio affect viral assembly, RNA packaging and maturation. Mimiviruses use both PRF and readthrough to encode a polypeptide chain release factor homolog Jeudy et al. Alternatively, some DNA and RNA viruses express multiple proteins from a polycistronic transcript using a reinitiation mechanism ribosomal termination-reinitiation or stop—start Wise et al.
To produce a single polypeptide from two discrete ORFs, bacteriophage T4 relies on a translational bypass or ribosome hopping. This hopping mechanism likely requires a compact structure in the gap region to bring together the two glycine codons in the translating ribosome and to prevent the release factor from entering the A site Todd and Walter Viruses modulate downstream ORF expression by leaky scanning, which transpires when the 40S subunit scans past an upstream AUG in a weak or moderate Kozak consensus sequence context before initiating at a downstream AUG Wise et al.
For example, members of the triple gene block TGB superfamily of movement proteins encoded by many plant viruses, which allow cell-to-cell movement and vascular spread needed to cause disease, are often produced by leaky scanning along a single mRNA transcript that contains overlapping ORFs Lezzhov et al.
During cap-dependent initiation, the start codon is recognized when the Met-tRNA i Met base-pairs with the start codon. Alphaviruses use a stable RNA stem-loop structure located within their coding sequence to stall the ribosome on the initiation codon of the 26S mRNA when ternary complex levels are low and rely on an as-yet-unknown initiation mechanism to avoid a major antiviral defense Toribio et al.
Once the 60S subunit joins the stalled ribosome, it is released to translate the viral RNA. The categorical requirement for host ribosomes to translate viral mRNAs continues to provide powerful opportunities to investigate how protein synthesis is regulated. Indeed, exploiting virus model systems has defined fundamental features of the cellular protein synthesis machinery, how it is regulated in uninfected cells, and how it responds to physiological stress.
Insights gleaned from investigating viral mechanisms have implications for understanding how different forms of acute and chronic stress impact translational control of gene expression in health and disease. As virus reproduction is dependent on protein synthesis, the identity and roles of leading molecular actors during infection have been revealed.
RNA structural elements and modifications detected by host sentinel molecules coordinate powerful antiviral responses intended to restrict virus access to the translational apparatus. Included among these are virus-encoded functions that counter host dsRNA-dependent, antiviral responses. However, impaired cell-intrinsic immune responses in cancer cells support preferential virus reproduction and spread through tumor tissue.
This new class of biological therapeutics for cancer was an unexpected outgrowth of understanding and manipulating a translational control mechanism in virus-infected cells. New fundamental mechanisms of initiation and regulation have been revealed. In particular, roles for RNA modifications and the ribosome itself in regulating translation have emerged with discrete ribosomal proteins selectively controlling translation. Furthermore, application of genome-wide methodologies has revealed surprising insights into how host shut-off is achieved and how viruses that do not impair host protein synthesis globally impact the host translational landscape.
While the underlying mechanisms remain unknown, viral systems continue to be instrumental in delineating how ribosomes differentially recruit or exclude messages and how discrete modifications of ribosomes and mRNAs comprehensively shape translation in response to physiological and environmental stress. Additional Perspectives on Translation Mechanisms and Control available at www. Thompson 2 , Michael B.
Previous Section Next Section. Host Defenses and Antiviral Immunity While hijacking ribosomes enables virus protein production, it also is a vulnerability exploited by the host. Figure 1. Viral Tactics to Counter Host Defenses Viruses have acquired countermeasures that neutralize host dsRNA-activated defenses or allow their replication despite them.
Remodeling Host mRNA Translation in Infected Cells By interfering with host translation, which overwhelmingly is cap-dependent, viruses antagonize host defenses. Figure 2.
Figure 3. Harnessing Stress Responses to Control Viral Persistence Unlike acute infections, different viral lifestyles necessitate specialized interactions with host cells. View this table: In this window In a new window. Table 1. Major types of IRESs.
Controlling Elongation In comparison with initiation, our understanding of whether viruses control translation elongation is much less developed. Ribosomal Proteins Control Translation in Virus-Infected Cells Through discrete functions and modifications of specific protein subunits, ribosomes themselves selectively control viral and host mRNA translation Fig.
Figure 4. Genome Annotation Virus genomes contain densely packed coding information that is often accessed via specialized translation strategies.
Host Shut-Off Application of genome-wide technologies to investigate host shut-off has clarified our understanding of underlying mechanisms and their relative contribution to impairing host translation. Infected Cell Translational Landscape The notion of host shut-off as a blunt, indiscriminate instrument to halt host gene expression has been revised by genome-wide studies. Synthetic Genome Recoding Coding genes are biased in the relative frequencies of codons specifying the same amino acid.
Figure 5. Ribosome Stalling During cap-dependent initiation, the start codon is recognized when the Met-tRNA i Met base-pairs with the start codon. Previous Section. Abernathy E , Glaunsinger B. Emerging roles for RNA degradation in viral replication and antiviral defense.
Virology — : — Google Scholar. Viral nucleases induce an mRNA degradation-transcription feedback loop in mammalian cells. Cell Host Microbe 18 : — CrossRef Medline Google Scholar. The analysis of translation-related gene set boosts debates around origin and evolution of mimiviruses. PLoS Genet 13 : e The stress granule component TIA-1 binds tick-borne encephalitis virus RNA and is recruited to peri-nuclear sites of viral replication to inhibit viral translation.
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