Translational termination–reinitiation in RNA viruses

2010 ◽  
Vol 38 (6) ◽  
pp. 1558-1564 ◽  
Author(s):  
Michael L. Powell
Keyword(s):  
Translational Control ◽  
Rna Viruses ◽  
Stop Codon ◽  
Start Codon ◽  
Influenza B ◽  
Control Mechanisms ◽  
Reading Frame ◽  
Initiation Factors ◽  
Positive Strand Rna ◽  
Translational Termination

Viruses utilize a number of translational control mechanisms to regulate the relative expression levels of viral proteins on polycistronic mRNAs. One such mechanism, that of termination-dependent reinitiation, has been described in a number of both negative- and positive-strand RNA viruses. Dicistronic RNAs which exhibit termination–reinitiation typically have a start codon of the 3′-ORF (open reading frame) proximal to the stop codon of the upstream ORF. For example, the segment 7 RNA of influenza B is dicistronic, and the stop codon of the M1 ORF and the start codon of the BM2 ORF overlap in the pentanucleotide UAAUG (the stop codon of M1 is shown in bold and the start codon of BM2 is underlined). Recent evidence has highlighted the potential importance of mRNA–rRNA interactions in reinitiation on caliciviral and influenza B viral RNAs, probably used to tether 40S ribosomal subunits to the RNA after termination in time for initiation factors to be recruited to the AUG of the downstream ORF. The present review summarizes how such interactions regulate reinitiation in an array of RNA viruses, and discusses what is known about reinitiation in viruses that do not rely on apparent mRNA–rRNA interactions.

Translational termination–re-initiation in viral systems

2008 ◽  
Vol 36 (4) ◽  
pp. 717-722 ◽  
Author(s):  
Michael L. Powell ◽  
T. David K. Brown ◽  
Ian Brierley
Keyword(s):  
Translational Control ◽  
Stop Codon ◽  
Short Review ◽  
Start Codon ◽  
Influenza B ◽  
Control Mechanisms ◽  
Viral Mrnas ◽  
Reading Frame ◽  
Translational Termination ◽  
Stop Codon Readthrough

Viruses have evolved a number of translational control mechanisms to regulate the levels of expression of viral proteins on polycistronic mRNAs, including programmed ribosomal frameshifting and stop codon readthrough. More recently, another unusual mechanism has been described, that of termination-dependent re-initiation (also known as stop–start). Here, the AUG start codon of a 3′ ORF (open reading frame) is proximal to the termination codon of a uORF (upstream ORF), and expression of the two ORFs is coupled. For example, segment 7 mRNA of influenza B is bicistronic, and the stop codon of the M1 ORF and the start codon of the BM2 ORF overlap in the pentanucleotide UAAUG (stop codon of M1 is shown in boldface and start codon of BM2 is underlined). This short review aims to provide some insights into how this translational coupling process is regulated within different viral systems and to highlight some of the differences in the mechanism of re-initiation on prokaryotic, eukaryotic and viral mRNAs.

scholarly journals The Evolutionarily Conserved Eukaryotic Arginine Attenuator Peptide Regulates the Movement of Ribosomes That Have Translated It

1998 ◽  
Vol 18 (12) ◽  
pp. 7528-7536 ◽  
Author(s):  
Zhong Wang ◽  
Peng Fang ◽  
Matthew S. Sachs
Keyword(s):  
Translational Control ◽  
Stop Codon ◽  
Firefly Luciferase ◽  
Upstream Open Reading Frame ◽  
Start Codon ◽  
Leader Peptide ◽  
Translation System ◽  
Coding Region ◽  
Reading Frame ◽  
Arginine Attenuator Peptide

ABSTRACT Translation of the upstream open reading frame (uORF) in the 5′ leader segment of the Neurospora crassa arg-2 mRNA causes reduced initiation at a downstream start codon when arginine is plentiful. Previous examination of this translational attenuation mechanism using a primer-extension inhibition (toeprint) assay in a homologous N. crassa cell-free translation system showed that arginine causes ribosomes to stall at the uORF termination codon. This stalling apparently regulates translation by preventing trailing scanning ribosomes from reaching the downstream start codon. Here we provide evidence that neither the distance between the uORF stop codon and the downstream initiation codon nor the nature of the stop codon used to terminate translation of the uORF-encoded arginine attenuator peptide (AAP) is important for regulation. Furthermore, translation of the AAP coding region regulates synthesis of the firefly luciferase polypeptide when it is fused directly at the N terminus of that polypeptide. In this case, the elongating ribosome stalls in response to Arg soon after it translates the AAP coding region. Regulation by this eukaryotic leader peptide thus appears to be exerted through a novel mechanism ofcis-acting translational control.

scholarly journals A UV-Induced Mutation in Neurospora That Affects Translational Regulation in Response to Arginine

Genetics ◽  
1996 ◽  
Vol 142 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Michael Freitag ◽  
Nelima Dighde ◽  
Matthew S Sachs
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Fusion Gene ◽  
Mrna Translation ◽  
Small Subunit ◽  
Upstream Open Reading Frame ◽  
Control Mechanisms ◽  
Carbamoyl Phosphate ◽  
Altered Expression ◽  
Reading Frame

The Neurospora crmsu arg-2 gene encodes the small subunit of arginine-specific carbamoyl phosphate synthetase. The levels of arg-2 mRNA and mRNA translation are negatively regulated by arginine. An upstream open reading frame (uORF) in the transcript’s 5′ region has been implicated in arginine-specific control. An arg-2-hph fusion gene encoding hygromycin phosphotransferase conferred arginine-regulated resistance to hygromycin when introduced into N. crassa. We used an arg-2-hph strain to select for UV-induced mutants that grew in the presence of hygromycin and arginine, and we isolated 46 mutants that had either of two phenotypes. One phenotype indicated altered expression of both arg-2-hph and urg-2 genes; the other, altered expression of urg-2-hph but not arg-2. One of the latter mutations, which was genetically closely linked to arg-2-hph, was recovered from the 5′ region of the arg-2-hph gene using PCR. Sequence analyses and transformation experiments revealed a mutation at uORF codon 12 (Asp to Asn) that abrogated negative regulation. Examination of the distribution of ribosomes on arg-2-hph transcripts showed that loss of regulation had a translational component, indicating the uORF sequence was important for Arg-specific translational control. Comparisons with other uORFS suggest common elements in translational control mechanisms.

scholarly journals Molecular Mechanisms for Norovirus Genome Replication

2021 ◽  
Author(s):  
Muhammad Amir Yunus
Keyword(s):  
Molecular Mechanisms ◽  
Rna Viruses ◽  
Open Reading Frames ◽  
Productive Infection ◽  
Genome Replication ◽  
Subgenomic Rna ◽  
Positive Strand ◽  
Reading Frame ◽  
Viral Genome Replication ◽  
Positive Strand Rna

The genomes of positive strand RNA viruses often contain more than one open reading frame. Some of these viruses have evolved novel mechanisms to regulate the synthesis of the other open reading frames that in some cases involved the production of a subgenomic RNA or RNAs. Very often, the presence of the subgenomic RNA is used as indicator for active viral genome replication. Norovirus, a major cause for gastroenteritis as well as with all other caliciviruses follow a typical positive strand RNA viruses genome replication strategy. In addition, noroviruses also produce a subgenomic RNA during their replication in infected cells. Efficient and adequate synthesis of norovirus subgenomic RNA is crucial for successful viral replication and productive infection leading to the generation of infectious viral progeny. This chapter will dissect the significant findings on mechanisms involved in norovirus genome replication as well as focusing on subgenomic RNA production.

scholarly journals Determination of host proteins composing the microenvironment of coronavirus replicase complexes by proximity-labeling

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Philip V'kovski ◽  
Markus Gerber ◽  
Jenna Kelly ◽  
Stephanie Pfaender ◽  
Nadine Ebert ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Rna Synthesis ◽  
Rna Viruses ◽  
Host Factors ◽  
Viral Rna ◽  
Host Proteins ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Starting Point ◽  
Positive Strand Rna

Positive-sense RNA viruses hijack intracellular membranes that provide niches for viral RNA synthesis and a platform for interactions with host proteins. However, little is known about host factors at the interface between replicase complexes and the host cytoplasm. We engineered a biotin ligase into a coronaviral replication/transcription complex (RTC) and identified >500 host proteins constituting the RTC microenvironment. siRNA-silencing of each RTC-proximal host factor demonstrated importance of vesicular trafficking pathways, ubiquitin-dependent and autophagy-related processes, and translation initiation factors. Notably, detection of translation initiation factors at the RTC was instrumental to visualize and demonstrate active translation proximal to replication complexes of several coronaviruses. Collectively, we establish a spatial link between viral RNA synthesis and diverse host factors of unprecedented breadth. Our data may serve as a paradigm for other positive-strand RNA viruses and provide a starting point for a comprehensive analysis of critical virus-host interactions that represent targets for therapeutic intervention.

scholarly journals Upregulation of eIF4E, but not other translation initiation factors, in dendritic spines during memory consolidation

2021 ◽  
Author(s):  
Sofya Gindina ◽  
Benjamin Botsford ◽  
Kiriana Cowansage ◽  
Joseph LeDoux ◽  
Eric Klann ◽  
...  
Keyword(s):  
Pavlovian Conditioning ◽  
Translation Initiation ◽  
Dendritic Spines ◽  
Translational Control ◽  
Protein Targeting ◽  
Specific Protein ◽  
Control Mechanisms ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Transmission Electron

AbstractLocal translation can provide a rapid, spatially targeted supply of new proteins in distal dendrites to support synaptic changes that underlie learning. Learning and memory are especially sensitive to manipulations of translational control mechanisms, particularly those that target the initiation step, and translation initiation at synapses could be a means of maintaining synapse specificity during plasticity. Initiation predominantly occurs via recruitment of ribosomes to the 5’ mRNA cap by complexes of eukaryotic initiation factors (eIFs), and the interaction between eIF4E and eIF4G1 is a particularly important target of translational control pathways. Pharmacological inhibition of eIF4E-eIF4G1 binding impairs consolidation of memory for aversive Pavlovian conditioning as well as the accompanying increase in polyribosomes in the heads of dendritic spines in the lateral amygdala (LA). This is consistent with a role for initiation at synapses in memory formation, but whether eIFs are even present near synapses is unknown. To determine whether dendritic spines contain eIFs and whether eIF distribution is affected by learning, we combined immunolabeling with serial section transmission electron microscopy (ssTEM) volume reconstructions of LA dendrites after Pavlovian conditioning. Labeling for eIF4E, eIF4G1, and eIF2α – another key target of regulation – occurred in roughly half of dendritic spines, but learning effects were only found for eIF4E, which was upregulated in the heads of dendritic spines. Our results support the possibility of regulated translation initiation as a means of synapse-specific protein targeting during learning and are consistent with the model of eIF4E availability as a central point of control.

scholarly journals Bioinformatic Prediction of an tRNASec Gene Nested inside an Elongation Factor SelB Gene in Alphaproteobacteria

2021 ◽  
Vol 22 (9) ◽  
pp. 4605
Author(s):  
Takahito Mukai
Keyword(s):  
Insertion Sequence ◽  
Trna Gene ◽  
Stop Codon ◽  
Elongation Factor ◽  
Selenium Deficiency ◽  
Open Reading Frame ◽  
Start Codon ◽  
Sequence Element ◽  
Reading Frame ◽  
Insertion Sequence Element

In bacteria, selenocysteine (Sec) is incorporated into proteins via the recoding of a particular codon, the UGA stop codon in most cases. Sec-tRNASec is delivered to the ribosome by the Sec-dedicated elongation factor SelB that also recognizes a Sec-insertion sequence element following the codon on the mRNA. Since the excess of SelB may lead to sequestration of Sec-tRNASec under selenium deficiency or oxidative stress, the expression levels of SelB and tRNASec should be regulated. In this bioinformatic study, I analyzed the Rhizobiales SelB species because they were annotated to have a non-canonical C-terminal extension. I found that the open reading frame (ORF) of diverse Alphaproteobacteria selB genes includes an entire tRNASec sequence (selC) and overlaps with the start codon of the downstream ORF. A remnant tRNASec sequence was found in the Sinorhizobium melilotiselB genes whose products have a shorter C-terminal extension. Similar overlapping traits were found in Gammaproteobacteria and Nitrospirae. I hypothesized that once the tRNASec moiety is folded and processed, the expression of the full-length SelB may be repressed. This is the first report on a nested tRNA gene inside a protein ORF in bacteria.

scholarly journals Quantitative global studies reveal differential translational control by start codon context across the fungal kingdom

2020 ◽  
Vol 48 (5) ◽  
pp. 2312-2331 ◽  
Author(s):  
Edward W J Wallace ◽  
Corinne Maufrais ◽  
Jade Sales-Lee ◽  
Laura R Tuck ◽  
Luciana de Oliveira ◽  
...  
Keyword(s):  
Translational Control ◽  
Fungal Species ◽  
Open Reading Frames ◽  
Start Codon ◽  
Sequence Context ◽  
Translational Initiation ◽  
Kozak Sequence ◽  
Initiation Factors ◽  
Kozak Context ◽  
Codon Context

Abstract Eukaryotic protein synthesis generally initiates at a start codon defined by an AUG and its surrounding Kozak sequence context, but the quantitative importance of this context in different species is unclear. We tested this concept in two pathogenic Cryptococcus yeast species by genome-wide mapping of translation and of mRNA 5′ and 3′ ends. We observed thousands of AUG-initiated upstream open reading frames (uORFs) that are a major contributor to translation repression. uORF use depends on the Kozak sequence context of its start codon, and uORFs with strong contexts promote nonsense-mediated mRNA decay. Transcript leaders in Cryptococcus and other fungi are substantially longer and more AUG-dense than in Saccharomyces. Numerous Cryptococcus mRNAs encode predicted dual-localized proteins, including many aminoacyl-tRNA synthetases, in which a leaky AUG start codon is followed by a strong Kozak context in-frame AUG, separated by mitochondrial-targeting sequence. Analysis of other fungal species shows that such dual-localization is also predicted to be common in the ascomycete mould, Neurospora crassa. Kozak-controlled regulation is correlated with insertions in translational initiation factors in fidelity-determining regions that contact the initiator tRNA. Thus, start codon context is a signal that quantitatively programs both the expression and the structures of proteins in diverse fungi.

scholarly journals uORFlight: a vehicle toward uORF-mediated translational regulation mechanisms in eukaryotes

Database ◽  
2020 ◽  
Vol 2020 ◽  
Author(s):  
Ruixia Niu ◽  
Yulu Zhou ◽  
Yu Zhang ◽  
Rui Mou ◽  
Zhijuan Tang ◽  
...  
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Homo Sapiens ◽  
Phenotypic Diversity ◽  
Relevant Literature ◽  
Open Reading Frames ◽  
Control Element ◽  
Control Mechanisms ◽  
Reading Frame ◽  
Eukaryotic Mrnas

Abstract Upstream open reading frames (uORFs) are prevalent in eukaryotic mRNAs. They act as a translational control element for precisely tuning the expression of the downstream major open reading frame (mORF). uORF variation has been clearly associated with several human diseases. In contrast, natural uORF variants in plants have not ever been identified or linked with any phenotypic changes. The paucity of such evidence encouraged us to generate this database-uORFlight (http://uorflight.whu.edu.cn). It facilitates the exploration of uORF variation among different splicing models of Arabidopsis and rice genes. Most importantly, users can evaluate uORF frequency among different accessions at the population scale and find out the causal single nucleotide polymorphism (SNP) or insertion/deletion (INDEL), which can be associated with phenotypic variation through database mining or simple experiments. Such information will help to make hypothesis of uORF function in plant development or adaption to changing environments on the basis of the cognate mORF function. This database also curates plant uORF relevant literature into distinct groups. To be broadly interesting, our database expands uORF annotation into more species of fungus (Botrytis cinerea and Saccharomyces cerevisiae), plant (Brassica napus, Glycine max, Gossypium raimondii, Medicago truncatula, Solanum lycopersicum, Solanum tuberosum, Triticum aestivum and Zea mays), metazoan (Caenorhabditis elegans and Drosophila melanogaster) and vertebrate (Homo sapiens, Mus musculus and Danio rerio). Therefore, uORFlight will light up the runway toward how uORF genetic variation determines phenotypic diversity and advance our understanding of translational control mechanisms in eukaryotes.

scholarly journals Diversity of the population of Tick-borne encephalitis virus infecting Ixodes ricinus ticks in an endemic area of central Switzerland (Canton Bern)

2006 ◽  
Vol 87 (8) ◽  
pp. 2235-2241 ◽  
Author(s):  
Simona Casati ◽  
Lise Gern ◽  
Jean-Claude Piffaretti
Keyword(s):  
Ixodes Ricinus ◽  
Encephalitis Virus ◽  
Start Codon ◽  
Nucleotide Sequence Analysis ◽  
Natural Focus ◽  
Reading Frame ◽  
Tick Borne Encephalitis ◽  
Central Switzerland ◽  
Tick Borne Encephalitis Virus ◽  
Positive Strand Rna

Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, has a positive-strand RNA genome containing a single open reading frame flanked by non-coding regions (NCRs). Ixodes ricinus ticks (n=307) were collected from vegetation in a natural TBEV focus in Belp, Switzerland. The presence and identity of the virus were determined by nested RT-PCR followed by sequencing of the 5′-terminal region that comprises the 5′ NCR and the capsid-encoding region (C). The presence of the western European TBEV subtype (W-TBEV) genome was detected in 14.3 % of the ticks. Nucleotide sequence analysis revealed a high variability of 55.5 %. In particular, four DNA fragments (CS ‘A’, CS ‘B’, the folding-stem structure and the start codon) showed substantial heterogeneity, which has the potential of compromising replication, translation and packaging of the viral genome. This variability may reflect a viral strategy to select the fittest RNA molecule to produce a viral infection in the different vertebrate hosts that may be encountered by the ticks. It may also indicate a possible ancient introduction of TBEV to the Belp site. In addition, it may contribute to explaining the annual low incidence of tick-borne encephalitis in the natural focus of Belp, despite the high prevalence of TBEV genomes in ticks.

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