scholarly journals Norovirus-mediated modification of the translational landscape via virus and host-induced cleavage of translation initiation factors

2016 ◽  
Author(s):  
Edward Emmott ◽  
Frederic Sorgeloos ◽  
Sarah L. Caddy ◽  
Surender Vashist ◽  
Stanislav Sosnovtsev ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Host Response ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Innate Response ◽  
Viral Protease ◽  
Viral Protein Synthesis ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Covalently Linked

SummaryNoroviruses produce viral RNAs lacking a 5’ cap structure and instead use a virus-encoded VPg protein covalently linked to viral RNA to interact with translation initiation factors and drive viral protein synthesis. Norovirus infection results in the induction of the innate response leading to interferon stimulated gene (ISG) transcription. However the translation of the induced ISG mRNAs is suppressed. Using a novel mass spectrometry approach we demonstrate that diminished host mRNA translation correlates with changes to the composition of the eukaryotic initiation factor complex. The suppression of host ISG translation correlates with the activity of the viral protease (NS6) and the activation of cellular caspases leading to the establishment of an apoptotic environment. These results indicate that noroviruses exploit the differences between viral VPg-dependent and cellular cap-dependent translation in order to diminish the host response to infection.

scholarly journals Uncoupling Stress Granule Assembly and Translation Initiation Inhibition

2009 ◽  
Vol 20 (11) ◽  
pp. 2673-2683 ◽  
Author(s):  
Sophie Mokas ◽  
John R. Mills ◽  
Cristina Garreau ◽  
Marie-Josée Fournier ◽  
Francis Robert ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Binding Protein ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Ribosomal Subunits ◽  
Initiation Factors ◽  
Eif2α Phosphorylation ◽  
Translation Initiation Factors ◽  
Dependent Pathway ◽  
Regulatory Sites

Cytoplasmic stress granules (SGs) are specialized regulatory sites of mRNA translation that form under different stress conditions known to inhibit translation initiation. The formation of SG occurs via two pathways; the eukaryotic initiation factor (eIF) 2α phosphorylation-dependent pathway mediated by stress and the eIF2α phosphorylation-independent pathway mediated by inactivation of the translation initiation factors eIF4A and eIF4G. In this study, we investigated the effects of targeting different translation initiation factors and steps in SG formation in HeLa cells. By depleting eIF2α, we demonstrate that reduced levels of the eIF2.GTP.Met-tRNAiMet ternary translation initiation complexes is sufficient to induce SGs. Likewise, reduced levels of eIF4B, eIF4H, or polyA-binding protein, also trigger SG formation. In contrast, depletion of the cap-binding protein eIF4E or preventing its assembly into eIF4F results in modest SG formation. Intriguingly, interfering with the last step of translation initiation by blocking the recruitment of 60S ribosome either with 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamideis or through depletion of the large ribosomal subunits protein L28 does not induce SG assembly. Our study identifies translation initiation steps and factors involved in SG formation as well as those that can be targeted without induction of SGs.

Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F

1990 ◽  
Vol 10 (3) ◽  
pp. 1134-1144 ◽  
Author(s):  
F Rozen ◽  
I Edery ◽  
K Meerovitch ◽  
T E Dever ◽  
W C Merrick ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Translation Initiation ◽  
Direct Evidence ◽  
Rna Helicase ◽  
Initiation Factor ◽  
Helicase Activity ◽  
Ribosome Binding ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Hydrolysis Of

The mechanism of ribosome binding to eucaryotic mRNAs is not well understood, but it requires the participation of eucaryotic initiation factors eIF-4A, eIF-4B, and eIF-4F and the hydrolysis of ATP. Evidence has accumulated in support of a model in which these initiation factors function to unwind the 5'-proximal secondary structure in mRNA to facilitate ribosome binding. To obtain direct evidence for initiation factor-mediated RNA unwinding, we developed a simple assay to determine RNA helicase activity, and we show that eIF-4A or eIF-4F, in combination with eIF-4B, exhibits helicase activity. A striking and unprecedented feature of this activity is that it functions in a bidirectional manner. Thus, unwinding can occur either in the 5'-to-3' or 3'-to-5' direction. Unwinding in the 5'-to-3' direction by eIF-4F (the cap-binding protein complex), in conjunction with eIF-4B, was stimulated by the presence of the RNA 5' cap structure, whereas unwinding in the 3'-to-5' direction was completely cap independent. These results are discussed with respect to cap-dependent versus cap-independent mechanisms of ribosome binding to eucaryotic mRNAs.

Plant translation initiation factors: it is not easy to be green

2004 ◽  
Vol 32 (4) ◽  
pp. 589-591 ◽  
Author(s):  
K.S. Browning
Keyword(s):  
Translation Initiation ◽  
Binding Proteins ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Translational Machinery ◽  
Initiation Factors ◽  
Translation Initiation Factors

Plants have significant differences in some of the ‘parts’ of the translational machinery. There are two forms of eukaryotic initiation factor (eIF) 4F, eIF3 has two novel subunits, eIF4B is poorly conserved, and eIF2 kinases and eIF4E binding proteins (4E-BP) are yet to be discovered. These differences suggest that plants may regulate their translation in unique ways.

scholarly journals Translation initiation mediated by RNA looping

2015 ◽  
Vol 112 (4) ◽  
pp. 1041-1046 ◽  
Author(s):  
Ki Young Paek ◽  
Ka Young Hong ◽  
Incheol Ryu ◽  
Sung Mi Park ◽  
Sun Ju Keum ◽  
...  
Keyword(s):  
Reporter Gene ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Encephalomyocarditis Virus ◽  
Initiation Codon ◽  
Translation Efficiency ◽  
Upstream Gene ◽  
Translational Initiation ◽  
Initiation Factors ◽  
Translation Initiation Factors

Eukaryotic translation initiation commences at the initiation codon near the 5′ end of mRNA by a 40S ribosomal subunit, and the recruitment of a 40S ribosome to an mRNA is facilitated by translation initiation factors interacting with the m7G cap and/or poly(A) tail. The 40S ribosome recruited to an mRNA is then transferred to the AUG initiation codon with the help of translation initiation factors. To understand the mechanism by which the ribosome finds an initiation codon, we investigated the role of eIF4G in finding the translational initiation codon. An artificial polypeptide eIF4G fused with MS2 was localized downstream of the reporter gene through MS2-binding sites inserted in the 3′ UTR of the mRNA. Translation of the reporter was greatly enhanced by the eIF4G-MS2 fusion protein regardless of the presence of a cap structure. Moreover, eIF4G-MS2 tethered at the 3′ UTR enhanced translation of the second cistron of a dicistronic mRNA. The encephalomyocarditis virus internal ribosome entry site, a natural translational-enhancing element facilitating translation through an interaction with eIF4G, positioned downstream of a reporter gene, also enhanced translation of the upstream gene in a cap-independent manner. Finally, we mathematically modeled the effect of distance between the cap structure and initiation codon on the translation efficiency of mRNAs. The most plausible explanation for translational enhancement by the translational-enhancing sites is recognition of the initiation codon by the ribosome bound to the ribosome-recruiting sites through “RNA looping.” The RNA looping hypothesis provides a logical explanation for augmentation of translation by enhancing elements located upstream and/or downstream of a protein-coding region.

scholarly journals The regulation of protein translation and its implications for cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ping Song ◽  
Fan Yang ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Mrna Translation ◽  
Protein Translation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Precision Therapy ◽  
Novel Approaches

AbstractIn addition to the deregulation of gene transcriptions and post-translational protein modifications, the aberrant translation from mRNAs to proteins plays an important role in the pathogenesis of various cancers. Targeting mRNA translation are expected to become potential approaches for anticancer treatments. Protein translation is affected by many factors including translation initiation factors and RNA-binding proteins. Recently, modifications of mRNAs mainly N6-methyladenine (m6A) modification and noncoding RNAs, such as microRNAs and long noncoding RNAs are involved. In this review, we generally summarized the recent advances on the regulation of protein translation by the interplay between mRNA modifications and ncRNAs. By doing so, we hope this review could offer some hints for the development of novel approaches in precision therapy of human cancers.

Manipulation of the host translation initiation complex eIF4F by DNA viruses

2010 ◽  
Vol 38 (6) ◽  
pp. 1511-1516 ◽  
Author(s):  
Derek Walsh
Keyword(s):  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Viral Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Initiation Factor ◽  
Viral Protein Synthesis ◽  
Dna Viruses ◽  
Translational Machinery

In the absence of their own translational machinery, all viruses must gain access to host cell ribosomes to synthesize viral proteins and replicate. Ribosome recruitment and scanning of capped host mRNAs is facilitated by the multisubunit eIF (eukaryotic initiation factor) 4F, which consists of a cap-binding protein, eIF4E and an RNA helicase, eIF4A, assembled on a large scaffolding protein, eIF4G. Although inactivated by many viruses to inhibit host translation, a growing number of DNA viruses are being found to employ diverse strategies to stimulate eIF4F activity in infected cells and maximize viral protein synthesis. These strategies include stimulation of cellular mTOR (mammalian target of rapamycin) signalling to inactivate 4E-BPs (eIF4E-binding proteins), a family of translational repressors that limit eIF4E availability and eIF4F complex formation, together with modulating the activity of the eIF4E kinase Mnk (mitogen-activated protein kinase signal-integrating kinase) in a variety of manners to regulate both host and viral mRNA translation. In some cases, specific viral proteins that mediate these signalling events have been identified, whereas others have been shown to interact with host translation initiation factors or complexes and modify their activity and/or subcellular localization. The present review outlines current understanding of the role of eIF4F in the life cycle of various DNA viruses and discusses its potential as a therapeutic target to suppress viral infection.

scholarly journals Resistance to Plum pox virus Strain C in Arabidopsis thaliana and Chenopodium foetidum Involves Genome-Linked Viral Protein and Other Viral Determinants and Might Depend on Compatibility With Host Translation Initiation Factors

2014 ◽  
Vol 27 (11) ◽  
pp. 1291-1301 ◽  
Author(s):  
María Calvo ◽  
Sandra Martínez-Turiño ◽  
Juan Antonio García
Keyword(s):  
Arabidopsis Thaliana ◽  
Translation Initiation ◽  
Viral Protein ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Plum Pox Virus ◽  
Initiation Factors ◽  
Translation Initiation Factors

Research performed on model herbaceous hosts has been useful to unravel the molecular mechanisms that control viral infections. The most common Plum pox virus (PPV) strains are able to infect Nicotiana species as well as Chenopodium and Arabidopsis species. However, isolates belonging to strain C (PPV-C) that have been adapted to Nicotiana spp. are not infectious either in Chenopodium foetidum or in Arabidopsis thaliana. In order to determine the mechanism underlying this interesting host-specific behavior, we have constructed chimerical clones derived from Nicotiana-adapted PPV isolates from the D and C strains, which differ in their capacity to infect A. thaliana and C. foetidum. With this approach, we have identified the nuclear inclusion a protein (VPg+Pro) as the major pathogenicity determinant that conditions resistance in the presence of additional secondary determinants, different for each host. Genome-linked viral protein (VPg) mutations similar to those involved in the breakdown of eIF4E-mediated resistance to other potyviruses allow some PPV chimeras to infect A. thaliana. These results point to defective interactions between a translation initiation factor and the viral VPg as the most probable cause of host-specific incompatibility, in which other viral factors also participate, and suggest that complex interactions between multiple viral proteins and translation initiation factors not only define resistance to potyviruses in particular varieties of susceptible hosts but also contribute to establish nonhost resistance.

scholarly journals Targeted inhibition of mRNA translation initiation factors as a novel therapeutic strategy for mature B-cell neoplasms

2020 ◽  
Vol 1 (1) ◽  
pp. 3-25
Author(s):  
Joe Taylor ◽  
Alison M Yeomans ◽  
Graham Packham
Keyword(s):  
B Cell ◽  
Translation Initiation ◽  
Mrna Translation ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Lymphocytic Leukemia ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Promising Area ◽  
Targeted Inhibition

Cancer development is frequently associated with dysregulation of mRNA translation to enhance both increased global protein synthesis and translation of specific mRNAs encoding oncoproteins. Thus, targeted inhibition of mRNA translation is viewed as a promising new approach for cancer therapy. In this article we review current progress in investigating dysregulation of mRNA translation initiation in mature B-cell neoplasms, focusing on chronic lymphocytic leukemia, follicular lymphoma and diffuse large B-cell lymphoma. We discuss mechanisms and regulation of mRNA translation, potential pathways by which genetic alterations and the tumor microenvironment alters mRNA translation in malignant B cells, preclinical evaluation of drugs targeted against specific eukaryotic initiation factors and current progress towards clinical development. Overall, inhibition of mRNA translation initiation factors is an exciting and promising area for development of novel targeted anti-tumor drugs.

scholarly journals Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F.

1990 ◽  
Vol 10 (3) ◽  
pp. 1134-1144 ◽  
Author(s):  
F Rozen ◽  
I Edery ◽  
K Meerovitch ◽  
T E Dever ◽  
W C Merrick ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Translation Initiation ◽  
Direct Evidence ◽  
Rna Helicase ◽  
Initiation Factor ◽  
Helicase Activity ◽  
Ribosome Binding ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Hydrolysis Of

The mechanism of ribosome binding to eucaryotic mRNAs is not well understood, but it requires the participation of eucaryotic initiation factors eIF-4A, eIF-4B, and eIF-4F and the hydrolysis of ATP. Evidence has accumulated in support of a model in which these initiation factors function to unwind the 5'-proximal secondary structure in mRNA to facilitate ribosome binding. To obtain direct evidence for initiation factor-mediated RNA unwinding, we developed a simple assay to determine RNA helicase activity, and we show that eIF-4A or eIF-4F, in combination with eIF-4B, exhibits helicase activity. A striking and unprecedented feature of this activity is that it functions in a bidirectional manner. Thus, unwinding can occur either in the 5'-to-3' or 3'-to-5' direction. Unwinding in the 5'-to-3' direction by eIF-4F (the cap-binding protein complex), in conjunction with eIF-4B, was stimulated by the presence of the RNA 5' cap structure, whereas unwinding in the 3'-to-5' direction was completely cap independent. These results are discussed with respect to cap-dependent versus cap-independent mechanisms of ribosome binding to eucaryotic mRNAs.

scholarly journals The Eukaryotic Translation Initiation Factor 4F Complex Restricts Rotavirus Infection via Regulating the Expression of IRF1 and IRF7

2019 ◽  
Vol 20 (7) ◽  
pp. 1580 ◽  
Author(s):  
Sunrui Chen ◽  
Cui Feng ◽  
Yan Fang ◽  
Xinying Zhou ◽  
Lei Xu ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Negative Regulator ◽  
Initiation Factor ◽  
Loss Of Function ◽  
Rotavirus Infection ◽  
Eukaryotic Translation ◽  
Initiation Factors ◽  
Eif4f Complex ◽  
Translation Initiation Factors

The eIF4F complex is a translation initiation factor that closely regulates translation in response to a multitude of environmental conditions including viral infection. How translation initiation factors regulate rotavirus infection remains poorly understood. In this study, the knockdown of the components of the eIF4F complex using shRNA and CRISPR/Cas9 were performed, respectively. We have demonstrated that loss-of-function of the three components of eIF4F, including eIF4A, eIF4E and eIF4G, remarkably promotes the levels of rotavirus genomic RNA and viral protein VP4. Consistently, knockdown of the negative regulator of eIF4F and programmed cell death protein 4 (PDCD4) inhibits the expression of viral mRNA and the VP4 protein. Mechanically, we confirmed that the silence of the eIF4F complex suppressed the protein level of IRF1 and IRF7 that exert potent antiviral effects against rotavirus infection. Thus, these results demonstrate that the eIF4F complex is an essential host factor restricting rotavirus replication, revealing new targets for the development of new antiviral strategies against rotavirus infection.

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