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 Potyvirus Genome-linked Protein, VPg, Directly Affects Wheat Germ in Vitro Translation

2007 ◽  
Vol 283 (3) ◽  
pp. 1340-1349 ◽  
Author(s):  
Mateen A. Khan ◽  
Hiroshi Miyoshi ◽  
Daniel R. Gallie ◽  
Dixie J. Goss
Keyword(s):  
Translation Initiation ◽  
Wheat Germ ◽  
Mrna Translation ◽  
Kinetic Studies ◽  
Dissociation Rate ◽  
In Vitro Translation ◽  
Translation Efficiency ◽  
Viral Mrna ◽  
Initiation Factors

Potyvirus genome linked protein, VPg, interacts with translation initiation factors eIF4E and eIFiso4E, but its role in protein synthesis has not been elucidated. We show that addition of VPg to wheat germ extract leads to enhancement of uncapped viral mRNA translation and inhibition of capped viral mRNA translation. This provides a significant competitive advantage to the uncapped viral mRNA. To understand the molecular basis of these effects, we have characterized the interaction of VPg with eIF4F, eIFiso4F, and a structured RNA derived from tobacco etch virus (TEV RNA). When VPg formed a complex with eIF4F, the affinity for TEV RNA increased more than 4-fold compared with eIF4F alone (19.4 and 79.0 nm, respectively). The binding affinity of eIF4F to TEV RNA correlates with translation efficiency. VPg enhanced eIFiso4F binding to TEV RNA 1.6-fold (178 nm compared with 108 nm). Kinetic studies of eIF4F and eIFiso4F with VPg show ∼2.6-fold faster association for eIFiso4F·VPg as compared with eIF4F·VPg. The dissociation rate was ∼2.9-fold slower for eIFiso4F than eIF4F with VPg. These data demonstrate that eIFiso4F can kinetically compete with eIF4F for VPg binding. The quantitative data presented here suggest a model where eIF4F·VPg interaction enhances cap-independent translation by increasing the affinity of eIF4F for TEV RNA. This is the first evidence of direct participation of VPg in translation initiation.

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.

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.

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 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 Closely Related Poleroviruses Depend on Distinct Translation Initiation Factors to Infect Arabidopsis thaliana

2013 ◽  
Vol 26 (2) ◽  
pp. 257-265 ◽  
Author(s):  
C. Reinbold ◽  
S. Lacombe ◽  
V. Ziegler-Graff ◽  
D. Scheidecker ◽  
L. Wiss ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Translation Initiation ◽  
Direct Interaction ◽  
Mrna Translation ◽  
Beet Western Yellows Virus ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Turnip Yellows Virus ◽  
Mutant Lines ◽  
Virus Interactions

In addition to being essential for translation of eukaryotic mRNA, translation initiation factors are also key components of plant–virus interactions. In order to address the involvement of these factors in the infectious cycle of poleroviruses (aphid-transmitted, phloem-limited viruses), the accumulation of three poleroviruses was followed in Arabidopsis thaliana mutant lines impaired in the synthesis of translation initiation factors in the eIF4E and eIF4G families. We found that efficient accumulation of Turnip yellows virus (TuYV) in A. thaliana relies on the presence of eIF (iso)4G1, whereas Beet mild yellowing virus (BMYV) and Beet western yellows virus-USA (BWYV-USA) rely, instead, on eIF4E1. A role for these factors in the infectious processes of TuYV and BMYV was confirmed by direct interaction in yeast between these specific factors and the 5′ viral genome-linked protein of the related virus. Although the underlying molecular mechanism is still unknown, this study reveals a totally unforeseen situation in which closely related viruses belonging to the same genus use different translation initiation factors for efficient infection of A. thaliana.

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