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EIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166744 | GEO | 2022/07/07

REPOSITORIES: GEO

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eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation [MARS-seq]

Project description:The Ribo-seq and TI-seq analysis following i14G1s (eI1-eIF4G1 inhibitors) treatments uncover opposing roles of eIF1-eIF4G1 and eIF4E-eIF4G1 in scanning-dependent and independent translation. Furthermore, i14G1s inhibition of eIF4G1-eIF1 resulted in translation activation of ER/UPR stress-response genes via enhanced ribosome loading, elevated 5’UTR translation at near cognate AUGs, and unexpected concomitant upregulation of coding-region translation.

2022-07-07 | GSE166743 | GEO

eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation [Ribo-Seq and Ti-Seq]

2022-07-07 | GSE166742 | GEO

eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation

Project description:eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation

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eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation [MARS-seq]

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eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation [Ribo-Seq and Ti-Seq]

Project description:eIF1-eIF4G1 inhibitors uncover alternative translation activation of stress-response genes via enhanced ribosome loading and 5’UTR translation [Ribo-Seq and Ti-Seq]

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Inhibitors of eIF4G1-eIF1 uncover its regulatory role of ER/UPR stress-response genes independent of eIF2α-phosphorylation.

Project description:During translation initiation, eIF4G1 dynamically interacts with eIF4E and eIF1. While the role of eIF4E-eIF4G1 is well established, the regulatory functions of eIF4G1-eIF1 are poorly understood. Here, we report the identification of the eIF4G1-eIF1 inhibitors i14G1-10 and i14G1-12. i14G1s directly bind eIF4G1 and inhibit translation in vitro and in the cell, and their effects on translation are dependent on eIF4G1 levels. Translatome analyses revealed that i14G1s mimic eIF1 and eIF4G1 perturbations on the stringency of start codon selection and the opposing roles of eIF1-eIF4G1 in scanning-dependent and scanning-independent short 5' untranslated region (UTR) translation. Remarkably, i14G1s activate ER/unfolded protein response (UPR) stress-response genes via enhanced ribosome loading, elevated 5'UTR translation at near-cognate AUGs, and unexpected concomitant up-regulation of coding-region translation. These effects are, at least in part, independent of eIF2α-phosphorylation. Interestingly, eIF4G1-eIF1 interaction itself is negatively regulated by ER stress and mTOR inhibition. Thus, i14G1s uncover an unknown mechanism of ER/UPR translational stress response and are valuable research tools and potential drugs against diseases exhibiting dysregulated translation.

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Dynamic Interaction of Eukaryotic Initiation Factor 4G1 (eIF4G1) with eIF4E and eIF1 Underlies Scanning-Dependent and -Independent Translation.

Project description:Translation initiation of most mRNAs involves m7G-cap binding, ribosomal scanning, and AUG selection. Initiation from an m7G-cap-proximal AUG can be bypassed resulting in leaky scanning, except for mRNAs bearing the translation initiator of short 5' untranslated region (TISU) element. m7G-cap binding is mediated by the eukaryotic initiation factor 4E (eIF4E)-eIF4G1 complex. eIF4G1 also associates with eIF1, and both promote scanning and AUG selection. Understanding of the dynamics and significance of these interactions is lacking. We report that eIF4G1 exists in two complexes, either with eIF4E or with eIF1. Using an eIF1 mutant impaired in eIF4G1 binding, we demonstrate that eIF1-eIF4G1 interaction is important for leaky scanning and for avoiding m7G-cap-proximal initiation. Intriguingly, eIF4E-eIF4G1 antagonizes the scanning promoted by eIF1-eIF4G1 and is required for TISU. In mapping the eIF1-binding site on eIF4G1, we unexpectedly found that eIF4E also binds it indirectly. These findings uncover the RNA features underlying regulation by eIF4E-eIF4G1 and eIF1-eIF4G1 and suggest that 43S ribosome transition from the m7G-cap to scanning involves relocation of eIF4G1 from eIF4E to eIF1.

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Study of the translation initiation by Selective TCP-seq in the context of eIF1-eIF4G1 inhibitor

Project description:Start codon recognition by the 48S complex is a critical step in translation. However, understanding the in vivo initiation and its regulation at a global scale is limited. To better understand the mechanism in vivo, we have screened for small molecules that specifically inhibit the function of eIF1-eIF4G1 interaction. We performed Selective-48S footprinting against eIF1 (HA-tagged), eIF2a (HA-tagged), eIF4G1 and eIF3c to answer questions regarding the function of that interaction in the context of the scanning and initiating 48S ribosome.

2024-03-27 | GSE253652 | GEO

Translation inhibitors cause abnormalities in ribosome profiling experiments.

Project description:Ribosome profiling and high-throughput sequencing provide unprecedented opportunities for the analysis of mRNA translation. Using this novel method, several studies have demonstrated the widespread role of short upstream reading frames in translational control as well as slower elongation at the beginning of open reading frames in response to stress. Based on the initial studies, the importance of adding or omitting translation inhibitors, such as cycloheximide, was noted as it markedly affected ribosome coverage profiles. For that reason, many recent studies omitted translation inhibitors in the culture medium. Here, we investigate the influence of ranging cycloheximide concentrations on ribosome profiles in Saccharomyces cerevisiae and demonstrate that increasing the drug concentration can overcome some of the artifacts. We subjected cells to various manipulations and show that neither oxidative stress nor heat shock nor amino acid starvation affect translation elongation. Instead, the observations in the initial studies are the result of cycloheximide-inflicted artifacts. Likewise, we find little support for short upstream reading frames to be involved in widespread protein synthesis regulation under stress conditions. Our study highlights the need for better standardization of ribosome profiling methods.

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Translation initiator EIF4G1 mutations in familial Parkinson disease.

Project description:Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

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